Wei Cheng

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R(2) increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase.

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment.

Micromixing is a crucial process within microfluidic systems such as micro total analysis systems (μTAS). A state-of-art review on microstructured mixing devices and their mixing phenomena is given. The review first presents an overview of the characteristics of fluidic behavior at the microscale and their implications in microfluidic mixing processes. According to the two basic principles exploited to induce mixing at the microscale, micromixers are generally classified as being passive or active. Passive mixers solely rely on pumping energy, whereas active mixers rely on an external energy source to achieve mixing. Typical types of passive micromixers are discussed, including T- or Y-shaped, parallel lamination, sequential, focusing enhanced mixers, and droplet micromixers. Examples of active mixers using external forces such as pressure field, electrokinetic, dielectrophoretic, electrowetting, magneto-hydrodynamic, and ultrasound to assist mixing are presented. Finally, the advantages and disadvantages of mixing in a microfluidic environment are discussed.

There is an urgent demand from the areas of the environment and human heath to detect and to characterize nanoparticles (NPs) from the perspective of their physical properties and for fundamental understanding of the electrochemical interface at the nanoscale and associated reactions and kinetics. Recently, “nano-impact”-based electrochemical methods showed great promise for efficient detection and quantification of individual NPs properties, such as size, concentration, and aggregation/agglomeration state in liquid phase, and the study of the kinetics of individual NPs or chemical reactions at the nanoscale involving NPs as a mediator. This review covers recent developments in this important, emerging field, and summarizes the latest developments (from the year of 2012 to date) by addressing the following aspects of “nano-impacts”: direct detection of NPs via electrochemical reduction and oxidation; detection of surface-modified NPs; and, reactions through mediated NPs.

TiO2 (P25)–graphene (P25–GR) hybrids were prepared via solvothermal reaction of graphene oxide and P25 using ethanol as solvent. The as-prepared P25–GR nanocomposites were characterized by X-ray diffraction, Raman spectroscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, photoluminescence emission spectroscopy and ultraviolet-visible (UV–vis) diffuse reflectance spectroscopy. The results indicated that P25–GR nanocomposites possessed enhanced light absorption ability and charge separation efficiency. As photocatalysts, P25–GR hybrids were much better than the bare P25, when they were used in the hydrogen evolution from aqueous methanol solution under Xe-lamp illumination. A significant enhancement in the rate of hydrogen production was achieved through using P25–GR as photocatalysts, comparing to bare P25. The optimum mass ratio of GR to P25 in the hybrids was 0.5 wt%. The higher mass ratio of GR in P25–GR would decrease the photocatalytic activity of P25.

Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

<h3>Background and Objectives</h3> To investigate the independent associations of social isolation and loneliness with incident dementia and to explore the potential neurobiological mechanisms. <h3>Methods</h3> We utilized the UK Biobank cohort to establish Cox proportional hazard models with social isolation and loneliness as separate exposures. Demographic (sex, age, and ethnicity), socioeconomic (education level, household income, and Townsend deprivation index), biological (body mass index, <i>APOE</i> genotype, diabetes, cancer, cardiovascular disease, and other), cognitive (speed of processing and visual memory), behavioral (current smoker, alcohol intake, and physical activity), and psychological (social isolation or loneliness, depressive symptoms, and neuroticism) factors measured at baseline were adjusted. Then, voxel-wise brainwide association analyses were used to identify gray matter volumes (GMVs) associated with social isolation and with loneliness. Partial least squares regression was performed to test the spatial correlation of GMV differences and gene expression using the Allen Human Brain Atlas. <h3>Results</h3> We included 462,619 participants (mean age at baseline 57.0 years [SD 8.1]). With a mean follow-up of 11.7 years (SD 1.7), 4,998 developed all-cause dementia. Social isolation was associated with a 1.26-fold increased risk of dementia (95% CI, 1.15–1.37) independently of various risk factors including loneliness and depression (i.e., full adjustment). However, the fully adjusted hazard ratio for dementia related to loneliness was 1.04 (95% CI, 0.94–1.16) and 75% of this relationship was attributable to depressive symptoms. Structural MRI data were obtained from 32,263 participants (mean age 63.5 years [SD 7.5]). Socially isolated individuals had lower GMVs in temporal, frontal, and other (e.g., hippocampal) regions. Mediation analysis showed that the identified GMVs partly mediated the association between social isolation at baseline and cognitive function at follow-up. Social isolation–related lower GMVs were related to underexpression of genes that are downregulated in Alzheimer disease and to genes that are involved in mitochondrial dysfunction and oxidative phosphorylation. <h3>Discussion</h3> Social isolation is a risk factor for dementia that is independent of loneliness and many other covariates. Social isolation–related brain structural differences coupled with different molecular functions also support the associations of social isolation with cognition and dementia. Social isolation may thus be an early indicator of an increased risk of dementia.

About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts.To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples.Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]).GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition.The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04).In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

Encapsulating liposomes are widely used for controlled drug delivery. We report the use of nano-impact experiments for the electrochemical attomolar quantification of the liposome load, uniquely at the single liposome level, using vitamin C encapsulated liposomes as a model. The size of the liposomes and their picomolar concentration are also determined in biological buffer in real time.

Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on ∼400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases.1Mehta D. Tropf F.C. Gratten J. Bakshi A. Zhu Z. Bacanu S.-A. Hemani G. Magnusson P.K.E. Barban N. Esko T. et al.Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUKEvidence for genetic overlap between schizophrenia and age at first birth in women.JAMA Psychiatry. 2016; 73: 497-505Crossref PubMed Scopus (30) Google Scholar, 2Lee S.H. Byrne E.M. Hultman C.M. Kähler A. Vinkhuyzen A.A.E. Ripke S. Andreassen O.A. Frisell T. Gusev A. Hu X. et al.Schizophrenia Working Group of the Psychiatric Genomics Consortium and Rheumatoid Arthritis Consortium InternationalSchizophrenia Working Group of the Psychiatric Genomics Consortium AuthorsSchizophrenia Working Group of the Psychiatric Genomics Consortium CollaboratorsRheumatoid Arthritis Consortium International AuthorsRheumatoid Arthritis Consortium International CollaboratorsNew data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis.Int. J. Epidemiol. 2015; 44: 1706-1721Crossref PubMed Scopus (49) Google Scholar, 3Lee S.H. DeCandia T.R. Ripke S. Yang J. Sullivan P.F. Goddard M.E. Keller M.C. Visscher P.M. Wray N.R. Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC-SCZ)International Schizophrenia Consortium (ISC)Molecular Genetics of Schizophrenia Collaboration (MGS)Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs.Nat. Genet. 2012; 44: 247-250Crossref PubMed Scopus (439) Google Scholar The genetic correlation is the additive genetic covariance between two traits scaled by the square root of the product of the genetic variance for each trait (i.e., the geometric mean of the trait variances). The sign of the correlation shows the direction of sharing, and the parameter definition is based on genetic variants across the allelic spectrum. Methods to estimate genetic correlation based on genetic covariance structure are well established for both quantitative and disease traits, e.g., (restricted) maximum likelihood for linear mixed models (LMM).4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 5Harville D.A. Maximum likelihood approaches to variance component estimation and to related problems.J. Am. Stat. Assoc. 1977; 72: 320-338Crossref Scopus (1543) Google Scholar, 6Patterson H.D. Thompson R. Recovery of inter-block information when block sizes are unequal.Biometrika. 1971; 58: 545-554Crossref Scopus (2718) Google Scholar Genetic covariance structure can be derived from phenotypic records using pedigree information in twin or family-based designs.7Neale M. Cardon L. Methodology for Genetic Studies of Twins and Families. Springer Science & Business Media, 2013Google Scholar Recently, genome-wide single-nucleotide polymorphism (SNP) data have been used to construct a genomic relationship matrix for the genetic covariance structure in LMM that captures the contribution of causal variants that are in linkage disequilibrium (LD) with the genotyped SNPs.4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 8VanRaden P.M. Efficient methods to compute genomic predictions.J. Dairy Sci. 2008; 91: 4414-4423Abstract Full Text Full Text PDF PubMed Scopus (3096) Google Scholar, 9Yang J. Lee S.H. Goddard M.E. Visscher P.M. GCTA: a tool for genome-wide complex trait analysis.Am. J. Hum. Genet. 2011; 88: 76-82Abstract Full Text Full Text PDF PubMed Scopus (3814) Google Scholar Such estimates assume that the genetic correlation estimated from common SNPs is representative of the parameter that depends on all genetic variants; this seems like a reasonable assumption. In contrast to the genomic restricted maximum likelihood (GREML) approach, a linkage disequilibrium score regression (LDSC)10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar method does not require individual-level genotype data but instead uses GWAS summary statistics, regressing association test statistics of SNPs on their LD scores. The LD score of a SNP is the sum of LD r2 measured with all other SNPs and can be calculated in a reference sample of the same ethnicity when individual genotype data are not available for the GWAS sample, under the assumption that the GWAS sample has been drawn from the same ethnic population as the reference sample used to calculate the LD scores. The method exploits the relationship between association test statistic and LD score expected under polygenicity. Because of this simplicity, and the massively reduced computing burden in terms of memory and time, it is feasible for LDSC to be applied to a large number of multiple traits, e.g., Bulik-Sullivan et al.,11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar Zheng et al.,12Zheng J. Erzurumluoglu A.M. Elsworth B.L. Kemp J.P. Howe L. Haycock P.C. Hemani G. Tansey K. Laurin C. Pourcain B.S. et al.Early Genetics and Lifecourse Epidemiology (EAGLE) Eczema ConsortiumLD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis.Bioinformatics. 2017; 33: 272-279Crossref PubMed Scopus (484) Google Scholar Finucane et al.13Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. et al.ReproGen ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumRACI ConsortiumPartitioning heritability by functional annotation using genome-wide association summary statistics.Nat. Genet. 2015; 47: 1228-1235Crossref PubMed Scopus (980) Google Scholar Given the attractiveness of LDSC for a massive analysis of many sets of GWAS summary statistics, it has been widely used in the community. However, genetic correlations estimated by LDSC are often reported without caution although the approach is known to be less accurate, compared to GREML.11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar In fact, the accuracies of LDSC estimates have not been thoroughly studied. In this report, we compare both the bias (difference between the simulated true value and estimated value) and accuracy (magnitude of the standard error of an estimate [SE]) between GREML and LDSC for estimation of genetic correlation. We find that both methods show little evidence of bias. However, LDSC is less accurate as reported in Bulik Sullivan et al.,11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar with SE at least more than 1.5-fold higher than that of GREML regardless of the number of samples in data used to estimate the genetic correlation. When decreasing the number of SNPs, the accuracy of LDSC decreases further. When increasing the degree of genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the SE of LDSC estimates are up to 3-fold larger than those of the GREML estimates. We also show that GREML is more accurate in genomic partitioning analyses over LDSC or stratified LDSC (sLDSC). In genomic partitioning analyses, the genetic parameters are estimated for genomic subsets defined by user-specified annotations. In analyses of real data, we show that GREML is more accurate and powerful, e.g., GREML estimates based on ∼150,000 individuals give a higher accuracy than LDSC estimates based on 400,000 individuals in estimating genetic correlation between schizophrenia (SCZ) and body mass index (BMI) (−0.136 [SE = 0.017] and p value = 4.54E−15 for GREML versus −0.087 [SE = 0.019] and p value = 4.91E−06 for LDSC). In these analyses, the GREML estimate is based on UK sample only whereas the LDSC estimate is based on combined meta-datasets among which there is uncertainty about homogeneity. Furthermore, a GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which is less obvious by LDSC when using both whole-genome and partitioned estimates of genetic correlation. In the main methods, we used GREML14Lee S.H. van der Werf J.H. MTG2: an efficient algorithm for multivariate linear mixed model analysis based on genomic information.Bioinformatics. 2016; 32: 1420-1422Crossref PubMed Scopus (90) Google Scholar, 15Maier R. Moser G. Chen G.-B. Ripke S. Coryell W. Potash J.B. Scheftner W.A. Shi J. Weissman M.M. Hultman C.M. et al.Cross-Disorder Working Group of the Psychiatric Genomics ConsortiumJoint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder.Am. J. Hum. Genet. 2015; 96: 283-294Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar and LDSC10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar to compare their estimates of genetic correlation using simulated as well as real data. Simulations were based on UK Biobank imputed genotype data (UKBB16Collins R. What makes UK Biobank special?.Lancet. 2012; 379: 1173-1174Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar) after stringent quality control (QC) (see Supplemental Methods). We calculated a ratio of empirical SE and its 95% confidence interval (CI) to assess the accuracy of the methods for each set of simulated data. The 95% CIs of SE were estimated based on the delta method.17Lynch M. Walsh B. Genetics and Analysis of Quantitative Traits. Sinauer Sunderland, MA1998Google Scholar When estimating genetic correlation using simulated phenotypes based on UKBB genotype data, we found that the estimates were unbiased for both GREML and LDSC (Figure S1), but the SE of GREML was at least 1.5 times smaller than that of LDSC (Figure 1). The ratio of the empirical SE from LDSC to GREML was increased up to 3.5-fold when using a smaller number of SNPs (Figure 1). All values of the ratio were significantly different from 1. It is notable that the SE of GREML estimates showed almost no difference across different numbers of SNPs whereas that of LDSC estimates gradually increased with a smaller number of SNPs (Figure S2). The ratio was invariant to sample size (Figure S3). As expected, when using the intercept constrained to zero, LDSC estimates were substantially biased when there were overlapping samples (Figure S4). We also explored alternative genetic architectures (Figure S5), which consistently showed that GREML gives a smaller SE than LDSC in any scenario. To explore the stability of the accuracy for both methods, we used two additional genotype datasets without imputation, Wellcome Trust Case Control Consortium 2 (WTCCC218Sawcer S. Hellenthal G. Pirinen M. Spencer C.C. Patsopoulos N.A. Moutsianas L. Dilthey A. Su Z. Freeman C. Hunt S.E. et al.International Multiple Sclerosis Genetics ConsortiumWellcome Trust Case Control Consortium 2Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.Nature. 2011; 476: 214-219Crossref PubMed Scopus (2024) Google Scholar, 19Mells G.F. Floyd J.A.B. Morley K.I. Cordell H.J. Franklin C.S. Shin S.-Y. Heneghan M.A. Neuberger J.M. Donaldson P.T. Day D.B. et al.UK PBC ConsortiumWellcome Trust Case Control Consortium 3Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat. Genet. 2011; 43: 329-332Crossref PubMed Scopus (379) Google Scholar, 20Bellenguez C. Bevan S. Gschwendtner A. Spencer C.C. Burgess A.I. Pirinen M. Jackson C.A. Traylor M. Strange A. Su Z. et al.International Stroke Genetics Consortium (ISGC)Wellcome Trust Case Control Consortium 2 (WTCCC2)Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke.Nat. Genet. 2012; 44: 328-333Crossref PubMed Scopus (332) Google Scholar, 21Tsoi L.C. Spain S.L. Knight J. Ellinghaus E. Stuart P.E. Capon F. Ding J. Li Y. Tejasvi T. Gudjonsson J.E. et al.Collaborative Association Study of Psoriasis (CASP)Genetic Analysis of Psoriasis ConsortiumPsoriasis Association Genetics ExtensionWellcome Trust Case Control Consortium 2Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.Nat. Genet. 2012; 44: 1341-1348Crossref PubMed Scopus (702) Google Scholar) and genetic epidemiology research on adult health and aging cohort (GERA22Banda Y. Kvale M.N. Hoffmann T.J. Hesselson S.E. Ranatunga D. Tang H. Sabatti C. Croen L.A. Dispensa B.P. Henderson M. et al.Characterizing race/ethnicity and genetic ancestry for 100,000 subjects in the genetic epidemiology research on adult health and aging (GERA) cohort.Genetics. 2015; 200: 1285-1295Crossref PubMed Scopus (191) Google Scholar, 23Lee S.H. Weerasinghe W.M.S.P. Wray N.R. Goddard M.E. van der Werf J.H.J. Using information of relatives in genomic prediction to apply effective stratified medicine.Sci. Rep. 2017; 7: 42091Crossref PubMed Scopus (29) Google Scholar), which are publicly available (see Supplemental Methods for detailed data descriptions). We also used UKBB raw (non-imputed) genotype data (UKBBr). We calculated the correlation between the LD scores for the HapMap3 SNPs estimated based on the 1KG CEU reference sample (see Web Resources) and those based on in-sample genotype data, i.e., UKBB, WTCCC2, GERA, and UKBBr dataset (Table 1). We found that the WTCCC2, GERA, and UKBBr (raw) genotypes were less similar to the 1KG reference genotypes, compared to the UKBB (imputed) genotypes (noting that UKBB samples had been imputed to the combined data of 1KG reference and UK10K data). Table 2 shows that the SE ratio of LDSC estimate to GREML estimate was higher for WTCCC2, GERA, and UKBBr than that for UKBB. Figure 2 shows that the accuracy of GREML was consistent across different datasets, whereas that of LDSC was decreased for WTCCC2, GERA, or UKBBr, compared to UKBB dataset. This was probably due to higher (or lower) correlation between LD scores based on the 1KG reference and the in-sample genotype datasets (Table 1) which might positively or (negatively) affect the accuracy of LDSC estimates. For WTCCC2, GERA, and UKBBr data, the SE ratio of LDSC to GREML based on different number of individuals is shown in Figures S6–S8.Table 1Correlation between LD Scores Estimated Based on the HapMap3 SNPs using the 1KG CEU Reference Sample and that from Different Target PopulationsCorrelationNr.SNPsUKBBaUKBB was imputed to the combined data of the 1KG reference and UK10K data.0.946858,991UKBBrbUKBBr was based on the raw genotype data of UK Biobank data.0.720123,615cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.WTCCC20.899421,035cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.GERA0.661238,089cThe number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores.a UKBB was imputed to the combined data of the 1KG reference and UK10K data.b UKBBr was based on the raw genotype data of UK Biobank data.c The number of SNPs reduced further from the set of the QCed SNPs because of using only SNPs matched with the HapMap3 SNPs used in calculating LD scores. Open table in a new tab Table 2The Ratio of SE of LDSC Estimate to That of GREML Estimate using Simulated Phenotypes Based on UKBB, WTCCC2, GERA, and UKBBr Genotypes in the Scenarios without Overlapping Individuals800k400k200k100kUKBB1.60 (0.15)1.70 (0.18)1.85 (0.25)2.04 (0.33)WTCCC2NA2.15 (0.31)2.35 (0.43)2.68 (0.61)GERANANA2.87 (0.56)3.31 (1.17)UKBBrNANANA3.74 (0.79) Open table in a new tab Genome partitioning analyses are an emerging tool to estimate the genetic variance and covariance explained by functional categories (e.g., DNase I hypersensitive sites [DHS] and non-DHS24Gusev A. Lee S.H. Trynka G. Finucane H. Vilhjálmsson B.J. Xu H. Zang C. Ripke S. Bulik-Sullivan B. Stahl E. et al.Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumPartitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.Am. J. Hum. Genet. 2014; 95: 535-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar). Currently, genomic partitioning analyses focus on SNP-heritability enrichment analyses, formally testing for enrichment of signal compared to the expectation that the estimates are proportional to the number of SNPs allocated to each annotation. Considering genomic partitioning in cross-disorder analyses is a natural extension to identify regions where genetic correlations between disorders are highest and lowest. Here, we assessed the performance of the methods in the context of genome partitioning analyses using simulated phenotypes based on UKBB genotype data. A better LDSC approach to estimate genetic correlation for each category might be sLDSC, stratifying by genomic annotation; however, this method is currently under development (i.e., there is software [see Web Resources], but there is no published document or paper verifying the method). Nonetheless, since the sLDSC is available to the research community, we applied both LDSC and sLDSC to estimate partitioned genetic correlations for the simulated data (Supplemental Methods). For genome partitioning analyses, we showed that LDSC estimates of genetic correlation were biased whether using LD scores estimated from the 1KG reference or in-sample data (UKBB) while GREML estimates gave unbiased estimates for each functional category (Figure 3). sLDSC estimates were unbiased only when using LD scores from the in-sample data, and their SEs are relatively larger than those of GREML or LDSC (Figure 3). This was probably due to the fact that the different distribution of causal variants and their effects between DHS and non-DHS regions were better captured by an explicit covariance structure fitted in GREML. We also applied the methods to a range of simulation scenarios and found similar results in that GREML performed better than LDSC or sLDSC (Figure S9 and Table S1), which was consistent with the previous results (Figures 1 and 2). It is notable that in a deliberately severe scenario (e.g., causal variants are simulated only within few kb of a boundary), GREML could give biased estimation of genetic correlation.13Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. et al.ReproGen ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumRACI ConsortiumPartitioning heritability by functional annotation using genome-wide association summary statistics.Nat. Genet. 2015; 47: 1228-1235Crossref PubMed Scopus (980) Google Scholar, 24Gusev A. Lee S.H. Trynka G. Finucane H. Vilhjálmsson B.J. Xu H. Zang C. Ripke S. Bulik-Sullivan B. Stahl E. et al.Schizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumSchizophrenia Working Group of the Psychiatric Genomics ConsortiumSWE-SCZ ConsortiumPartitioning heritability of regulatory and cell-type-specific variants across 11 common diseases.Am. J. Hum. Genet. 2014; 95: 535-552Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar While focusing on the accuracy of genetic correlation estimates, there is an important implication for the bias in SNP-heritability estimates for both GREML and LDSC (Figure S10). When using the WTCCC2, GERA, and UKBBr data, which were less similar to the 1KG reference genotypes, compared to the UKBB data, LDSC estimates were substantially biased whereas GREML estimates were close to the true value in estimation of SNP heritability (Figure S10). However, this result is well known and LDSC was not recommended for SNP heritability by the original authors,10Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. Schizophrenia Working Group of the Psychiatric Genomics ConsortiumLD Score regression distinguishes confounding from polygenicity in genome-wide association studies.Nat. Genet. 2015; 47: 291-295Crossref PubMed Scopus (1923) Google Scholar but rather only for relative enrichment analysis. Despite this, LDSC is widely used for SNP-heritability estimation (because it is quick and simple). Thus, for completeness we include analyses for different scenarios to quantify the properties of the methods. When reducing the number of SNPs, estimated SNP heritabilities from LDSC were consistently unbiased; however, those from GREML were proportionally underestimated (Figure S11). When using non-HapMap3 SNPs, LDSC estimates were consistently biased (Figure S12) and less accurate, compared to GREML estimates (Figures S13 and S14), which probably explains why LDSC is implemented using only HapMap3 SNPs. Although the genetic correlation is robust to such biasedness,4Lee S.H. Yang J. Goddard M.E. Visscher P.M. Wray N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542Crossref PubMed Scopus (379) Google Scholar, 11Bulik-Sullivan B. Finucane H.K. Anttila V. Gusev A. Day F.R. Loh P.R. Duncan L. Perry J.R. Patterson N. Robinson E.B. et al.ReproGen ConsortiumPsychiatric Genomics ConsortiumGenetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3An atlas of genetic correlations across human diseases and traits.Nat. Genet. 2015; 47: 1236-1241Crossref PubMed Scopus (1656) Google Scholar SNP heritability itself should be carefully interpreted for both GREML and LDSC. We also noted that LDSC and sLDSC estimates for SNP heritability were biased in the genome partitioning analysis (Figure S15) although the estimated enrichment was close to the true value when using sLDSC and in-sample LD scores (Figure S15). We used real phenotype and individual genotype data from the Psychiatric Genomics Consortium (PGC) and UKBB to estimate genetic variance and covariance between SCZ and BMI using LDSC and GREML (Table 3 and Figure S16). We also used publicly available GWAS summary statistics for LDSC to see how much the SE of estimates could be reduced by increasing the number of samples and number of SNPs. For real data analyses, we obtained theoretical SE to assess the accuracy of the methods. GREML and LDSC estimates for the SNP heritability were 0.192 (SE 0.004) and 0.280 (SE 0.016) for SCZ and 0.184 (SE 0.004) and 0.255 (SE 0.014) for BMI. The notable difference between GREML and LDSC was probably because of a relatively small number of SNPs (500K) that might result in underestimated GREML SNP heritability (see Figure S11). This is one of the caveats of using GREML with real data that usually comprise multiple cohorts genotyped on different platforms, such that, even with imputation, the overlapping set of SNPs imputed with high confidence may be limited. The estimated genetic correlation for GREML and LDSC was −0.136 (SE 0.017) and −0.173 (SE 0.031). This indicated that the GREML estimate was 3.5 and 1.8 times more precise than LDSC estimates for the SNP heritability and genetic correlation, respectively. For LDSC, we also considered using additional GWAS summary statistics from publicly available resources.25Schizophrenia Working Group of the Psychiatric Genomics ConsortiumBiological insights from 108 schizophrenia-associated genetic loci.Nature. 2014; 511: 421-427Crossref PubMed Scopus (5068) Google Scholar, 26Locke A.E. Kahali B. Berndt S.I. Justice A.E. Pers T.H. Day F.R. Powell C. Vedantam S. Buchkovich M.L. Yang J. et al.LifeLines Cohort StudyADIPOGen ConsortiumAGEN-BMI Working GroupCARDIOGRAMplusC

Stimuli-responsive polymers are an important component for preparation of stimuli-responsive drug delivery systems with less side effects and improved efficacy for cancer treatment. There are endogenous stimuli and exogenous stimuli which can be explored. Here we review the developments in both endogenous stimuli- including redox-/pH-/enzyme-responsive polymers and exogenous stimuli- including thermo-/photo- and ultrasound-responsive polymers for delivery of anti-cancer drugs.

Dual-targeted delivery of drugs and energy by nanohybrids can potentially alleviate side effects and improve the unique features required for precision medicine. To realize this aim, however, the hybrids which are often rapidly removed from circulation and the piled up tumors periphery near the blood vessels must address the difficulties in low blood half-lives and tumor penetration. In this study, a sponge-inspired carbon composites-supported red blood cell (RBC) membrane that doubles as a stealth agent and photolytic carrier that transports tumor-penetrative agents (graphene quantum dots and docetaxel (GQD-D)) and heat with irradiation was developed. The RBC-membrane enveloped nanosponge (RBC@NS) integrated to a targeted protein that accumulates in tumor spheroids via high lateral bilayer fluidity exhibits an 8-fold increase in accumulation compared to the NS. Penetrative delivery of GQDs to tumor sites is actuated by near-infrared irradiation through a one-atom-thick structure, facilitating penetration and drug delivery deep into the tumor tissue. The synergy of chemotherapy and photolytic effects was delivered by the theranostic GQDs deep into tumors, which effectively damaged and inhibited the tumor in 21 days when treated with a single irradiation. This targeted RBC@GQD-D/NS with the capabilities of enhanced tumor targeting, NIR-induced drug penetration into tumors, and thermal ablation for photolytic therapy promotes tumor suppression and exhibits potential for other biomedical applications.

A thorough analysis of clinical trial data in the Ionis integrated safety database (ISDB) was performed to determine if there is a class effect on platelet numbers and function in subjects treated with 2'-O-methoxyethyl (2'MOE)-modified antisense oligonucleotides (ASOs). The Ionis ISDB includes over 2,600 human subjects treated with 16 different 2'MOE ASOs in placebo-controlled and open-label clinical trials over a range of doses up to 624 mg/week and treatment durations as long as 4.6 years. This analysis showed that there is no class generic effect on platelet numbers and no incidence of confirmed platelet levels below 50 K/μL in subjects treated with 2'MOE ASOs. Only 7 of 2,638 (0.3%) subjects treated with a 2'MOE ASO experienced a confirmed postbaseline (BSLN) platelet count between 100 and 50 K/μL. Three of sixteen 2'MOE ASOs had >10% incidence of platelet decreases >30% from BSLN, suggesting that certain sequences may associate with clinically insignificant platelet declines. Further to these results, we found no evidence that 2'MOE ASOs alter platelet function, as measured by the lack of clinically relevant bleeding in the presence or absence of other drugs that alter platelet function and/or number and by the results from trials conducted with the factor XI (FXI) ASO.

The size of organic nanoparticles (NPs) can be electrochemically determined by Faradaic charge transfer when nanoparticles strike an electrode. Indigo NPs were used as a model (see distribution of the NP diameter). This strategy could be used for monitoring the size of a wide range of organic nanoparticles.

The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2'-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2'-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied.

Na3V2(PO4)2O2F (NVPOF) is attracting great interest due to its large capacity and high working voltage. However, poor electronic conductivity limits the electrochemical performance of NVPOF. Herein, we fabricate N/P-dual-doped carbon-coated NVPOF microspheres (labeled as NVPOF@P/N/C) via a hydrothermal process followed by heat treatment. This microsphere-structured NVPOF@P/N/C composite has a relatively high tap density of 1.22 g/cm3. TEM and XPS results reveal that the dual-doped carbon layer is tightly coated on the NVPOF surface due to the bridging effect of P and has a good protective effect on NVPOF. Density functional theory (DFT) calculations confirm that a N/P-dual-doped carbon layer is advantageous to achieve higher electronic conductivity and lower migration activation energy than those of the undoped and single N- or P-doped carbon layer. As a cathode material for a sodium-ion battery (SIB), NVPOF@P/N/C exhibits high capacity (128 mAh/g at 0.5 C and 122 mAh/g at 2 C) and ultralong cycle performance (only 0.037% capacity fading rate per cycle in 500 cycles at 2 C). We believe that the NVPOF@P/N/C composite is appealing for high-performance SIBs with large energy density.

Prussian blue analogs with unique open frame structure have aroused great concern because of their low cost, environmental friendliness and relatively easy synthesis. Especially, nickel hexacyanoferrate (NiHCF) attracts great attention due to its outstanding cycling stability. Herein, we regulate the structure of NiHCF by K-doping at Na-site and investigate the sodium storage performance by combining experiments with density functional theory calculations. Our results reveal that K-doping induces the transformation of NiHCF from cubic to monoclinic and provides more sodium storage sites. In addition, K+ ions can play a role of pillar in stabling the structure. More importantly, K-doping can improve the transport ability of sodium ions and electrons. As a result, the K-doped NiHCF electrode delivers an extremely high initial discharge capacity of 87.1 mAh g−1 at 10 mA g−1 with a very low capacity fading ratio of 0.016% per cycle at 800 mA g−1 over 1000 cycles. Such K-doped NiHCF composite shows its potential application prospects in the field of sodium-ion batteries.

Objective: Increased anxiety in response to the COVID-19 pandemic has been widely noted. The purpose of this study was to test whether the prepandemic functional connectome predicted individual anxiety induced by the pandemic. Methods: Anxiety scores from healthy undergraduate students were collected during the severe and remission periods of the pandemic (first survey, February 22–28, 2020, N=589; second survey, April 24 to May 1, 2020, N=486). Brain imaging data and baseline (daily) anxiety ratings were acquired before the pandemic. The predictive performance of the functional connectome on individual anxiety was examined using machine learning and was validated in two external undergraduate student samples (N=149 and N=474). The clinical relevance of the findings was further explored by applying the connectome-based neuromarkers of pandemic-related anxiety to distinguish between individuals with specific mental disorders and matched healthy control subjects (generalized anxiety disorder, N=43; major depression, N=536; schizophrenia, N=72). Results: Anxiety scores increased from the prepandemic baseline to the severe stage of the pandemic and remained high in the remission stage. The prepandemic functional connectome predicted pandemic-related anxiety and generalized to the external sample but showed poor performance for predicting daily anxiety. The connectome-based neuromarkers of pandemic-related anxiety further distinguished between participants with generalized anxiety and healthy control subjects but were not useful for diagnostic classification in major depression and schizophrenia. Conclusions: These findings demonstrate the feasibility of using the functional connectome to predict individual anxiety induced by major stressful events (e.g., the current global health crisis), which advances our understanding of the neurobiological basis of anxiety susceptibility and may have implications for developing targeted psychological and clinical interventions that promote the reduction of stress and anxiety.

Abstract Prussian blue analogue Na 2 Ni[Fe(CN) 6 ] (Ni–PB) has been widely studied as a cathode material for sodium‐ion battery due to its excellent cycling performance. However, Ni–PB has a low theoretical capacity of 85 mAh g −1 because of the electrochemical inertness of Ni. Herein, ternary Ni–PB is successfully synthesized by double doping with Co and Fe at Ni‐site, and the effect of doping with Co and Fe on the electrochemical performance of Ni–PB is systematically investigated through theoretical calculations and electrochemical tests. The first principles calculations confirm that double doping with Co and Fe can significantly reduce the energy barrier and bandgap of Ni–PB. X‐ray diffraction and composition analysis results indicate that ternary NiCoFe–PB composite not only has good crystallinity and high Na content but also has low defects and crystal water. Electrochemical tests reveal that, besides the capacity contribution of high‐spin Co/Fe and low‐spin Fe, Co‐doping enhances the electrochemical activity of low‐spin Fe and Fe‐doping improves the activity of high‐spin Co; moreover, double doping can decrease the diffusion resistance of Na + ions through solid electrolyte interface film, accelerate the kinetics for both ion diffusion process and Faradic reaction, and increase active sites. Under the synergistic effect of Co and Fe, this ternary NiCoFe–PB exhibits outstanding electrochemical performance with a high initial discharge capacity of 120.4 mAh g −1 at 20 mA g −1 and an extremely low capacity fading rate of 0.0044% per cycle at a high current density of 2 A g −1 even after 10,000 cycles, showing great application potential of ternary NiCoFe–PB in the field of large‐scale energy storage.

<h2>Abstract</h2><h3>Background</h3> The purpose of this study was to investigate the associations between courses of depression, the application of depression treatment, and the risk of incident dementia. <h3>Methods</h3> In this prospective cohort study, 354,313 participants ages 50–70 years were recruited from the UK Biobank between 2006 and 2010 and were followed until 2020, with a total of 4,212,929 person-years. We initially studied the effect of depression on dementia incidence across 4 subgroups characterized by courses of depressive symptoms. Then, 46,820 participants with a diagnosis of depression were further categorized into treated and untreated groups. We compared the risk of dementia among different depression treatment groups in all participants who were depressed as well as 4 courses of depressive symptoms by performing survival analyses. <h3>Results</h3> Depression was associated with a 51% higher risk of dementia, among which the increasing, chronically high, and chronically low courses were associated with increased dementia risk, while no association was found in the decreasing course. Compared to those who were depressed but untreated, receiving depression treatments corresponded to a hazard ratio of 0.7 (95% CI, 0.62–0.77). Among the 3 detrimental courses, treatments for increasing and chronically low symptoms of depression were associated with a 32% and 28% lower risk of dementia, respectively, while the reduction effect for chronically high symptoms was insignificant. <h3>Conclusions</h3> The negative association between depression treatment and incident dementia was significant in the increasing and chronically low courses, highlighting the necessity of timely interventional strategies before depression progresses to a chronically severe state.

Coal water slurry (CWS) gasification technology, which is one of clean and efficient coal gasification approaches, catches wide attention presently. To investigate breakup and atomization of coal water slurry, eight kinds of CWS are observed using high speed digital camera. Based on morphology, the breakup regimes of CWS can be termed different modes: Rayleigh-type breakup, fiber-type breakup and atomization. The Rayleigh-type breakup is the main atomization regime of high viscosity CWS. When the viscosity of CWS is low, the CWS jet is Rayleigh-type breakup at low air velocity; and fiber-type breakup at high air velocity. When the air velocity is very high, all CWS jets are in atomization regime. The dimensionless CWS jet breakup length is studied and correlated, which decreases with Weber number and momentum flux ratio, increases with Ohnesorge number. Finally, a simplified formula is studied to estimate the oscillation frequency of CWS jet. The model estimates are consistent with the experimental results.

PLA toughening agent: selectively dodecylated lignin-<italic>graft</italic>-PLA obtained which improves the elongation of PLA by 40 times.

Michael addition polymerizations of amines and acrylic monomers are versatile approaches to biomaterials for various applications. A combinatorial library of poly(β-amino ester)s and diverse poly(amido amine)s from diamines and diacrylates or bis(acrylamide)s have been reported, respectively. Furthermore, novel linear and hyperbranched polymers from Michael addition polymerizations of trifunctional amines and acrylic monomers significantly enrich this category of biomaterials. In this Review, we focus on the biomaterials from Michael addition polymerizations of trifunctional amines and acrylic monomers. First we discuss how the polymerization mechanisms, which are determined by the reactivity sequence of the three types of amines of trifunctional amines, i.e., secondary (2°) amines (original), primary (1°) amines, and 2° amines (formed), are affected by the chemistry of monomers, reaction temperature, and solvent. Then we update how to design and synthesize linear and hyperbranched polymers based on the understanding of polymerization mechanisms. Linear polymers containing 2° amines in the backbones can be obtained from polymerizations of diacrylates or bis(acrylamide)s with equimolar trifunctional amine, and several approaches, e.g., 2A2+BB'B″, A3+2BB'B', A2+BB'B″, to hyperbranched polymers are developed. Further through molecular design of monomers, conjugation of functional species to 2° amines in the backbones of linear polymers and the abundant terminal groups of hyperbranched polymers, the amphiphilicity of polymers can be adjusted, and additional stimuli, e.g., thermal, redox, reactive oxidation species (ROS), and light, responses can be integrated with the intrinsic pH response. Finally we discuss the applications of the polymers for gene/drug delivery and bioimaging through exploring their self-assemblies in various motifs, e.g., micelles, polyplexes particles/nanorings and hydrogels. Redox-responsive hyperbranched polymers can display 300 times higher in vitro gene transfection efficiency and provide a higher in vivo siRNA efficacy than PEI. Also redox-responsive micelle carriers can improve the efficacy of anticancer drug and the bioimaging contrast. Further molecular design and optimization of this category of polymers together with in vivo studies should provide safe and efficient biomaterials for clinical applications.

Redox-responsive hyperbranched poly(amido amine)s (PAAs) with tertiary amino cores and amine, poly(ethylene glycol) (PEG) and hydroxyl terminal groups were prepared for DNA delivery respectively. The DNA condensation capability of PAAs was investigated using gel electrophoresis, and the results showed that PAA terminated with 1-(2-aminoethyl)piperazine (AEPZ) (BAA) is the most efficient in binding plasmid DNA (pDNA). The diameter and zeta-potential of polyplexes from PAAs were characterized using dynamic light scattering (DLS), and the morphology of the polyplexes was obtained using atomic force microscopy (AFM). All the PAAs were able to condense pDNA into nanoparticles with diameters between 50 and 200 nm with a positive surface charge when the weight ratio of polymer/DNA was higher than 20. Glutathione (GSH)-induced DNA release from polyplexes and the buffering capability of PAAs were investigated as well. Cytotoxicity of PAAs and in vitro gene transfection of polyplexes were evaluated in HEK293, COS-7, MCF-7 and Hep G2 cell lines, respectively. The results reflect that PAAs show remarkably low or even no cytotoxicity, and that PAA with amino terminal groups mediates the most efficient gene transfection with the transfection efficiency comparable to that of 25 kDa polyethylenimine. Further the effects of the presence of buthionine sulfoximine (BSO) on the transfection efficiency and cytotoxicity of BAA polyplexes were investigated.

Pairwise and random addition processes are ordinarily indistinguishable in hydrogenation reactions. The distinction becomes important only when the fate of spin correlation matters, such as in parahydrogen-induced polarization (PHIP). Supported metal catalysts were not expected to yield PHIP signals given the rapid diffusion of H atoms on the catalyst surface and in view of the sequential stepwise nature of the H atom addition in the Horiuti–Polanyi mechanism. Thus, it seems surprising that supported metal hydrogenation catalysts can yield detectable PHIP NMR signals. Even more remarkably, supported Pt and Ir nanoparticles are shown herein to catalyze pairwise replacement on propene and 3,3,3-trifluoropropene. By simply flowing a mixture of parahydrogen and alkene over the catalyst, the scalar symmetrization order of the former is incorporated into the latter without a change in molecular structure, producing intense PHIP NMR signals on the alkene. An important indicator of the mechanism of the pairwise replacement is its stereoselectivity, which is revealed with the aid of density matrix spectral simulations. PHIP by pairwise replacement has the potential to significantly diversify the substrates that can be hyperpolarized by PHIP for biomedical utilization.

We report the use of single Vitamin B12 nanodroplets to mediate the reduction of oxygen in neutral buffer. Electron transfer to single Vitamin B12 nanodroplets is observed using the nano-impacts method and shown to be quantitative. The mechanism of mediated oxygen reduction by single VB12 droplets is revealed as via both Co(II) and Co(I) reduced from Co(III) in VB12 through one or two electron transfer followed by the four-electron reduction of oxygen.

Glypican-3 (gpc3) is the gene responsible for Simpson-Golabi-Behmel overgrowth syndrome. Previously, we have shown that GPC3 is overexpressed in hepatocellular carcinoma (HCC). In this study, we demonstrated the mechanisms for GPC3-mediated oncogenesis. Firstly, GPC3 overexpression in NIH3T3 cells gave to cancer cell phenotypes including growing in serum-free medium and forming colonies in soft agar, or on the other way, GPC3 knockdown in HuH-7 cells decreased oncogenecity. We further demonstrated that GPC3 bound specifically through its N-terminal proline-rich region to both Insulin-like growth factor (IGF)-II and IGF-1R. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule extracellular signal-regulated kinase (ERK) in an IGF-II-dependent way. Also, GPC3 knockdown in HCC cells decreased the phosphorylation of both IGF-1R and ERK. Therefore, GPC3 confers oncogenecity through the interaction between IGF-II and its receptor, and the subsequent activation of the IGF-signaling pathway. This data are novel to the current understanding of the role of GPC3 in HCC and will be important in future developments of cancer therapy.

Microreactors have been shown to be a powerful tool for the production of nanoparticles (NPs); however, there is still a lack of understanding of the role that the microfluidic environment plays in directing the nanoprecipitation process. Here we investigate the mechanism of nanoprecipitation of block copolymer stabilized organic NPs using a microfluidic-based reactor in combination with computational fluid dynamics (CFD) modelling of the microfluidic implementation. The latter also accounts for the complex interplay between molecular and hydrodynamic phenomena during the nanoprecipitation process, in order to understand the hydrodynamics and its influence on the NP formation process. It is demonstrated that the competitive reactions result in the formation of two types of NPs, i.e., either with or without loading organic actives. The obtained results are interpreted by taking into consideration a new parameter representing the mismatching between the aggregations of the polymers and actives, which plays a decisive role in determining the size and polydispersity of the prepared hybrid NPs. These results expand the current understanding of the co-nanoprecipitation mechanism of active and block copolymer stabilizer, and on the role exerted by the microfluidic environment, giving information that could be translated to the emerging fields of microfluidic formation of NPs and nanomedicine.

Angewandte ChemieVolume 125, Issue 49 p. 13218-13220 Zuschrift Electrochemical Sizing of Organic Nanoparticles† Dr. Wei Cheng, Dr. Wei Cheng Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)Search for more papers by this authorXiao-Fei Zhou, Xiao-Fei Zhou Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)Search for more papers by this authorProf. Dr. Richard G. Compton, Corresponding Author Prof. Dr. Richard G. Compton richard.compton@chem.ox.ac.uk Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)===Search for more papers by this author Dr. Wei Cheng, Dr. Wei Cheng Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)Search for more papers by this authorXiao-Fei Zhou, Xiao-Fei Zhou Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)Search for more papers by this authorProf. Dr. Richard G. Compton, Corresponding Author Prof. Dr. Richard G. Compton richard.compton@chem.ox.ac.uk Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)Department of Chemistry, Physical & Theoretical Chemistry Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QZ (United Kingdom)===Search for more papers by this author First published: 16 October 2013 https://doi.org/10.1002/ange.201307653Citations: 43 † The European Research Council under the European Union's Seventh Framework Programme (ERC grant agreement number 320403) is gratefully acknowledged for partly funding this work. We thank Dr. D. Omanović (Center for Marine and Environmental Research Zagreb, Croatia) for developing Signal Counter software for data analysis, and the Leverhulme Trust for support for W.C.. Read the full textAboutPDF ToolsRequest permissionAdd to favorites ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Die Größe organischer Nanopartikel (NPs) kann elektrochemisch über den faradayschen Ladungstransfers bestimmt werden, wenn die Nanopartikel eine Elektrode streifen. Indigo-NPs wurden als Modell verwendet (siehe Verteilung des NP-Durchmessers). Das Verfahren könnte zur Bestimmung der Größe zahlreicher organischer Nanopartikel genutzt werden. Citing Literature Supporting Information As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Filename Description ange_201307653_sm_miscellaneous_information.pdf628.6 KB miscellaneous_information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume125, Issue49December 2, 2013Pages 13218-13220 This is the German version of Angewandte Chemie. Note for articles published since 1962: Do not cite this version alone. Take me to the International Edition version with citable page numbers, DOI, and citation export. We apologize for the inconvenience. RelatedInformation

ABSTRACT Effective antimicrobial polymers have been attracting more interests because of the low propensity to cause drug‐resistant microorganisms. The recent progresses in antimicrobial polymers are updated according to the action approaches, that is, antimicrobial polymers with free mobility or fixed on surfaces, respectively. Free antimicrobial polymers kill pathogens majorly via electrostatic interaction followed by disruption of the cell membranes; strong antimicrobial activity of primary/secondary amines, new chemical units, and peptides without facial amphiphilicity are highlighted; and the dependences on amphiphilicity, topology, and self‐assembly profiles are summarized. Antimicrobial polymers fixed on surfaces kill pathogens via interaction with the cell membranes of pathogens via electrostatic or hydrophobic interaction; approaches to antimicrobial surfaces based on covalently grafting, anchoring, and bulk‐mixing of polymers are summarized; and new designs of sustainable antimicrobial surfaces and hydrogels are highlighted. Deep biology understanding and development strategies of materials are suggested for the future. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 632–639

Abstract We report the electrocatalytic dehalogenation of trichloroethylene (TCE) by single soft nanoparticles in the form of Vitamin B 12 ‐containing droplets. We quantify the turnover number of the catalytic reaction at the single soft nanoparticle level. The kinetic data shows that the binding of TCE with the electro‐reduced vitamin in the Co I oxidation state is chemically reversible.

In the early phases of the COVID-19 epidemic labor markets exhibited considerable churn, which we relate to three primary findings.First, reopening policies generated asymmetrically large increases in reemployment of those out of work, compared to modest decreases in job loss among those employed.Second, most people who were reemployed appear to have returned to their previous employers, but the rate of reemployment decreases with time since job loss.Lastly, the groups that had the highest unemployment rates in April also tended to have the lowest reemployment rates, potentially making churn harmful to people and groups with more and/or longer job losses.Taken together, these estimates suggest that employment relationships are durable in the short run, but raise concerns that employment gains requiring new employment matches may not be as rapid and may be particularly slow for hard-hit groups including Hispanic and Black workers, youngest and oldest workers, and women.

Herein, a novel MoO3/Zn–Al LDHs composite photocatalyst was successfully prepared. Morphology, chemical composition, and photoelectrochemical properties of the prepared catalyst were explored by different characterization methods, including X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), Brunauer Emmett-Teller (BET), UV–Vis diffuse reflectance spectrometry (DRS) and Electron Spin Resonance (ESR). Using tetracycline as a target pollutant, the photocatalytic activity of MoO3 (10 wt%)/Zn–Al LDHs composite was tested by photodegradation of tetracycline under visible light irradiation. The experimental results indicate that the MoO3 (10 wt%)/Zn–Al LDHs composite exhibited higher photocatalytic removal efficiency than pure Zn–Al LDHs and MoO3. The removal efficiency of TC in 60 min could reach 90.5%. It was confirmed that the optimal conditions were a catalyst dosage of 1.0 g/L, an initial pH of 9, and an initial concentration of TC of 40 mg/L. In addition, a possible mechanism for the photodegradation of TC with MoO3 (10 wt%)/Zn–Al LDHs composite was proposed. The introduction of MoO3 facilitates the separation of electron-hole pairs. It could be seen that the MoO3 (10 wt%)/Zn–Al LDHs composite has great application prospects for the treatment of antibiotic wastewater.

[email protected] composites as anode materials in Lithium-ion batteries have attracted intensive interest due to the inherent high capacity. On the other side, the high atomic ratio (Li4.4Sn) induces the pulverization of the electrode with cycling. Thus, suppressing pulverization by designing the structure of the materials is an essential key for improving cyclability. Applying the nanotechnologies such as electrospinning, soft/hard nano template strategy, surface modification, multi-step chemical vapor deposition (CVD), and so on has demonstrated the huge advantage on this aspect. These strategies are generally used for homogeneous dispersing Sn nanomaterials in graphene matrix or constructing the voids in the inner of the materials to obtain the mechanical buffer effect. Unfortunately, these processes induce huge energy consumption and complicated operation. To solve the issue, new nanotechnology for the composites by the bottom-up strategy (Organic Molecule Confinement Reaction (OMCR)) was shown in this report. A 3D organic nanoframes was synthesized as a graphene precursor by low energy nano emulsification and photopolymerization. SnO2 [email protected] organic nanoframes as the composites precursor were in-situ formed in the hydrothermal reaction. After the redox process by the calcination, the Sn nanoparticles with nanovoids (~100 nm, uniform size) were homogeneously dispersed in a Two-Dimensional Laminar Matrix of graphene nanosheets (2DLMG) by the in-situ patterning and confinement effect from the 3D organic nanoframes. The pulverization and crack of the composites were effectively suppressed, which was proved by the electrochemical testing. The Sn [email protected]G not delivered just the high cyclability during 200 cycles, but also firstly achieved a high specific capacity (539 mAh g−1) at the low loading Sn (19.58 wt%).

Bandpass microwave photonic filter (MPF) can be achieved based on the well-known phase to intensity conversion method by using phase modulation and single micro-ring resonator (MRR) notch filter. Since MRR could introduce residual phase in handling one optical sideband, the out-of-band radio frequency (RF) rejection ratio and the shape factor of the bandpass MPF are very limited. Here, by introducing another MRR to handle the other optical sideband, the residual phase can be greatly suppressed, thus the filter’s performance can be greatly improved. The proposed bandpass MPF was both verified theoretically and experimentally. Compared with the single MRR, the out-of-band RF rejection ratio and the shape factor were improved by 20 dB and 1.67, respectively. Furthermore, the bandpass MPF’s bandwidth is reconfigurable by adjusting the optical carrier’s frequency or the two MRRs’ amplitude coupling coefficients. The bandpass MPF’s center frequency is also tunable by changing the resonant wavelengths of two MRRs in the opposite direction simultaneously. Experimentally, bandwidth reconfiguration from 0.38 GHz to 15.74 GHz, the shape factor optimization from 2 to 1.23, and frequency tuning from 4 GHz to 21.5 GHz were achieved. We believe that the proposed bandpass MPF has great potential for microwave photonic signal processing.

We demonstrate the generic value of a rigorous analysis of spike shapes observed in nanoimpact experiments. To this end, we investigate the electrochemical doping of insoluble nanoparticles impacting on a biased electrode surface and develop an analytical model of the doping process is developed that accounts for the diffusion of ions inside nanoparticles as well as a numerical model for the response characteristics of the analogue measurement circuitry. By this means, spike shapes that are experimentally observed in the electrode current are predicted and directly compared with experimental data, while appropriate fitting procedures allow detailed physical insights into the ionic mass transport within the particle. Using the oxidative doping of ferrocene nanoparticles with tetrafluoroborate anions as a paradigm case, we demonstrate that size distributions of particle populations showing excellent agreement with scanning electron microscopy measurements can be extracted from experimental data and ionic diffusion inside the particle can be quantified.

Nonexchangeable K (NEK) is the major portion of the reserve of available K in soil and a primary factor in determining soil K fertility. The questions of how much NEK is in soils and how to quantify total NEK in soils are so far still unclear due to the complicated effects of various minerals on K fixation. In this study, the NEK in 9 soils was extracted with sodium tetraphenylboron (NaBPh4) for various time periods longer than 1 d. The results showed that the NEK extracted by NaBPh4 gradually increased with time, but showed no more increase after the duration of extraction exceeded 10–20 d. As the temperature increased from 25 to 45 °C, the duration to obtain the maximum extraction of NEK was reduced from 20 to 10 d, and the maximum values of NEK released at both temperatures was almost the same for each soil. The maximum NEK (MNEK) of the 9 soils extracted by NaBPh4 varied from 3 074 to 10 081 mg kg−1, accounting for 21%–56% of the total soil K. There was no significant correlation between MNEK released by NaBPh4 and other forms of K, such as NH4OAc-extracted K, HNO3-extracted K and total K in soils, which indicates that NEK is a special form of K that has no inevitable relationship to the other forms of K in soils. The MNEK extraction by NaBPh4 in this study indicated that the total NEK in the soils could be differentiated from soil structural K and quantified with the modified NaBPh4 method. The high MNEK in soils made NEK much more important in the role of the plant-available K pool. How to fractionate NEK into different fractions and establish the methods to quantify each NEK fraction according to their bioavailability is of great importance for future research.

T lymphocyte infiltration with immunotherapy potentially suppresses most devastating brain tumors. However, local immune privilege and tumor heterogeneity usually limit the penetration of immune cells and therapeutic agents into brain tumors, leading to tumor recurrence after treatment. Here, a rabies virus glycoprotein (RVG)-camouflaged gold yarnball (RVG@GY) that can boost the targeting efficiency at a brain tumor via dual hierarchy- and RVG-mediated spinal cord transportation, facilitating the decrease of tumor heterogeneity for T cell infiltration, is developed. Upon magnetoelectric irradiation, the electron current generated on the GYs activates the electrolytic penetration of palbociclib-loaded dendrimer (Den[Pb]) deep into tumors. In addition, the high-density GYs at brain tumors also induces the disruption of cell–cell interactions and T cell infiltration. The integration of the electrolytic effects and T cell infiltration promoted by drug-loaded RVG@GYs deep in the brain tumor elicits sufficient T cell numbers and effectively prolongs the survival rate of mice with orthotopic brain tumors.

Previous studies found that cancer survivors had a reduced risk of dementia compared with the general population. However, these findings were uncertain because of survivor bias and a lack of stratification by cancer types. This current cohort study used data from the UK Biobank to explore these associations.Multivariable Cox regression analyses were used to examine the association of cancer status and the risk of dementia with its subtypes after adjusting for age and sex. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated as a measure of relative risk by comparing observed dementia incidence among cancer patients.We included 263,151 participants in the observational analysis. During a median follow-up of 9.18 years, dementia was diagnosed in 472 individuals with cancer and 3685 individuals without cancer, respectively. Cancer patients had lower risks of dementia (hazard ratio: 0.89, confidence interval: 0.81-0.98) and its subtypes (Alzheimer's disease [AD]: 0.85 [0.74-0.98]; vascular dementia [VD]: 0.81 [0.66-0.99]) in the Cox regression adjusted for age and sex. Individuals with cancers in the male genital system had substantially reduced risks of dementia (0.66 [0.46-0.93]) and AD (0.53 [0.29-0.97]) than those with cancers in other systems. Moreover, non-melanoma skin cancer and prostate cancer were associated with a reduced risk of dementia (0.79 [0.62-0.99]; 0.69 [0.49-0.97]), but not with AD or VD (P>0.05).The current study supported a negative association between cancer and dementia risk, and encourages further exploration of the mechanistic basis of this inverse relationship to improve understanding.

We report the development of a microfluidic-based process for the production of polymeric micelles (PMs) in continuous-flow microreactors where Pluronic® tri-block copolymer is used as model polymeric biomaterial relating to drug delivery applications. A flow focusing configuration is used enabling a controllable, and fast mixing process to assist the formation of polymeric micelles through nanoprecipitation which is triggered by a solvent exchange process when organic solutions of the polymer mixed with a non-solvent. We experientially investigate the effect of polymer concentration, flow rate ratio and microreactor dimension on the PMs size characteristics. The mixing process within the microfluidic reactors is further analyzed by computational modeling in order to understand the hydrodynamic process and its implication for the polymeric micelles formation process. The results obtained show that besides the effect of the flow rate ratio, the chemical environment in which the aggregation takes place plays an important role in determining the dimensional characteristics of the produced polymeric micelles. It is demonstrated that microfluidic reactors provide a useful platform for the continuous-flow production of polymeric micelles with improved controllability, reproducibility, and homogeneity of the size characteristics.

Reactive oxygen species (ROS) elicited by oxidative stress are widely recognized as a major initiator in the dege-neration of dopaminergic neurons distinctive of Parkinson's disease (PD). The interaction of ROS with mitochondria triggers sequential events in the mitochondrial cell death pathway, which is thought to be responsible for ROS-mediated neurodegeneration in PD. α-lipoic acid (LA) is a pleiotropic compound with potential pharmacotherapeutic value against a range of pathophysiological insults. Its protective actions against oxidative damage by scavenging ROS and reducing production of free radicals have been reported in various in vitro and in vivo systems. This study analyzed the ability of LA to protect PC12 neuronal cells from toxicity of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which is known to kill dopaminergic neurons selectively and to cause severe parkinsonism-like symptoms in humans and primate animals. Our results demonstrate that the apoptosis of PC12 cells elicited by MPP+ could be significantly prevented by pretreatment with LA for 1 h. In addition, LA inhibits intercellular ROS levels and the mitochondrial transmembrane permeability, the key players in the pathogenesis of PD, thereby protecting dopaminergic neuronal cells against oxidative damage.

Abstract Encapsulating liposomes are widely used for controlled drug delivery. We report the use of nano‐impact experiments for the electrochemical attomolar quantification of the liposome load, uniquely at the single liposome level, using vitamin C encapsulated liposomes as a model. The size of the liposomes and their picomolar concentration are also determined in biological buffer in real time.

Abstract Organic nanoparticles are attracting many significant applications in bio‐imaging and nanomedicine. However, in comparison with intensive studies of metal and inorganic nanoparticles, the research of organic nanoparticles is still at a very early stage due to their complex physical and chemical properties. Most recently, there are increasingly significant interests in developing nano‐capacitors and nano‐scale energy storage and sensor devices based on organic materials. Herein, we report for the first time the kinetics and mechanism of electron transfer to individual organic nanoparticles, using indigo nanoparticles as a model system, via analysis of the charge transferred in the reduction of individual organic nanoparticles. We conclude the indigo nanoparticles display irreversible (slow) electron transfer kinetics and that the charge transfer is the rate‐determining step in the reductive dissolution of the nanoparticles; protonation and detachment of molecules from the nanoparticles occurs after this rate‐determining step. The transfer coefficient, α , of the electron transfer is found to be 0.25±0.05, whilst the rate constant ( k 0 ) is determined as the composite parameter ${k^0 \exp \left( {{{0.25F} \over {RT}}E_{\rm{f}}^{\rm{{\rm \theta} }} } \right)}$ , where ${E_{\rm{f}}^{\rm{{\rm \theta} }} }$ is the formal potential, which is found to have the value of 1.7×10 −8 m s −1 . Given the high importance of the electron transfer mechanism for organic nanomaterials, this report may have great significance on future research of organic nanomaterials for diverse applications.

The surface processes resulting in the correlation of semi-hydrogenation selectivity and stereoselective addition to propyne are revealed by parahydrogen enhanced NMR.

Abstract Tin‐based chalcogenide semiconductors, though attractive materials for photovoltaics, have to date exhibited poor performance and stability for photoelectrochemical applications. Here, a novel strategy is reported to improve performance and stability of tin monosulfide (SnS) nanoplatelet thin films for H 2 production in acidic media without any use of sacrificial reagent. P‐type SnS nanoplatelet films are coated with the n ‐CdS buffer layer and the TiO 2 passivation layer to form type II heterojunction photocathodes. These photocathodes with subsequent deposition of Pt nanoparticles generate a photovoltage of 300 mV and a photocurrent density of 2.4 mA cm −2 at 0 V versus reversible hydrogen electrode (RHE) for water splitting under simulated visible‐light illumination (λ &gt; 500 nm, P in = 80 mW cm −2 ). The incident photon‐to‐current efficiency at 0 V versus RHE for H 2 production reach a maximum of 12.7% at 575 nm with internal quantum efficiency of 13.8%. The faradaic efficiency for hydrogen evolution remains close to unity after 6000 s of illumination, confirming the robustness of the heterojunction for solar H 2 production.

Minimizing Pt loading is essential for designing cost-effective water electrolyzers and fuel cell systems. Recently, three-dimensional macroporous open-pore electroactive supports have been widely regarded as promising architectures to lower loading amounts of Pt because of its large surface area, easy electrolyte access to Pt sites, and superior gas diffusion properties to accelerate diffusion of H2 bubbles from the Pt surface. However, studies to date have mainly focused on Pt loading on Ni-based 3D open pore supports which are prone to corrosion in highly acidic and alkaline conditions. Here, we investigate electrodeposition of Pt nanoparticles in low-loading amounts on commercially available, inexpensive, 3D carbon foam (CF) support and benchmark their activity and stability for electrolytic hydrogen production. We first elucidate the effect of deposition potential on the Pt nanoparticle size, density and subsequently its coverage on 3D CF. Analysis of the Pt deposit using scanning electron microscopy images reveal that for a given deposition charge density, the particle density increases (with cubic power) and particle size decreases (linearly) with deposition overpotential. A deposition potential of 0.4 V vs. standard calomel electrode (SCE) provided the highest Pt nanoparticle coverage on 3D CF surface. Different loading amounts of Pt (0.0075 - 0.1 mgPt/cm2) was then deposited on CF at 0.4 V vs. SCE and subsequently studied for its hydrogen evolution reaction (HER) activity in acidic 1M H2SO4 electrolyte. The Pt/CF catalyst with loading amounts as low as 0.06 mgPt/cm2 (10-fold lower than state-of-the-art commercial electrodes) demonstrated a mass activity of 2.6 ampere per milligram Pt, nearly 6-fold greater than the commercial Pt/C catalyst tested under similar conditions. The 3D architectured electrode also demonstrated excellent stability, showing less than 7% loss in activity after 60 hours of constant current water electrolysis at 100 mA/cm2.

The optical properties of a photonic crystals slab (PCS) are highly sensitive to environmental variation. PCS thus are an attractive platform for sensing application. We numerically demonstrate a terahertz refractive index sensor based on the guided resonance in a two-dimensional PCS. The PCS consists of a square lattice of air holes in a silicon slab fabricated on a quartz substrate. By varying each structural parameter systematically, we study the dependence of the resonance located around 0.508 THz on the structural parameters of PCS, and then optimize the structural parameters of PCS for a higher sensitivity. We apply the PCS sensor to detect the refractive index of analytes. The sensitivity of the sensor reaches 23.08 GHz/RIU for the resonance located around 0.508 THz. Our results provide insight into the future terahertz spectroscopy for sensing detection.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInverse gas chromatography. 6. Thermodynamics of poly(.epsilon.-caprolactone)-polyepichlorohydrin blendsMohammad Jamal El-Hibri, Weizhuang Cheng, and Petr MunkCite this: Macromolecules 1988, 21, 12, 3458–3463Publication Date (Print):December 1, 1988Publication History Published online1 May 2002Published inissue 1 December 1988https://doi.org/10.1021/ma00190a019RIGHTS & PERMISSIONSArticle Views115Altmetric-Citations41LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (755 KB) Get e-Alerts Get e-Alerts

An optimized condition is identified to prepare linear poly(amido amine)s via Michael Addition polymerization of trifunctional amine, 4-(aminomethyl)piperidine (AMPD), with an equimolar diacrylamide, N,N-cystaminebis(acrylamide) (BAC). Poly(ethylene glycol) (PEG) and cholesterol (CE) are conjugated to linear poly(BAC-AMPD) through the reactions with the secondary amino groups in the backbone, respectively, to form poly(BAC-AMPD)-g-PEG-g-CE. The chemical structures of poly(BAC-AMPD) and poly(BAC-AMPD)-g-PEG-g-CE are characterized using NMR and gel permeation chromatography (GPC). Transmission electron microscopy (TEM), dynamic light scattering (DLS) and (1)H NMR results show that micelles with PEG shells and hydrophobic cores composed of poly(BAC-AMPD) and CE are formed via self-assembly of poly(BAC-AMPD)-g-PEG-g-CE in aqueous solution, and the micelles of poly(BAC-AMPD)-g-PEG-g-CE can be degraded by the presence of L-dithiothreitol and show a limited cytotoxicity in vitro. The anti-cancer drug, doxorubicin (DOX), can be loaded into the micelles. The DOX loaded micelles of poly(BAC-AMPD)-g-PEG-g-CE show pH- and redox-responsive drug release and redox-induced formation of aggregates, and it is shown that the DOX loaded micelles can deliver DOX into cells and show a higher efficacy in killing cancer cells than free drug.

The ability to perform efficient and affordable field detection and quantification of nanoparticles in aquatic environmental systems remains a significant technical challenge. Recently we reported a proof of concept of using 'sticky' electrodes for the detection of silver nanoparticles (Tschulik et al 2013 Nanotechnology 29 295502). Now a disposable electrode for detection and quantification of commercial Ag nanoparticles in natural seawater is presented. A disposable screen printed electrode is modified with cysteine and characterized by sticking and stripping experiments, with silver nanoparticle immobilization on the electrode surface and subsequent oxidative stripping, yielding a quantitative determination of the amount of Ag nanoparticles adhering to the electrode surface. The modified electrode was applied to natural seawater to mimic field-based environmental monitoring of Ag NPs present in seawater. The results demonstrated that commercial Ag NPs in natural seawater can be immobilized, enriched and quantified within short time period using the disposable electrodes without any need for elaborate experiments.

Na3V2(PO4)2O2F (NVPOF) is considered as a promising cathode material for sodium-ion batteries due to its high structural stability and high average operating voltage (3.8 V). However, its low electronic conductivity and slow sodium-ion diffusion kinetics hinder its practical application. Here, an approach of Na-site regulation is proposed to adjust the intrinsic Na+ diffusion efficiency and electronic conductivity, thus improving the electrochemical performance of NVPOF. Guided by density functional theory calculations, we demonstrate that Na-site regulation can be subtly realized by accurate Li substitution on the Na2 site in NVPOF. The as-prepared Na2.75Li0.25V2(PO4)2O2F (NLVPOF) shows an increase of 1.53 and 1.55 times in rate capability and capacity retention (500 cycles) than NVPOF, respectively. Such a simple and effective Na-site regulation provides a new avenue in constructing advanced Li/Na-ion cathode materials.

Background Considerable uncertainty remains regarding associations of multiple risk factors with Alzheimer’s disease (AD). We aimed to systematically screen and validate a wide range of potential risk factors for AD. Methods Among 502,493 participants from the UK Biobank, baseline data were extracted for 4171 factors spanning 10 different categories. Phenome-wide association analyses and time-to-event analyses were conducted to identify factors associated with both polygenic risk scores for AD and AD diagnosis at follow-up. We performed two-sample Mendelian randomization analysis to further assess their potential causal relationships with AD and imaging association analysis to discover underlying mechanisms. Results We identified 39 factors significantly associated with both AD polygenic risk scores and risk of incident AD, where higher levels of education, body size, basal metabolic rate, fat-free mass, computer use, and cognitive functions were associated with a decreased risk of developing AD, and selective food intake and more outdoor exposures were associated with an increased risk of developing AD. The identified factors were also associated with AD-related brain structures, including the hippocampus, entorhinal cortex, and inferior/middle temporal cortex, and 21 of these factors were further supported by Mendelian randomization evidence. Conclusions To our knowledge, this is the first study to comprehensively and rigorously assess the effects of wide-ranging risk factors on AD. Strong evidence was found for fat-free body mass, basal metabolic rate, computer use, selective food intake, and outdoor exposures as new risk factors for AD. Integration of genetic, clinical, and neuroimaging information may help prioritize risk factors and prevention targets for AD.

Finding a uniform method to evaluate plant-available potassium (K) in a variety of soils has been a challenge. In this study, the sodium tetraphenylboron (NaBPh4) method was modified and compared with the conventional ammonium acetate (NH4OAc) method to evaluate K availability to perennial ryegrass (Lolium perenne L.) in soils with different K fertilities. The amount of K extracted using NaBPh4 was influenced by extraction time and concentrations of NaCl and NaBPh4. Without NaCl, the NaBPh4 method with low concentrations of NaBPh4 (0.001 and 0.003 mol L−1) could only extract soluble and exchangeable soil K, equivalent to three sequential extractions using the NH4OAc method, whereas the NaBPh4 method with a high NaBPh4 concentration (0.2 mol L−1) could extract all the NH4OAc-extractable K and some easily released nonexchangeable K (NEK) in soils. Easily released NEK contributed significantly to K uptake by ryegrass. Soil K availability estimated using the 60-min (r2 = 0.83-0.92) and 120-min (r2 = 0.84-0.94) modified NaBPh4 methods correlated well to the K removed by one to eight crops of ryegrass. The 60-min modified NaBPh4 method without NaCl (0.2 mol L−1 NaBPh4 + 0.01 mol L−1 EDTA) was suitable for evaluating K availability to plants in a variety of soils, whereas the NH4OAc method was only suitable for evaluating K availability in soils of the same type or with similar K-buffering capacities, but not in soils with variable K buffer capacities or in which the NEK contribution to plant K uptake varied.

The synthesis and characterization of Oil Blue Dye nanoparticles is reported along with their use for nano-impacts experiments in aqueous solution. The latter reveal current spikes corresponding to quantitative two electron reductions due to the reduction of the quinone groups and quantitative two electron oxidations from the 1,4-phenylenediamine groups presented in the Oil Blue Dye molecules within the nanoparticles. In both cases, the oxidation or reduction leads to size distributions in good agreement with independent measurements made using dynamic light scattering showing that the redox events accompanying the nano-impacts lead to the full dissolution of the nanoparticles.

Abstract We theoretically and experimentally investigate the influence of partial surface blocking on the electrochemistry of nanoparticles impacting at an electrode. To this end, we introduce an analytical model for the adsorption of single blocking molecules on the electrode and calculate the resulting fractional electrode coverage. We find that even small amounts of adsorbed molecules can fully suppress detection of impacts of nanoparticles while the electrode characteristics in the detection of electroactive molecules hardly change. Our findings are supported by experimental data on the indigo nanoparticle electroreduction at a carbon microelectrode (radius 5.5 μm) in aqueous solution. We find that nanoimpacts are fully suppressed in the presence of acetone at concentrations of 250 n m, which have a negligible effect on the electrode kinetics of the Fe(CN) ${_6^{3 - /4 - } }$ couple.

Abstract Electrostatic interactions between surface‐charged nanoparticles (NPs) and electrodes studied using existing techniques unavoidably and significantly alter the system being analyzed. Here we present a methodology that allows the probing of unperturbed electrostatic interactions between individual NPs and charged surfaces. The uniqueness of this approach is that stochastic NP impact events are used as the probe. During a single impact, only an attomole of the redox species reacts and is released at the interface during each sensing event. As an example, the effect of electrostatic screening on the reduction of negatively charged indigo NPs at a mercury microelectrode is explored at potentials positive and negative of the potential of zero charge. At suitable overpotentials fully driven electron transfer is seen for all but very low (&lt;0.005 M ) ionic strengths. The loss of charge transfer in such dilute electrolytes is unambiguously shown to arise from a reduced driving force for the reaction rather than a reduced population of NPs near the electrode, contradicting popular perceptions. Electrostatics were found not to significantly affect the reactivity of the studied NPs. Importantly, the presented technique is general and can be applied to a wide variety of NPs, including metals, metal oxides and organic compounds.

Micelles formed from self-assembly of amphiphilic PEGylated hyperbranched poly(amido amine)s can release doxorubicin at low pH or in the presence of high GSH concentration to kill cancer cells.

Abstract Photoelectrooxidation of chloride ions to chlorine with co-production of hydrogen by water reduction has been proposed as a means of decreasing the net solar hydrogen production cost. So far, however, most such solar-to-chlorine production systems use cost-prohibitive materials and/or show rather small faradaic yield or stability. Here we report the development of earth-abundant, nanostructured bismuth vanadate/tungsten oxide (BiVO 4 /WO 3 ) photoanode assemblies that operate in acidic sodium chloride solution (pH 1; 4 M) to produce chlorine while generating hydrogen at the dark cathode. We show that electrodeposition of 20 nm WO 3 coating protects BiVO 4 from harsh pH and oxidative environments while being catalytically active for chlorine evolution. The heterostructured BiVO 4 /WO 3 photoanodes yield average photocurrent densities of 2.5 ± 0.3 mA cm −2 at 1.42 V RHE (Reversible Hydrogen Electrode) under 1 sun illumination. After two hours of continuous illumination, the best performing devices demonstrate faradaic efficiencies of 85% for chlorine production and ~100% for hydrogen production.

Exposure of specific crystallographic planes as catalyst surfaces has been reported to effectively affect the performance of noble metal cocatalysts used for photocatalytic hydrogen production via water splitting. However, the performance of noble metals for hydrogen production in alkaline solutions is usually 2 orders of magnitude lower than that in acidic media because of the weak dissociative adsorption ability of noble metals to water molecules, which may greatly limit their applications in photocatalytic hydrogen production. In this research we report a Pt-based composite cocatalyst (Ni(OH)2/PtNi nanocubes), designed by separating the dissociative sites of water molecules from active sites for photocatalytic hydrogen production. Compared with PtNi nanocube-loaded CdS, Ni(OH)2/PtNi nanocube-modified CdS exhibits a much higher photocatalytic performance for hydrogen production in alkaline solutions. This study provides a method for synthesizing highly active water-splitting/reducing photocatalysts under alkaline conditions.

In this article, we present Biologically Annotated Neural Networks (BANNs), a nonlinear probabilistic framework for association mapping in genome-wide association (GWA) studies. BANNs are feedforward models with partially connected architectures that are based on biological annotations. This setup yields a fully interpretable neural network where the input layer encodes SNP-level effects, and the hidden layer models the aggregated effects among SNP-sets. We treat the weights and connections of the network as random variables with prior distributions that reflect how genetic effects manifest at different genomic scales. The BANNs software uses variational inference to provide posterior summaries which allow researchers to simultaneously perform ( i ) mapping with SNPs and ( ii ) enrichment analyses with SNP-sets on complex traits. Through simulations, we show that our method improves upon state-of-the-art association mapping and enrichment approaches across a wide range of genetic architectures. We then further illustrate the benefits of BANNs by analyzing real GWA data assayed in approximately 2,000 heterogenous stock of mice from the Wellcome Trust Centre for Human Genetics and approximately 7,000 individuals from the Framingham Heart Study. Lastly, using a random subset of individuals of European ancestry from the UK Biobank, we show that BANNs is able to replicate known associations in high and low-density lipoprotein cholesterol content.

BMEMatVolume 2, Issue 1 e12073 COVEROpen Access Bio-inspired photonic crystals: Tailoring the dielectric building blocks to control the light propagation (1/2024) Cun Zhu, Cun ZhuSearch for more papers by this authorLei Tian, Lei TianSearch for more papers by this authorWei Cheng, Wei ChengSearch for more papers by this authorZhongze Gu, Zhongze GuSearch for more papers by this author Cun Zhu, Cun ZhuSearch for more papers by this authorLei Tian, Lei TianSearch for more papers by this authorWei Cheng, Wei ChengSearch for more papers by this authorZhongze Gu, Zhongze GuSearch for more papers by this author First published: 01 March 2024 https://doi.org/10.1002/bmm2.12073AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Taking advantage of the spatial ordered structures, bio-inspired photonic crystals have drawn tremendous attention in bioassays, sensors, and optical devices. In article number 10.1002/bmm2.12056, Cun Zhu and Lei Tian et al. have comprehensively summarized the recent progress toward bio-inspired photonic crystals, including the origination of vivid structural color in living creatures, and strategies to construct the periodic ordered structures and manipulate the photonic stop band to achieve the control of light propagation. Volume2, Issue1February 2024e12073 RelatedInformation

Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.

Using toluene droplets as a model for artificial oxygen carriers, the real-time measurement of attomole oxygen contents at the individual droplet level is reported for the first time.

Abstract We show the electrochemical determination of attomole glutathione contents within single individual liposomes at low overpotentials through mediated electron transfer by using copper (II) as a catalyst for the oxidation of liposomal glutathione. A “titration‐like” behaviour of individual liposomes was observed when impacting with the electrode to quantify the content within single liposomes. The nanoimpacts “titration” strategy allows the characterisation of nanoparticles containing redox‐inactive molecules at the single‐nanoparticle level.

Since 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from self-identified European individuals are not transferable to non-European individuals because of various confounding challenges. Here, we demonstrate that enrichment analyses that aggregate SNP-level association statistics at multiple genomic scales—from genes to genomic regions and pathways—have been underutilized in the GWA era and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the robust associations generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven diverse self-identified human ancestries in the UK Biobank and the Biobank Japan as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. We identify 1,000 gene-level associations that are genome-wide significant in at least two ancestry cohorts across these 25 traits as well as highly conserved pathway associations with triglyceride levels in European, East Asian, and Native Hawaiian cohorts.

The cerebellum is recognized as being involved in neurocognitive and motor functions with communication with extra-cerebellar regions relying on the white matter integrity of the cerebellar peduncles. However, the genetic determinants of cerebellar white matter integrity remain largely unknown.We conducted a genome-wide association analysis of cerebellar white matter microstructure using diffusion tensor imaging data from 25,415 individuals from UK Biobank. The integrity of cerebellar white matter microstructure was measured as fractional anisotropy (FA) and mean diffusivity (MD). Identification of independent genomic loci, functional annotation, and tissue and cell-type analysis were conducted with FUMA. The linkage disequilibrium score regression (LDSC) was used to calculate genetic correlations between cerebellar white matter microstructure and regional brain volumes and brain-related traits. Furthermore, the conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was employed to identify the shared genetic basis between cerebellar white matter microstructure and common brain disorders.We identified 11 genetic loci (P < 8.3 × 10-9) and 86 genes associated with cerebellar white matter microstructure. Further functional enrichment analysis implicated the involvement of GABAergic neurons and cholinergic pathways. Significant polygenetic overlap between cerebellar white matter tracts and their anatomically connected or adjacent brain regions was detected. In addition, we report the overall genetic correlation and specific loci shared between cerebellar white matter microstructural integrity and brain-related traits, including movement, cognitive, psychiatric, and cerebrovascular categories.Collectively, this study represents a step forward in understanding the genetics of cerebellar white matter microstructure and its shared genetic etiology with common brain disorders.

Abstract Background Comorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning. Methods We studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9–10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder), externalizing (attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder) diagnostic groups, a group with comorbidity of the two and a healthy control group. Genome-wide association analysis (GWAS) and cell type specificity analysis were performed on 4468 unrelated European participants from this cohort. Results Smaller cortical surface area but higher thickness was noted across patient groups when compared to controls. Children with comorbid internalizing and externalizing disorders had more pronounced areal reduction than those without comorbidity, indicating an additive burden. In contrast, cortical thickness had a non-linear effect with comorbidity: the comorbid group had no significant CT differences, while those patient groups without comorbidity had significantly higher thickness compare to healthy controls. Distinct biological pathways were implicated in regional SA and CT differences. Specifically, CT differences were associated with immune-related processes implicating astrocytes and oligodendrocytes, while SA-related differences related mainly to inhibitory neurons. Conclusion The emergence of comorbidity across distinct clusters of psychopathology is unlikely to be due to a simple additive neurobiological effect alone. Distinct developmental risk moderated by immune-related adaptation processes, with unique genetic and cell-specific factors, may contribute to underlying SA and CT differences. Children with the highest risk but lowest resilience, both captured in their developmental morphometry, may develop a comorbid illness pattern.

With the continuous progress of the epidemic of coronavirus disease 2019 (COVID-19) infection and the constant mutation of the virus strain, reinfection occurred in previously infected individuals and caused waves of the epidemic in many countries. Therefore, we aimed to explore the characteristics of COVID-19 reinfection during the epidemic period in Yangzhou and provide a scientific basis for assessing the COVID-19 situation and optimizing the allocation of medical resources.We chose previously infected individuals of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reported locally in Yangzhou city from January 2020 to November 30, 2022. A telephone follow-up of cases was conducted from February to March 2023 to collect the COVID-19 reinfection information. We conducted a face-to-face survey on that who met the definition of reinfection to collect information on clinical symptoms, vaccination status of COVID-19, and so on. Data were analyzed using SPSS 19.0.Among the 999 eligible respondents (92.24% of all the participants), consisting of 42.28% males and 57.72% females, the reinfection incidence of females was significantly higher than that of male cases (χ2 = 5.197, P < 0.05); the ages of the respondents ranged from 1 to 91 years, with the mean age of 42.28 (standard deviation 22.73) years; the most of the sufferers were infected initially with Delta variant (56.88%), followed by the Omicron subvariants BA.1/BA.2 (39.52%). Among all the eligible respondents, 126 (12.61%) reported COVID-19 reinfection appearing during the epidemic period, and the intervals between infections were from 73 to 1,082 days. The earlier the initial infection occurred, the higher the reinfection incidence and the reinfection incidence was significantly increased when the interval was beyond 1 year (P < 0.01) .119 reinfection cases (94.4%) were symptomatic when the most common symptoms included fever (65.54%) and cough (61.34%); compared with the initial infection cases, the proportion of clinical symptoms in the reinfected cases was significantly higher (P < 0.01). The reinfection incidence of COVID-19 vaccination groups with different doses was statistically significant (P < 0.01). Fewer reinfections were observed among the respondents with three doses of COVID-19 vaccination compared to the respondents with two doses (χ2 = 14.595, P < 0.001) or without COVID-19 vaccination (χ2 =4.263, P = 0.039).After the epidemic period of COVID-19, the reinfection incidence varied with different types of SARS-CoV-2 strains. The reinfection incidence was influenced by various factors such as virus characteristics, vaccination, epidemic prevention policies, and individual variations. As the SARS-CoV-2 continues to mutate, vaccination and appropriate personal protection have practical significance in reducing the risk of reinfection.

We propose and demonstrate a widely tunable microwave photonic filter with controlled frequency agility, bandwidth reconfigurability and flexible switching functions. It is based on the self-interference microring aided by an asymmetric Mach–Zehnder interferometer, breaking the fundamental microring footprint limit and achieving a doubled free spectral range (123.2 GHz) with a strong out-of-band rejection. Simulation results show that a bandpass microwave photonic filter can be tuned across a 60 GHz frequency range with a varied 3-dB bandwidth from 2.13 GHz to 40.7 GHz in a cascaded dual-ring topology. Its RF out-of-band rejection ratio is improved by more than 60 dB in the high frequency region due to a perfect residual phase cancellation. A dual-band notch microwave photonic filter with an extinction ratio of about 50 dB and a frequency tunable range of about 27.7 GHz is also demonstrated, showing its broadly applicability. Our method highlights its suitability to improve chip-scale wideband and high-performance RF receiver systems.

White matter hyperintensities (WMH) increase the risk of stroke and cognitive impairment. This study aims to determine the cross-sectional and longitudinal associations between adiposity and WMH.Participants were enrolled from the UK Biobank cohort. Associations of concurrent, past, and changes in overall and central adiposity with WMH were investigated by linear and nonlinear regression models. The association of longitudinal adiposity and WMH volume changes was determined by a linear mixed model. Mediation analysis investigated the potential mediating effect of blood pressure.In 34,653 participants with available adiposity measures and imaging data, the concurrent obese group had a 25.3% (β [95% CI] = 0.253 [0.222-0.284]) higher WMH volume than the ideal weight group. Increment in all adiposity measures was associated with a higher WMH volume. Among them, waist circumference demonstrated the strongest effect (β [95% CI] = 0.113 [0.101-0.125]). Past adiposity also demonstrated similar effects. Among the subset of 2664 participants with available WMH follow-up data, adiposity measures were predictive of WMH change. Regarding changes of adiposity, compared with ideal weight stable group, those who turned from ideal weight to overweight/obese had a 8.1% higher WMH volume (β [95% CI] = 0.081 [0.039-0.123]), while participants who turned from overweight/obese to ideal weight demonstrated no significant WMH volume change. Blood pressure partly meditates the associations between adiposity and WMH.Both concurrent and past adiposity were associated with a higher WMH volume. The detrimental effects of adiposity on WMH occurred throughout midlife and in the elderly and may still exist after changes in obesity status.

Carbonyl-modified solid-state carbon nitrogen quantum dots (m-O═CNQDs) have emerged as promising room-temperature phosphorescent (RTP) materials close to commercialization. However, high-crystallinity m-O═CNQDs are insensitive to external stimuli such as water and heat due to strong stacking interactions between layers, restricting their applications in stimulus responsive fields. Here, a polymer template space-confined growth strategy is established for the large-scale synthesis of water stimulus responsive polyvinylpyrrolidone-functionalized m-O═CNQDs with ultralong room-temperature phosphorescence (181 ms) using urea and PVP as precursors. Theoretical and experimental results indicate that the PVP template linked at the rim of m-O═CNQDs formed by in situ self-polymerization of urea inhibits interactions between layers and increases their affinity for water, which is the key to increasing their sensitivity with water. This strategy offers a new path for developing commercial stimulus responsive RTP materials.

Abstract The current challenge of wearable/implantable personal dosimeters for medical diagnosis and radiotherapy applications is lack of suitable detector materials possessing both excellent detection performance and biocompatibility. Here, we report a solution-grown biocompatible organic single crystalline semiconductor (OSCS), 4-Hydroxyphenylacetic acid (4HPA), achieving real-time spectral detection of charged particles with single-particle sensitivity. Along in-plane direction, two-dimensional anisotropic 4HPA exhibits a large electron drift velocity of 5 × 10 5 cm s −1 at “radiation-mode” while maintaining a high resistivity of (1.28 ± 0.003) × 10 12 Ω·cm at “dark-mode” due to influence of dense π-π overlaps and high-energy L1 level. Therefore, 4HPA detectors exhibit the record spectra detection of charged particles among their organic counterparts, with energy resolution of 36%, ( μt ) e of (4.91 ± 0.07) × 10 −5 cm 2 V −1 , and detection time down to 3 ms. These detectors also show high X-ray detection sensitivity of 16,612 μC Gy abs −1 cm −3 , detection of limit of 20 nGy air s −1 , and long-term stability after 690 Gy air irradiation.

Extracellular vesicles (EVs) are novel biomarkers evaluated during liquid biopsy and are involved in many physiological functions in cells as well as various pathological processes in diseases. There is an urgent need for a specific, sensitive, and rapid detection platform to facilitate clinical diagnosis. Researchers have recently developed new biosensing technologies for the detection of EVs owing to their unique advantages. In this chapter, we review recent developments and technical breakthroughs in biosensor-based EV detection, including electrochemical, fluorescent, chemiluminescent, surface plasmon resonance, Raman spectroscopy, and other biosensors, in the field of cancer and other diseases. The working strategies, analytical performance, advantages, shortcomings, and future perspectives of these biosensors are summarized.

Objectives:The purpose of this study was to examine the proportion of CD161 on CD56+Natural Killer(NK) cells in peripheral blood of primary Sjögren’s syndrome(pSS) and investigate its clinical relevance of pSS. Methods:The proportion of CD56+NK cells and CD161 on CD56+NK cells was detected by flow cytometry in 31 pSS patients and 29 healthy controls (HCs). The correlations between proportion of CD161+CD56+NK cells and clinical features and disease activity of pSS were further analysed. Meanwhile, we drew the receiver operating characteristic(ROC) curve to evaluate the diagnostic value of CD161+CD56+NK cells in pSS. Results: The proportion of CD56+ NK cells and CD161+CD56+NK cells decreased markly in pSS patients compared to HCs. The correlation analysis showed that proportion of CD161+CD56+NK cells negatively correlated with WBC,IgA,IgM,IgG,ESSRPI and ESSDAI,and positively correlated with complement C4.The proportion of CD161+CD56+NK cells in pSS patients with decayed tooth, fatigue, arthralgia, skin involvement, primary biliary cirrhosis(PBC),interstitial lung disease(ILD), anti-SSA/Ro60 positive, anti-SSB positive and high IgG was lower than that in negative patients. Furthermore, compared with innactive patients,the proportion of CD161+CD56+NK cells decreased obviously in active patients. The area under the curve(AUC)was 0.7375(P=0.0016),the results indicated that CD161+CD56+NK cells had certain diagnostic value for pSS. Conclusion: This study suggested that the proportion of CD56+NK cells and CD161+CD56+NK cells decreased significantly in pSS patients,and the proportion of CD161+CD56+NK cells negatively associated with the clinical features and disease activity of pSS patients. The CD161+CD56+NK cells may present as a potential target for therapy and a biomarker of disease activity in pSS .

The redox environment between intracellular compartments and extracellular matrix is significantly different, and the cellular redox homeostasis determines many physiological functions. Here, redox‐responsive nanoparticles with aggregation‐induced emission (AIE) characteristic for fluorescence imaging are developed by encapsulation of fluorophore with redox “turn‐on” AIE characteristic, TPE‐MI, into the micelles of poly(ethylene glycol) (PEG)‐ and cholesterol (CE)‐conjugated disulfide containing poly(amido amine)s. The redox‐responsive fluorescence profiles of the nanoparticles are investigated after reaction with glutathione (GSH). The encapsulation of TPE‐MI in micelles leads to a higher efficiency and red shift in emission, and the fluorescence intensity of the nanoparticles increases with the concentration of GSH. Confocal microscopy imaging shows that the nanoparticles can provide obvious contrast between the intracellular compartments and the extracellular matrix in MCF‐7 and HepG2 cells. So the nanoparticles with PEG shells and low cytotoxicity are promising to provide fluorescence bioimaging with a high contrast and for differentiation of cellular redox environment.

Abstract The oxidative doping of single poly( N ‐vinylcarbazole) (PVK) nanoparticles is reported in aqueous sodium perchlorate using the nanoimpact method. Complete oxidative doping of single PVK nanoparticles with a size of approximately 120 nm is demonstrated, showing for the first time a simple strategy to synthesize and characterize doped polymeric nanoparticles at the single nanoparticle level.

In order to solve the problem of low sensitivity and poor selectivity in biochemical sensing using terahertz technology, a new sensing scheme based on photonic crystal cavity structure is proposed. It is composed of two identical photonic crystal slabs, each of which consists of a square lattice of silicon-based cylindrical pillars on a silicon substrate. The geometric parameters of the cavity are optimized to obtain a guided resonance peak at 529.2 GHz with a high quality factor of 529. The detected object is located in the middle of cavity where the electric field is strongly localized and confined. The effective detection of lactose with only a few microns thick is taken as an example to demonstrate the sensing performance of this cavity. A distinct decrease in transmittance at resonance peak is observed. The sensitivity using our proposed cavity is 31 times higher than that of using a substrate. Moreover, the selectivity of this photonic crystal cavity for the target is also verified by using fructose as the non-target. These results show that the photonic crystal cavity has potential to be applied for fingerprint detection with high sensitivity as well as selectivity in terahertz sensing.

The dependence of electrooxidation on experimental conditions of organic molecules was investigated to optimize the production of hydrogen from potential wastewater sources using low voltage sources (∼1 V dc). Electrooxidation on platinum, gold, and stainless steel anodes with hydrogen production on the cathode was investigated using several different organic reductants, including: methanol, ethanol, glycerol, isopropanol, propanal, glycerol, glucose, sucrose, citric acid, and propionic acid. The electrolyte pH was varied from 2 to 12 in a 1 M Na2SO4 supporting solution. At 1 V, glycerol, citric acid, ethanol and methanol were found to yield the highest currents at low pH values (pH 2 and 7) on platinum electrode, glucose on gold electrode at pH 12 in 1 M Na2SO4 solution produced the highest total current density at 1 V with measured Faradaic efficiency for 1 M glucose of 70%. The hydrogen energy production efficiency was 86%. Practical limitations of glucose oxidation at optimum experimental conditions are discussed.

A significant improvement in the stability of high-quality GaN films, for photoelectrochemical hydrogen generation, has been demonstrated using near neutral NaCl(aq) electrolyte instead of conventional acidic HCl(aq). The experimental results conclude that the as-grown surface oxide passivates the surface from corrosion and, therefore, leads to a higher photocurrent. Our result paves the way for the future development of stable hydrogen generation with abundant sea water and high-efficiency III–V compound semiconductors.

Cervical cancer is a multifactorial disease involving a complex interplay between genetic and environmental factors.An important role of HIF-1α in cervical cancer carcinogenesis has been studied by multiple researches.We hypothesized that there is a possible association between HIF-1α gene polymorphisms and the risk of cervical cancer in Chinese women.In a case-control study of 518 cervical cancer patients and 553 cancer-free controls, we genotyped three single-nucleotide polymorphisms (SNPs) (rs11549465, rs11549467 and rs2057482) of HIF-1α using the TaqMan SNP Genotyping Assays and assessed its associations with the cervical cancer risk.Besides, 17 cervical cancer tissues were used to assess the expression of the mature mRNA expression of HIF-1α by real-time quantitative reverse transcription PCR.We found that a significantly increased risk of cervical cancer was associated with the CC genotype of rs2057482 in the 3´-untranslated region (3'-UTR) of HIF-1α (odds ratio (OR), 1.44; 95% confidence interval (CI), 1.11-1.88),compared with the CT/TT genotypes.Moreover, the carriers of CT/TT genotypes had significantly decreased HIF-1α mRNA expression levels compared to those with CC genotype.No association was observed between the two polymorphisms (rs11549465, rs11549467) and cervical cancer risk.So that, our results provided the first insight into rs2057482 polymorphism of in the 3´-untranslated region of HIF-1α contributed to the risk of cervical cancer in a Chinese population and thus may serve as a reliable predictive factor of cervical cancer.

Abstract We report the electrocatalytic dehalogenation of trichloroethylene (TCE) by single soft nanoparticles in the form of Vitamin B 12 ‐containing droplets. We quantify the turnover number of the catalytic reaction at the single soft nanoparticle level. The kinetic data shows that the binding of TCE with the electro‐reduced vitamin in the Co I oxidation state is chemically reversible.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLight scattering of liquids and liquid mixtures. 2. Thermodynamics of benzene-cyclohexane mixturesAbdel-Azim A. Abdel-Azim, Weizhuang Cheng, Mohammad J. El-Hibri, and Petr MunkCite this: J. Phys. Chem. 1988, 92, 9, 2663–2668Publication Date (Print):May 1, 1988Publication History Published online1 May 2002Published inissue 1 May 1988https://doi.org/10.1021/j100320a052RIGHTS & PERMISSIONSArticle Views80Altmetric-Citations21LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (729 KB) Get e-Alerts

A rapid and efficient procedure for allylation and benzylation of aldimines mediated by zinc powder under solvent-free conditions is described. The procedure is operationally simple, higher regioselective, and gives good to excellent yields.

A biodegradable novel polydisulfide MRI contrast agent forming self-assembly in aqueous solution with a low cytotoxicity and a higher<italic>r</italic>₁is promising for producing better MRI imaging with fewer side effects.

Abstract The oxidative doping of single poly( N ‐vinylcarbazole) (PVK) nanoparticles is reported in aqueous sodium perchlorate using the nanoimpact method. Complete oxidative doping of single PVK nanoparticles with a size of approximately 120 nm is demonstrated, showing for the first time a simple strategy to synthesize and characterize doped polymeric nanoparticles at the single nanoparticle level.

Abstract Unambiguous identification of trace amounts of biochemical molecules in a complex background using terahertz spectroscopy is extremely challenging owing to the extremely small absorption cross sections of these molecules in the terahertz regime. Herein, we numerically propose a terahertz nonresonant nano-slits structure that serves as a powerful sensor. The structure exhibits strongly enhanced electric field in the slits (five orders of magnitude), as well as high transmittance over an extra-wide frequency range that covers the characteristic frequencies of most molecules. Fingerprint features of lactose and maltose are clearly detected using this slits structure, indicating that this structure can be used to identify different saccharides without changing its geometrical parameters. The absorption signal strengths of lactose and maltose with a thickness of 200 nm are strongly enhanced by factors of 52.5 and 33.4, respectively. This structure is very sensitive to thin thickness and is suitable for the detection of trace sample, and the lactose thickness can be predicted on the basis of absorption signal strength when the thickness is less than 250 nm. The detection of a mixture of lactose and maltose indicates that this structure can also achieve multi-sensing which is very difficult to realize by using the resonant structures.

Traditional univariate genome-wide association studies generate false positives and negatives due to difficulties distinguishing associated variants from variants with spurious nonzero effects that do not directly influence the trait. Recent efforts have been directed at identifying genes or signaling pathways enriched for mutations in quantitative traits or case-control studies, but these can be computationally costly and hampered by strict model assumptions. Here, we present gene-ε, a new approach for identifying statistical associations between sets of variants and quantitative traits. Our key insight is that enrichment studies on the gene-level are improved when we reformulate the genome-wide SNP-level null hypothesis to identify spurious small-to-intermediate SNP effects and classify them as non-causal. gene-ε efficiently identifies enriched genes under a variety of simulated genetic architectures, achieving greater than a 90% true positive rate at 1% false positive rate for polygenic traits. Lastly, we apply gene-ε to summary statistics derived from six quantitative traits using European-ancestry individuals in the UK Biobank, and identify enriched genes that are in biologically relevant pathways.

Gezuckert: Das im Titel genannte Verfahren zur Parallelanalyse intakter Zelloberflächenglycane (siehe Bild) ist hinsichtlich Empfindlichkeit, Stabilität und Praktikabilität ausgezeichnet. Mit dieser Strategie können die dynamische Variation des Zelloberflächenglycoms analysiert und pathophysiologische Zellprozesse entschlüsselt werden. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide.Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R).In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling.We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels.GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation.GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R-cells.Grb10 overexpression decreased GPC3-promoted cell growth.Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC.

Application of the graphene-based composites in practice was hampered due to the lack of the controllable synthesis strategy. To solve the problem, we envisaged the organic nanodroplets as a nano-reaction environment to obtain the organic nanoframes by photo-polymerization, then to directly graphitize for the graphene-based materials. In such strategy, two-dimensional laminar matrix of graphene nanosheets (2DLMG) was obtained with millimeter-scale surface, which rendered the matrix high electron conductivity. Thanks to the confinement effect of the nanodroplets, the composited materials were homogeneously dispersed in the organic nanoframes. Then, the organic nanoframes converted directly to 2DLMG-based composites after calcination. In this paper, the transformation from organic nanoframes to 2DLMG has been revealed in detail by comprehensive analyses from SEM, XRD and XPS. To demonstrate the versatility of 2DLMG, the superiority in lithium ion battery has been indicated by the high specific capacity (565 mA h g−1), high cycling performance after 500 cycles and the 100% retention capacity in rate measurement. For the synthesis of the composites, Sn nanoparticles and γ-Fe2O3 nanoparticles were distributed in 2DLMG without the aggregation with high loading. The proposed organic molecule confinement reaction strategy was expected to point out a promising direction for the preparation of graphene-based materials.

Variability exists in the trajectories of Alzheimer's disease (AD). We aimed to identify genetic modulators of clinical progression in AD.We conducted the first genome-wide survival study on AD using a two-stage approach. The discovery and replication stage separately included 1158 and 211,817 individuals without dementia from the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, respectively (325 and 1103 progressed in average follow-up of 4.33 and 8.63 years, respectively). Cox proportional hazards models were applied with time to AD dementia as the phenotype of clinical progression. A series of bioinformatic analyses and functional experiments was performed to validate the novel findings.We found that APOE and PARL, a novel locus tagged by rs6795172 (hazard ratio = 1.66, p = 1.45 × 10-9), were significantly associated with AD clinical progression and were successfully replicated. The novel locus was linked to accelerated cognitive changes, higher tau levels, and faster atrophy of AD-specific brain structures, which were also verified in UK Biobank neuroimaging follow-up. Gene analysis and summary data-based Mendelian randomization indicated PARL as the most functionally relevant gene in the locus. Expression quantitative trait locus analyses and dual-luciferase reporter assays confirmed that PARL expression could be regulated by rs6795172. Three different AD mouse models consistently showed decreased PARL expression accompanied by elevated tau levels, and in vitro experiments revealed that knockdown/overexpression of PARL inversely changed tau levels.Collectively, genetic, bioinformatic, and functional evidence suggests that PARL modulates clinical progression and neurodegeneration in AD. Targeting PARL may potentially modify AD progression and have implications for disease-modifying therapies.

Background Internalising disorders are highly prevalent emotional dysregulations during preadolescence but clinical decision-making is hampered by high heterogeneity. During this period impulsivity represents a major risk factor for psychopathological trajectories and may act on this heterogeneity given the controversial anxiety–impulsivity relationships. However, how impulsivity contributes to the heterogeneous symptomatology, neurobiology, neurocognition and clinical trajectories in preadolescent internalising disorders remains unclear. Aims The aim was to determine impulsivity-dependent subtypes in preadolescent internalising disorders that demonstrate distinct anxiety–impulsivity relationships, neurobiological, genetic, cognitive and clinical trajectory signatures. Method We applied a data-driven strategy to determine impulsivity-related subtypes in 2430 preadolescents with internalising disorders from the Adolescent Brain Cognitive Development study. Cross-sectional and longitudinal analyses were employed to examine subtype-specific signatures of the anxiety–impulsivity relationship, brain morphology, cognition and clinical trajectory from age 10 to 12 years. Results We identified two distinct subtypes of patients who internalise with comparably high anxiety yet distinguishable levels of impulsivity, i.e. enhanced (subtype 1) or decreased (subtype 2) compared with control participants. The two subtypes exhibited opposing anxiety–impulsivity relationships: higher anxiety at baseline was associated with higher lack of perseverance in subtype 1 but lower sensation seeking in subtype 2 at baseline/follow-up. Subtype 1 demonstrated thicker prefrontal and temporal cortices, and genes enriched in immune-related diseases and glutamatergic and GABAergic neurons. Subtype 1 exhibited cognitive deficits and a detrimental trajectory characterised by increasing emotional/behavioural dysregulations and suicide risks during follow-up. Conclusions Our results indicate impulsivity-dependent subtypes in preadolescent internalising disorders and unify past controversies about the anxiety–impulsivity interaction. Clinically, individuals with a high-impulsivity subtype exhibit a detrimental trajectory, thus early interventions are warranted.

AbstractThis article studies the inference of the regression coefficient matrix under multivariate response linear regressions in the presence of hidden variables. A novel procedure for constructing confidence intervals of entries of the coefficient matrix is proposed. Our method first uses the multivariate nature of the responses by estimating and adjusting the hidden effect to construct an initial estimator of the coefficient matrix. By further deploying a low-dimensional projection procedure to reduce the bias introduced by the regularization in the previous step, a refined estimator is proposed and shown to be asymptotically normal. The asymptotic variance of the resulting estimator is derived with closed-form expression and can be consistently estimated. In addition, we propose a testing procedure for the existence of hidden effects and provide its theoretical justification. Both our procedures and their analyses are valid even when the feature dimension and the number of responses exceed the sample size. Our results are further backed up via extensive simulations and a real data analysis. Supplementary materials for this article are available online.KEYWORDS: Confidence intervalsConfoundingHidden variablesHigh-dimensional regressionHypothesis testingMultivariate response regressionSurrogate variable analysis Supplementary MaterialsThe supplement contains the rate of maxj‖XF̂j−XFj‖2, the statement of asymptotic normality of multiple components of Θ˜−Θ and all the proofs.AcknowledgmentsThe authors would like to thank the Associate Editor and two reviewers for their insightful comments which have improved the manuscript substantially.Disclosure StatementThe authors report there are no competing interests to declare.Notes1 A centered random vector X∈Rd is γ sub-Gaussian if E[exp (〈u,X〉)]≤ exp (‖u‖22γ2/2) for any u∈Rd.2 If DK is not invertible, we use its Moore-Penrose inverse instead.3 Since Guo, Ćevid, and Bühlmann (Citation2020) only provides guarantees of DDL for large p, we compare with DDL in the high-dimensional scenarios. Also due to the long running time of DDL, we only report its results for m=20 and p = 500.Additional informationFundingNing was supported by the NSF grant CAREER Award DMS-1941945 and DMS-2311291, and NIH 1RF1AG077820-01A1. Bing was partially supported by a discovery grant from the Natural Sciences and Engineering Research Council of Canada.

An efficient electroselective α-deuteration of amides was realized via H–D exchange under mild neutral conditions. Its utility has been well exemplified in the late-stage modification of drug molecules and transformation to β-bisdeuterated amines.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLight scattering of liquids and liquid mixtures. 3. Thermodynamic interaction data for selected binary mixturesWeizhuang Cheng, Abdel Azim A. Abdel-Azim, Mohammad J. El-Hibri, Qiangguo Du, and Petr MunkCite this: J. Phys. Chem. 1989, 93, 25, 8248–8253Publication Date (Print):December 1, 1989Publication History Published online1 May 2002Published inissue 1 December 1989https://doi.org/10.1021/j100362a020RIGHTS & PERMISSIONSArticle Views62Altmetric-Citations17LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (617 KB) Get e-Alerts

Abstract We report the detection and characterisation of polymer nanoparticles using electrochemistry using poly( N ‐vinylcarbazole) nanoparticles (PVK NPs) as a model system. These were synthesised using the reprecipitation method. The number of electrons ( n =2) transferred per PVK monomer was characterised by drop‐casting method. Sticking and sensing experiments were then conducted, which involve PVK nanoparticle immobilisation on the electrode surface and subsequent oxidative sensing, to enable rapid detection of polymer nanoparticles in aqueous solution. It is shown for the first time, that using this “stick and sense” method, polymer nanoparticles in aqueous solution can be immobilised, preconcentrated and quantified.

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).