Yi Liu

The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the ‘cancerous’ translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted. Ribosome profiling reveals specialized translation of the prostate cancer genome by oncogenic mTOR signalling; stringent inhibition of mTOR signalling reduces prostate cancer invasion and metastasis in a mouse model. The mTOR pathway is important in the regulation of protein synthesis and is activated in many human cancers. Two papers in this issue of Nature use ribosome profiling to study the control of messenger RNA translation by mTOR signalling. Hsieh et al. find that in prostate cancer cells and mouse prostate tumours, the translation of several genes involved in cancer invasion is regulated by mTOR by means of the 4EBP1 translational repressor. The experimental drug INK128, currently in clinical trials in people with prostate cancer, inhibits mTOR signalling and reduces the progression of prostate cancers to invasive carcinomas in a mouse model. Thoreen et al. show that through the 4E-BP protein family, the mTORC1 kinase recognizes and regulates a subset of mRNAs with an oligopyrimidine motif at the 5′ end.

Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Two dimensional (2D) materials with a monolayer of atoms represent an ultimate control of material dimension in the vertical direction. Molybdenum sulfide (MoS2) monolayers, with a direct bandgap of 1.8 eV, offer an unprecedented prospect of miniaturizing semiconductor science and technology down to a truly atomic scale. Recent studies have indeed demonstrated the promise of 2D MoS2 in fields including field effect transistors, low power switches, optoelectronics, and spintronics. However, device development with 2D MoS2 has been delayed by the lack of capabilities to produce large-area, uniform, and high-quality MoS2 monolayers. Here we present a self-limiting approach that can grow high quality monolayer and few-layer MoS2 films over an area of centimeters with unprecedented uniformity and controllability. This approach is compatible with the standard fabrication process in semiconductor industry. It paves the way for the development of practical devices with 2D MoS2 and opens up new avenues for fundamental research.

The prognostic value of FoxP3(+) regulatory T cells (Tregs) in cancer remains controversial. We did a meta-analysis to assess the prognostic effect of FoxP3(+) Treg across different types of cancer and to investigate factors associated with variations in this effect. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched to identify eligible studies. In total, we analyzed 76 articles encompassing 17 types of cancer, and including 15,512 cancer cases. The overall pooled analysis including all types of cancer suggested FoxP3(+)Tregs had a significant negative effect on overall survival (OS) (OR 1.46, P < 0.001), but the prognostic effect varied greatly according to tumor site. High FoxP3(+) Tregs infiltration was significantly associated with shorter OS in the majority of solid tumors studied, including cervical, renal, melanomas, and breast cancers, et al; whereas, FoxP3(+) Tregs were associated with improved survival in colorectal, head and neck, and oesophageal cancers. The stratified analysis suggested the molecular subtype and tumor stage significantly influenced the prognostic value of FoxP3(+) Tregs in certain types of cancer. In conclusion, our meta-analysis suggests that the prognostic role of FoxP3(+) Tregs was highly influenced by tumor site, and was also correlated with the molecular subtype and tumor stage.

While convenient solution-based procedures have been realized for the synthesis of colloidal perovskite nanocrystals, the impact of surfactant ligands on the shape, size, and surface properties still remains poorly understood, which calls for a more detailed structure–morphology study. Herein we have systematically varied the hydrocarbon chain composition of carboxylic acids and amines to investigate the surface chemistry and the independent impact of acid and amine on the size and shape of perovskite nanocrystals. Solution phase studies on purified nanocrystal samples by 1H NMR and IR spectroscopies have confirmed the presence of both carboxylate and alkylammonium ligands on surfaces, with the alkylammonium ligand being much more mobile and susceptible to detachment from the nanocrystal surfaces during polar solvent washes. Moreover, the chain length variation of carboxylic acids and amines, ranging from 18 carbons down to two carbons, has shown independent correlation to the size and shape of nanocrystals in addition to the temperature effect. We have additionally demonstrated that employing a more soluble cesium acetate precursor in place of the universally used Cs2CO3 results in enhanced processability without sacrificing optical properties, thus offering a more versatile recipe for perovskite nanocrystal synthesis that allows the use of organic acids and amines bearing chains shorter than eight carbon atoms. Overall our studies have shed light on the influence of ligand chemistry on crystal growth and stabilization of the nanocrystals, which opens the door to functionalizable perovskite nanocrsytals through surface ligand manipulation.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. To comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, we employed single-cell RNA-seq (scRNA-seq) to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases, and identified diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, in PDAC. We found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, we found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, our findings provide a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response3,4. Here we show that durable neoantigen-specific immunity is regulated by mRNA N6-methyadenosine (m6A) methylation through the m6A-binding protein YTHDF15. In contrast to wild-type mice, Ythdf1-deficient mice show an elevated antigen-specific CD8+ T cell antitumour response. Loss of YTHDF1 in classical dendritic cells enhanced the cross-presentation of tumour antigens and the cross-priming of CD8+ T cells in vivo. Mechanistically, transcripts encoding lysosomal proteases are marked by m6A and recognized by YTHDF1. Binding of YTHDF1 to these transcripts increases the translation of lysosomal cathepsins in dendritic cells, and inhibition of cathepsins markedly enhances cross-presentation of wild-type dendritic cells. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1−/− mice, implicating YTHDF1 as a potential therapeutic target in anticancer immunotherapy. The m6A reader protein YTHDF1 suppresses the clearance of tumour cells by enhancing the translation of lysosomal proteases in dendritic cells and thereby suppressing tumour antigen presentation.

Thermosensation is an essential sensory function that is subserved by a variety of transducer molecules, including those from the Transient Receptor Potential (TRP) ion channel superfamily. One of its members, TRPM8 (CMR1), a ligand-gated, nonselective cation channel, is activated by both cold and chemical stimuli in vitro. However, its roles in cold thermosensation and pain in vivo have not been fully elucidated. Here, we show that sensory neurons derived from TRPM8 null mice lack detectable levels of TRPM8 mRNA and protein and that the number of these neurons responding to cold (18 degrees C) and menthol (100 microM) is greatly decreased. Furthermore, compared with WT mice, TRPM8 null mice display deficiencies in certain behaviors, including icilin-induced jumping and cold sensation, as well as a significant reduction in injury-induced responsiveness to acetone cooling. These results suggest that TRPM8 may play an important role in certain types of cold-induced pain in humans.

Abstract Building on economic and social exchange theories, this study investigates the different roles transactional and relational mechanisms have in hindering opportunism and improving relationship performance in an emerging economy. Our study applied to manufacturer–distributor dyads in China and used matched survey data (225 paired sample firms) to test our hypotheses. Our hierarchical multivariate regression and semipartial correlation analyses suggest that transactional mechanisms are more effective in restraining opportunism while relational mechanisms are more powerful in improving relationship performance. This performance is improved more significantly when both contracts and relational norms are used jointly than when used separately. Likewise, opportunism is curbed more effectively when both contracts and trust are used jointly than when used individually.

Some clinical case reports have shown that immature permanent teeth with periradicular periodontitis or abscess can undergo apexogenesis after conservative endodontic treatment. A call for a paradigm shift and new protocol for the clinical management of these cases has been brought to attention. Concomitantly, a new population of mesenchymal stem cells residing in the apical papilla of permanent immature teeth recently has been discovered and was termed stem cells from the apical papilla (SCAP). These stem cells appear to be the source of odontoblasts that are responsible for the formation of root dentin. Conservation of these stem cells when treating immature teeth may allow continuous formation of the root to completion. This article reviews current findings on the isolation and characterization of these stem cells. The potential role of these stem cells in the following respects will be discussed: (1) their contribution in continued root maturation in endodontically treated immature teeth with periradicular periodontitis or abscess and (2) their potential utilization for pulp/dentin regeneration and bioroot engineering.

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogen and nutrient signals to control cell proliferation and cell size. Hence, mTORC1 is implicated in a large number of human diseases--including diabetes, obesity, heart disease, and cancer--that are characterized by aberrant cell growth and proliferation. Although eukaryotic translation initiation factor 4E-binding proteins (4E-BPs) are critical mediators of mTORC1 function, their precise contribution to mTORC1 signaling and the mechanisms by which they mediate mTORC1 function have remained unclear. We inhibited the mTORC1 pathway in cells lacking 4E-BPs and analyzed the effects on cell size, cell proliferation, and cell cycle progression. Although the 4E-BPs had no effect on cell size, they inhibited cell proliferation by selectively inhibiting the translation of messenger RNAs that encode proliferation-promoting proteins and proteins involved in cell cycle progression. Thus, control of cell size and cell cycle progression appear to be independent in mammalian cells, whereas in lower eukaryotes, 4E-BPs influence both cell growth and proliferation.

Two switchable, palindromically constituted bistable [3]rotaxanes have been designed and synthesized with a pair of mechanically mobile rings encircling a single dumbbell. These designs are reminiscent of a “molecular muscle” for the purposes of amplifying and harnessing molecular mechanical motions. The location of the two cyclobis(paraquat-p-phenylene) (CBPQT4+) rings can be controlled to be on either tetrathiafulvalene (TTF) or naphthalene (NP) stations, either chemically (1H NMR spectroscopy) or electrochemically (cyclic voltammetry), such that switching of inter-ring distances from 4.2 to 1.4 nm mimics the contraction and extension of skeletal muscle, albeit on a shorter length scale. Fast scan-rate cyclic voltammetry at low temperatures reveals stepwise oxidations and movements of one-half of the [3]rotaxane and then of the other, a process that appears to be concerted at room temperature. The active form of the bistable [3]rotaxane bears disulfide tethers attached covalently to both of the CBPQT4+ ring components for the purpose of its self-assembly onto a gold surface. An array of flexible microcantilever beams, each coated on one side with a monolayer of 6 billion of the active bistable [3]rotaxane molecules, undergoes controllable and reversible bending up and down when it is exposed to the synchronous addition of aqueous chemical oxidants and reductants. The beam bending is correlated with flexing of the surface-bound molecular muscles, whereas a monolayer of the dumbbell alone is inactive under the same conditions. This observation supports the hypothesis that the cumulative nanoscale movements within surface-bound “molecular muscles” can be harnessed to perform larger-scale mechanical work.

T-cell receptor (TCR) diversity, a prerequisite for immune system recognition of the universe of foreign antigens, is generated in the first two decades of life in the thymus and then persists to an unknown extent through life via homeostatic proliferation of naïve T cells. We have used next-generation sequencing and nonparametric statistical analysis to estimate a lower bound for the total number of different TCR beta (TCRB) sequences in human repertoires. We arrived at surprisingly high minimal estimates of 100 million unique TCRB sequences in naïve CD4 and CD8 T-cell repertoires of young adults. Naïve repertoire richness modestly declined two- to fivefold in healthy elderly. Repertoire richness contraction with age was even less pronounced for memory CD4 and CD8 T cells. In contrast, age had a major impact on the inequality of clonal sizes, as estimated by a modified Gini-Simpson index clonality score. In particular, large naïve T-cell clones that were distinct from memory clones were found in the repertoires of elderly individuals, indicating uneven homeostatic proliferation without development of a memory cell phenotype. Our results suggest that a highly diverse repertoire is maintained despite thymic involution; however, peripheral fitness selection of T cells leads to repertoire perturbations that can influence the immune response in the elderly.

The interaction between monoammonium glycyrrhizinate (MAG) and bovine serum albumin (BSA) were studied by fluorescence and absorption spectroscopy. The quenching mechanism of fluorescence of bovine serum albumin by monoammonium glycyrrhizinate was discussed. The binding sites number n and apparent binding constant K were measured by fluorescence quenching method. The thermodynamic parameters DeltaH degrees , DeltaG degrees , DeltaS degrees at different temperatures were calculated. The distance r between donor (bovine serum albumin) and acceptor (monoammonium glycyrrhizinate) was obtained according to Forster theory of non-radiation energy transfer. The results of synchronous fluorescence spectra and UV-vis absorption spectra show that the conformation of bovine serum albumin has been changed.

Abstract KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRASG12C that inhibits mutant KRAS–driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry–based assay for assessing KRAS activation status, we show that the nucleotide state of KRASG12C is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRASG12C mutation generates a “hyperexcitable” rather than a “statically active” state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. Significance: A cell-active, mutant-specific, covalent inhibitor of KRASG12C is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRASG12C oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state. Cancer Discov; 6(3); 316–29. ©2016 AACR. See related commentary by Westover et al., p. 233. This article is highlighted in the In This Issue feature, p. 217

Chitosan samples with different molecular weights were prepared by depolymerization with hemicellusase, and water-soluble half N-acetylated chitosan samples were obtained by N-acetylation with acetic anhydride. The action of chitosans with molecular weights Mw from 1.4×103 to 4.0×105 on the growth of Staphylococcus aureus, Escherichia coli and Candida albicans was explored by microcalorimetry. The water-soluble half N-acetylated chitosans and chitooligomers had no significant antimicrobial activity. Moreover, water-soluble chitosans and chitooligomers promoted the growth of C. albicans. In contrast, water-insoluble chitosan in acidic medium exhibited inhibitory effect against these microorganisms. The water-insoluble chitosans with Mw around 5×104 were the optimum for antimicrobial action in these tested samples. The antimicrobial mechanism of dissolved water-insoluble chitosan was hypothesized as forming an impervious layer around the cell. The results suggest that optimum chitosan as food preservative should be water-insoluble chitosan from mild depolymerization of native chitosan.

Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.

The effects of transformational leadership on the outcomes of specific change initiatives are not well understood. Conversely, organizational change studies have examined leader behaviors during specific change implementations yet have failed to link these to broader leadership theories. In this study, the authors investigate the relationship between transformational and change leadership and followers' commitment to a particular change initiative as a function of the personal impact of the changes. Transformational leadership was found to be more strongly related to followers' change commitment than change-specific leadership practices, especially when the change had significant personal impact. For leaders who were not viewed as transformational, good change-management practices were found to be associated with higher levels of change commitment.

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Abstract Glucose is a key energy supplier and nutrient for tumor growth. Herein, inspired by the glucose oxidase (GOx)‐assisted conversion of glucose into gluconic acid and toxic H 2 O 2 , a novel treatment paradigm of starving‐like therapy is developed for significant tumor‐killing effects, more effective than conventional starving therapy by only cutting off the energy supply. Furthermore, the generated acidic H 2 O 2 can oxidize l ‐Arginine ( l ‐Arg) into NO for enhanced gas therapy. By using hollow mesoporous organosilica nanoparticle (HMON) as a biocompatible/biodegradable nanocarrier for the co‐delivery of GOx and l ‐Arg, a novel glucose‐responsive nanomedicine ( l ‐Arg‐HMON‐GOx) has been for the first time constructed for synergistic cancer starving‐like/gas therapy without the need of external excitation, which yields a remarkable H 2 O 2 –NO cooperative anticancer effect with minimal adverse effect.

Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection into mice, the protein induced rapid onset of crypt cell proliferation involving beta-catenin stabilization, possibly by a process that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced intestinal mucositis and may have therapeutic application in gastrointestinal diseases.

Periodontitis is a periodontal tissue infectious disease and the most common cause for tooth loss in adults. It has been linked to many systemic disorders, such as coronary artery disease, stroke, and diabetes. At present, there is no ideal therapeutic approach to cure periodontitis and achieve optimal periodontal tissue regeneration. In this study, we explored the potential of using autologous periodontal ligament stem cells (PDLSCs) to treat periodontal defects in a porcine model of periodontitis. The periodontal lesion was generated in the first molars area of miniature pigs by the surgical removal of bone and subsequent silk ligament suture around the cervical portion of the tooth. Autologous PDLSCs were obtained from extracted teeth of the miniature pigs and then expanded ex vivo to enrich PDLSC numbers. When transplanted into the surgically created periodontal defect areas, PDLSCs were capable of regenerating periodontal tissues, leading to a favorable treatment for periodontitis. This study demonstrates the feasibility of using stem cell-mediated tissue engineering to treat periodontal diseases.

CsPbX3 (X = Cl, Br, I) perovskite quantum dots (QDs) are potential emitting materials for illumination and display applications, but toxic Pb is not environment- and user-friendly. In this work, we demonstrate the partial replacement of Pb with Mn through phosphine-free hot-injection preparation of CsPbxMn1-xCl3 QDs in colloidal solution. The Mn substitution ratio is up to 46%, and the as-prepared QDs maintain the tetragonal crystalline structure of the CsPbCl3 host. Meaningfully, Mn substitution greatly enhances the photoluminescence quantum yields of CsPbCl3 from 5 to 54%. The enhanced emission is attributed to the energy transfer of photoinduced excitons from the CsPbCl3 host to the doped Mn, which facilitates exciton recombination via a radiative pathway. The intensity and position of this Mn-related emission are also tunable by altering the experimental parameters, such as reaction temperature and the Pb-to-Mn feed ratio. A light-emitting diode (LED) prototype is further fabricated by employing the as-prepared CsPbxMn1-xCl3 QDs as color conversion materials on a commercially available 365 nm GaN LED chip.

During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha, encoded by Ppargc1a) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.

In the fungus Neurospora crassa , the blue light photoreceptor(s) and signaling pathway(s) have not been identified. We examined light signaling by exploiting the light sensitivity of the Neurospora biological clock, specifically the rapid induction by light of the clock component frequency ( frq ). Light induction of frq is transcriptionally controlled and requires two cis-acting elements (LREs) in the frq promoter. Both LREs are bound by a White Collar–1 (WC-1)/White Collar–2 (WC-2)–containing complex (WCC), and light causes decreased mobility of the WCC bound to the LREs. The use of in vitro–translated WC-1 and WC-2 confirmed that WC-1, with flavin adenine dinucleotide as a cofactor, is the blue light photoreceptor that mediates light input to the circadian system through direct binding (with WC-2) to the frq promoter.

Abstract Data generated by genome-wide association studies (GWAS) are growing fast with the linkage of biobank samples to health records, and expanding capture of high-dimensional molecular phenotypes. However the utility of these efforts can only be fully realised if their complete results are collected from their heterogeneous sources and formats, harmonised and made programmatically accessible. Here we present the OpenGWAS database, an open source, open access, scalable and high-performance cloud-based data infrastructure that imports and publishes complete GWAS summary datasets and metadata for the scientific community. Our import pipeline harmonises these datasets against dbSNP and the human genome reference sequence, generates summary reports and standardises the format of results and metadata. Users can access the data via a website, an application programming interface, R and Python packages, and also as downloadable files that can be rapidly queried in high performance computing environments. OpenGWAS currently contains 126 billion genetic associations from 14,582 complete GWAS datasets representing a range of different human phenotypes and disease outcomes across different populations. We developed R and Python packages to serve as conduits between these GWAS data sources and a range of available analytical tools, enabling Mendelian randomization, genetic colocalisation analysis, fine mapping, genetic correlation and locus visualisation. OpenGWAS is freely accessible at https://gwas.mrcieu.ac.uk , and has been designed to facilitate integration with third party analytical tools.

During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes.

Codon usage bias is a universal feature of eukaryotic and prokaryotic genomes and has been proposed to regulate translation efficiency, accuracy, and protein folding based on the assumption that codon usage affects translation dynamics. The roles of codon usage in translation, however, are not clear and have been challenged by recent ribosome profiling studies. Here we used a Neurospora cell-free translation system to directly monitor the velocity of mRNA translation. We demonstrated that the preferred codons enhance the rate of translation elongation, whereas non-optimal codons slow elongation. Codon usage also controls ribosome traffic on mRNA. These conclusions were supported by ribosome profiling results in vitro and in vivo with template mRNAs designed to increase the signal-to-noise ratio. Finally, we demonstrate that codon usage regulates protein function by affecting co-translational protein folding. These results resolve a long-standing fundamental question and suggest the existence of a codon usage code for protein folding.

Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro . These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that ∼7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons.

Voltage-activated K+ channels are integral membrane proteins that open or close a K(+)-selective pore in response to changes in transmembrane voltage. Although the S4 region of these channels has been implicated as the voltage sensor, little is known about how opening and closing of the pore is accomplished. We explored the gating process by introducing cysteines at various positions thought to lie in or near the pore of the Shaker K+ channel, and by testing their ability to be chemically modified. We found a series of positions in the S6 transmembrane region that react rapidly with water-soluble thiol reagents in the open state but not the closed state. An open-channel blocker can protect several of these cysteines, showing that they lie in the ion-conducting pore. At two of these sites, Cd2+ ions bind to the cysteines without affecting the energetics of gating; at a third site, Cd2+ binding holds the channel open. The results suggest that these channels open and close by the movement of an intracellular gate, distinct from the selectivity filter, that regulates access to the pore.

We present the cloning and characterization of two novel calcium-activated potassium channel β subunits, hKCNMB3 and hKCNMB4, that are enriched in the testis and brain, respectively. We compare and contrast the steady state and kinetic properties of these β subunits with the previously cloned mouse β1 (mKCNMB1) and the human β2 subunit (hKCNMB2). Once inactivation is removed, we find that hKCNMB2 has properties similar to mKCNMB1. hKCNMB2 slows<i>Hslo1</i> channel gating and shifts the current-voltage relationship to more negative potentials. hKCNMB3 and hKCNMB4 have distinct effects on <i>slo</i> currents not observed with mKCNMB1 and hKCNMB2. Although we found that hKCNMB3 does interact with Hslo channels, its effects on <i>Hslo1</i> channel properties were slight, increasing <i>Hslo1</i> activation rates. In contrast, hKCNMB4 slows <i>Hslo1</i> gating kinetics, and modulates the apparent calcium sensitivity of <i>Hslo1</i>. We found that the different effects of the β subunits on some <i>Hslo1</i> channel properties are calcium-dependent. mKCNMB1 and hKCNMB2 slow activation at 1 μm but not at 10 μm free calcium concentrations. hKCNMB4 decreases <i>Hslo1</i> channel openings at low calcium concentrations but increases channel openings at high calcium concentrations. These results suggest that β subunits in diverse tissue types fine-tune <i>slo</i> channel properties to the needs of a particular cell.

Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na(v)1.8 have shown that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na(v)1.8 (IC(50) = 8 nM) and was >100-fold selective vs. human Na(v)1.2, Na(v)1.3, Na(v)1.5, and Na(v)1.7 (IC(50) values >or=1 microM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

Cisplatin-based chemotherapy is frequently used to treat advanced gastric cancer (GC). However, the resistance often occurs with the mechanisms being not well understood. Recently, emerging evidence indicates that tumor-associated macrophages (TAMs) play an important role in chemoresistance of cancer. As the important mediators in intercellular communications, exosomes secreted by host cells mediate the exchange of genetic materials and proteins to be involved in tumor aggressiveness. The aim of the study was to investigate whether exosomes derived from TAMs mediate cisplatin resistance in gastric cancer. M2 polarized macrophages were obtained from mouse bone marrow or human PBMCs stimulated with IL-4 and IL-13. Exosomes isolated from M2 macrophages culture medium were characterized, and miRNA expression profiles of M2 derived exosomes (M2-exos) were analyzed using miRNA microarray. In vitro cell coculture was further conducted to investigate M2-exos mediated crosstalk between TAMs and tumor cells. Moreover, the in vivo experiments were performed using a subcutaneous transplantation tumor model in athymic nude mice. In this study, we showed that M2 polarized macrophages promoted cisplatin (DDP) resistance in gastric cancer cells and exosomes derived from M2 macrophages (M2-exos) are involved in mediating the resistance to DDP. Using miRNA profiles assay, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and cell lysate isolated from M2 polarized macrophage. Functional studies revealed that exosomal miR-21 can be directly transferred from macrophages to the gastric cancer cells, where it suppresses cell apoptosis and enhances activation of PI3K/AKT signaling pathway by down-regulation of PTEN. Our findings suggest that exosomal transfer of tumor-associated macrophages derived miR-21 confer DDP resistance in gastric cancer, and targeting exosome communication may be a promising new therapeutic strategy for gastric cancer patients.

In everyday life, a macroscopic valve is a device with a movable control element that regulates the flow of gases or liquids by blocking and opening passageways. Construction of such a device on the nanoscale level requires (i) suitably proportioned movable control elements, (ii) a method for operating them on demand, and (iii) appropriately sized passageways. These three conditions can be fulfilled by attaching organic, mechanically interlocked, linear motor molecules that can be operated under chemical, electrical, or optical stimuli to stable inorganic porous frameworks (i.e., by self-assembling organic machinery on top of an inorganic chassis). In this article, we demonstrate a reversibly operating nanovalve that can be turned on and off by redox chemistry. It traps and releases molecules from a maze of nanoscopic passageways in silica by controlling the operation of redox-activated bistable [2]rotaxane molecules tethered to the openings of nanopores leading out of a nanoscale reservoir.

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

With prolonged stimulation, voltage-activated K+ channels close by a gating process called inactivation. This inactivation gating can occur by two distinct molecular mechanisms: N-type, in which a tethered particle blocks the intracellular mouth of the pore, and C-type, which involves a closure of the external mouth. The functional motion involved in C-type inactivation was studied by introducing cysteine residues at the outer mouth of Shaker K+ channels through mutagenesis, and by measuring state-dependent changes in accessibility to chemical modification. Modification of three adjacent residues in the outer mouth was 130-10,000-fold faster in the C-type inactivated state than in the closed state. At one position, state-dependent bridging or crosslinking between subunits was also possible. These results give a consistent picture in which C-type inactivation promotes a local rearrangement and constriction of the channel at the outer mouth.

Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499.Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Pd has been the focus of recent research for Pt-alternative catalysts for the oxygen reduction reaction (ORR). It has been found that upon appropriate modification of its electronic structure, the catalytic activity of Pd can become comparable to that of Pt. However, the structure-activity relationships of Pd catalysts have hitherto not been well studied or understood. In the present work, we report a new finding that there is a strong dependence of the activity of Pd toward the ORR on its morphology. By simply adjusting the precursor concentration in the electrochemical deposition of Pd, we are able to tailor the morphology of the deposited Pd from nanoparticles to nanorods. Surprisingly, the surface-specific activity of Pd nanorods (Pd-NRs) toward the ORR was found to be not only 10-fold higher than that of Pd nanoparticles (Pd-NPs), the conventional shape of electrocatalysts, but also comparable to that of Pt at operating potentials of fuel cell cathodes. The morphology-activity relationships of Pd-NRs were further studied through a combination of electrochemical experiments and density functional theory (DFT) calculations. As revealed by its characteristic profile for CO stripping, the morphology of Pd-NRs features the exposure of Pd(110) facets, which exhibit superior ORR activity. The underlying mechanism, indicated by DFT calculations, could be ascribed to the exceptionally weak interaction between an O adatom and a Pd(110) facet. This finding furthers our understanding of Pd catalysis and casts a new light on the relevant catalyst design criteria.

The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivation-like mechanism. We hypothesized that the compounds target Glut1 and are efficacious in vivo as anticancer agents. Here, we report that a novel representative compound WZB117 not only inhibited cell growth in cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal injection of WZB117 at 10 mg/kg resulted in a more than 70% reduction in the size of human lung cancer of A549 cell origin. Mechanism studies showed that WZB117 inhibited glucose transport in human red blood cells (RBC), which express Glut1 as their sole glucose transporter. Cancer cell treatment with WZB117 led to decreases in levels of Glut1 protein, intracellular ATP, and glycolytic enzymes. All these changes were followed by increase in ATP-sensing enzyme AMP-activated protein kinase (AMPK) and declines in cyclin E2 as well as phosphorylated retinoblastoma, resulting in cell-cycle arrest, senescence, and necrosis. Addition of extracellular ATP rescued compound-treated cancer cells, suggesting that the reduction of intracellular ATP plays an important role in the anticancer mechanism of the molecule. Senescence induction and the essential role of ATP were reported for the first time in Glut1 inhibitor-treated cancer cells. Thus, WZB117 is a prototype for further development of anticancer therapeutics targeting Glut1-mediated glucose transport and glucose metabolism.

The interactions of chlorogenic acid and ferulic acid with human serum albumin (HSA) have been investigated by fluorescence and Fourier transformed infrared (FT-IR) spectrometry. Fluorescence results showed that one molecule of protein combined with one molecule of drugs at the molar ratio of drug to HSA ranging from 1 to 10, and their binding affinities (KA) are 4.37 x 10(4) M(-1) and 2.23 x 10(4) M(-1) for chlorogenic acid and ferulic acid, respectively. The primary binding site for chlorogenic acid is most likely located on IIA and that for ferulic acid in IIIA. The main mechanism of protein fluorescence quenching was static quenching process. Combining the curve-fitting results of infrared amide I and amide III bands, the alterations of protein secondary structure after drug complexation were estimated. With increasing the drug concentration, the protein alpha-helix structure decreased gradually and the reduction of protein alpha-helix structure reached about 7% and 5% for protein binding with chlorogenic acid and ferulic acid individually at the drug to protein molar ratio of 30. This indicated a partial unfolding of HSA in the presence of the two acids. From the fluorescence and FT-IR results, the binding mode was discussed.

Structural reforms are currently the key way to achieve emissions reduction targets. A comprehensive investigation of the relationship between structural changes and carbon emissions is essential for further policy formulation. This paper aimed to discuss the impact of structural changes on per capita carbon emissions from the four aspects of energy, trade, society and economy, while considering the effects of economic growth and energy intensity. The ordinary least squares, fully modified ordinary least squares regression analysis and Granger causality test were used to analyze the situation of 147 countries and four income groups from 1990 to 2015. The results showed that at the global level, economic growth and economic structure were respectively the most significant positive and negative factors affecting carbon emissions. There was the bidirectional granger causality relationship between global per capita carbon emissions and economic growth, and between global per capita carbon emissions and economic structure. At the income group level, consistent with the global results, economic growth and energy intensity increase promoted the increase in carbon emissions, whereas increasing renewable energy consumption helped to reduce carbon emissions. The influence direction and degree of the remaining three factors differed among different income groups. In addition, the causal relationships among the variables of the income groups except the low income group were relatively complicated. Finally, policy recommendations were offered to reduce per-capita carbon emission through adjusting economic, energy, social, and trade structure.

In order to boost the low-temperature activity, a series of Mn–Ce/TiO2-X (X = Hk, N1, N2 and N3) were prepared by adopting incipient wetness technique and investigated for the low-temperature selective catalytic reduction (SCR) of NOx with NH3 at industrial relevant conditions. Prior to that, hydrous TiO2-nanosized samples were synthesized by a deposition technique at constant pH kept in the range of 5–8 and constant temperature 30–80 °C. Titanium oxide hydrates (N1, N2, and N3) possess high specific surface area as 620 m2/g, 457 m2/g, 398 m2/g, whereas TiO2 (Hk) preserves 309 m2/g surface area. In our studies, it was found that the NOx conversion over Mn–Ce/TiO2-Hk with the atomic ratio of Mn/Ce = 5.1 was apparently higher compared with that over Mn–Ce(5.1)/TiO2-X (X = N1, N2, and N3). Our activity results showed that 93.0% NOx conversion was obtained over Mn–Ce(5.1)/TiO2-Hk at 100 °C at a space velocity of 80,000 h−1. Our XRD results suggest that the loading of manganese and ceria onto hydrated titania led to the evolution of diffraction peaks which can be attributed to the formation of crystalline manganese dioxide (MnO2). Among all the catalysts, Mn–Ce/TiO2 N2 showed high intensity diffraction peaks at 2θ = 37.2°, which corresponds to the highly crystalline (1 0 1) plane of manganese dioxide. Once the catalysts with the best performance were identified, experiments were performed with the aim of optimizing these formulations with respect to the dopant and Mn/Ce atomic ratio. Both the ceria co-doping and Mn/Ce atomic ratios played a key role to achieve high NOx conversions at 100 °C. The disappearance or low-temperature shift of ceria reduction peak in H2-TPR indicates the increase of active components’ reduction potential, oxygen vacancies, and the existence of surface-capping oxygen species in Mn–Ce/TiO2 (Hk). The H2-TPR results are in good accordance with our XPS analysis where the relative atomic ratios of Mn4+/Mn3+, Ce3+/Ce4+, and the existence of surface oxygen species greatly enhanced in Mn–Ce/TiO2 (Hk) compared to other catalysts in this work. The relative atomic ratio of Mn4+/Mn3+ (2.19) in Mn–Ce(5.1)/TiO2-Hk calculated from deconvoluted XPS spectra is much higher than that of other catalysts (1.90, 0.89, and 2.03 for N1, N2, and N3, respectively). Moreover, the superior ratio of Ce3+/Ce4+ can generate a charge imbalance, oxygen vacancies, and unsaturated chemical bonds over the catalyst surface to promote the oxidation of NO to NO2. It is highly remarkable to note that the deNOx efficiency of all the prepared catalysts is indeed correlated with the surface concentrations of Ce3+/Ce4+ and Mn4+/Mn3+. NH3-TPD results imply that the co-doping of manganese and ceria onto Hk TiO2 can remarkably improve the acid sites distribution and the concentration of acid sites of the Mn–Ce/TiO2 catalyst. Our investigation results illustrate that the enhancement in reduction potential of active components, broadening of acid sites distribution, and the promotion of Mn4+/Mn3+, Ce3+/Ce4+ ratios including surface labile oxygen and small pore openings seem to be the reason for high deNOx efficiency of Mn–Ce/TiO2 (Hk) at low temperatures.

The practical levels of density functional theory (DFT) for solids (LDA, PBE, PW91, B3LYP) are well-known not to account adequately for the London dispersion (van der Waals attraction) so important in molecular solids, leading to equilibrium volumes for molecular crystals ∼10–15% too high. The ReaxFF reactive force field is based on fitting such DFT calculations and suffers from the same problem. In the paper we extend ReaxFF by adding a London dispersion term with a form such that it has low gradients (lg) at valence distances leaving the already optimized valence interactions intact but behaves as 1/R6 for large distances. We derive here these lg corrections to ReaxFF based on the experimental crystal structure data for graphite, polyethylene (PE), carbon dioxide, and nitrogen and for energetic materials: hexahydro-1,3,5-trinitro-1,3,5-s-triazine (RDX), pentaerythritol tetranitrate (PETN), 1,3,5-triamino-2,4,6-trinitrobenzene (TATB), and nitromethane (NM). After this dispersion correction the average error of predicted equilibrium volumes decreases from 18.5 to 4.2% for the above systems. We find that the calculated crystal structures and equation of state with ReaxFF-lg are in good agreement with experimental results. In particular, we examined the phase transition between α-RDX and γ-RDX, finding that ReaxFF-lg leads to excellent agreement for both the pressure and volume of this transition occurring at ∼4.8 GPa and ∼2.18 g/cm3 density from ReaxFF-lg vs 3.9 GPa and ∼2.21 g/cm3 from experiment. We expect ReaxFF-lg to improve the descriptions of the phase diagrams for other energetic materials.

Blue light regulates many physiological processes in fungi, but their photoreceptors are not known. In Neurospora crassa, all light responses depend on the Per-Arnt-Sim (PAS) domain-containing transcription factor white collar-1 (wc-1). By removing the WC-1 light, oxygen, or voltage domain, a specialized PAS domain that binds flavin mononucleotide in plant phototropins, we show that light responses are abolished, including light entrainment of the circadian clock. However, the WC-1-mediated dark activation of frq remains normal in this mutant, and the circadian clock can be entrained by temperature. Furthermore, we demonstrate that the purified Neurospora WC-1-WC-2 protein complex is associated with stoichiometric amounts of the chromophore flavin-adenine dinucleotide. Together, these observations suggest that WC-1 is the blue-light photoreceptor for the circadian clock and other light responses in Neurospora.

Abstract Metal–organic frameworks (MOFs) have attracted tremendous interest due to their promising applications including electrocatalysis originating from their unique structural features. However, it remains a challenge to directly use MOFs for oxygen electrocatalysis because it is quite difficult to manipulate their dimension, composition, and morphology of the MOFs with abundant active sites. Here, a facile ambient temperature synthesis of unique NiCoFe‐based trimetallic MOF nanostructures with foam‐like architecture is reported, which exhibit extraordinary oxygen evolution reaction (OER) activity as directly used catalyst in alkaline condition. Specifically, the (Ni 2 Co 1 ) 0.925 Fe 0.075 ‐MOF‐NF delivers a minimum overpotential of 257 mV to reach the current density of 10 mA cm −2 with a small Tafel slope of 41.3 mV dec −1 and exhibits high durability after long‐term testing. More importantly, the deciphering of the possible origination of the high activity is performed through the characterization of the intermediates during the OER process, where the electrochemically transformed metal hydroxides and oxyhydroxides are confirmed as the active species.

Redox-controllable molecular nanovalves based on mesoporous silica nanoparticles have been fabricated, using two bistable [2]rotaxanes with different spacer lengths between their recognition sites as the gatekeepers. Three different linkers with varying chain lengths have been employed to attach the bistable [2]rotaxane molecules covalently to the silica substrate. These nanovalves can be classified as having IN or OUT locations, based on the positions of the tethered bistable [2]rotaxanes with respect to the entrances to the nanopores. The nanovalves are more efficient when the bistable [2]rotaxane-based gatekeepers are anchored deep within (IN) the pores than when they are attached closer to (OUT) the pores' orifices. The silica nanopores can be closed and opened by moving the mechanically interlocked ring component of the bistable [2]rotaxane closer to and away from the pores' orifices, respectively, a process which allows luminescent probe molecules, such as coumarins, tris(2-phenylpyridine)iridium, and rhodamine B, to be loaded into or released from the mesoporous silica substrate on demand. The lengths of the linkers between the surface and the rotaxane molecules also play a critical role in determining the effectiveness of the nanovalves. The shorter the linkers, the less leaky are the nanovalves. However, the distance between the recognition units on the rod section of the rotaxane molecules does not have any significant influence on the nanovalves' leakiness. The controlled release of the probe molecules was investigated by measuring their luminescence intensities in response to ascorbic acid, which induces the ring's movement away from the pores' orifices, and consequently opens the nanovalves.

Raising the bar: the efficacy of bioorthogonal reactions for bioconjugation has been thoroughly evaluated in four different biological settings. Powered by the development of new biocompatible ligands, the copper-catalyzed azide-alkyne cycloaddition has brought about unsurpassed bioconjugation efficiency, and thus it holds great promise as a highly potent and adaptive tool for a broader spectrum of biological applications.

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an alpha subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We evaluated 28 unrelated Chinese kindreds with AF and sequenced eight genes of potassium channels (KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5, and KCNJ2). An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not alter the functions of the HCN channel family either. Thus, KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of AF.

Chromophoric iridium(III) complex-coated NaYF(4): 20%Yb, 1.6%Er, 0.4%Tm nanocrystals are demonstrated as a ratiometric upconversion luminescence (UCL) probe for highly selective detection of cyanide anion and bioimaging of CN(-) in living cells through inhibition of the energy transfer from the UCL of the nanocrystals to the absorbance of the chromophoric complex. The UCL probe provides a very low detection limit of 0.18 μM CN(-) in the aqueous solution.

Based upon cognitive radio technology, we propose a new Machine-to-Machine (M2M) communications paradigm, namely Cognitive M2M (CM2M) communication. We first motivate the use of cognitive radio technology in M2M communications from different point of views, including technical, applications, industry support, and standardization perspectives. Then, our CM2M network architecture and cognitive machine model are presented and the CM2M systems coexistence in TV white spaces is discussed. After that, a CM2M communications architecture for the smart grid is presented, for which we also propose an energy-efficiency driven spectrum discovery scheme. Numerical results demonstrate significant energy saving and the reliability in supporting data transmissions in the smart grid.

Abstract The growing interest in two-dimensional imine-based covalent organic frameworks (COFs) is inspired by their crystalline porous structures and the potential for extensive π-electron delocalization. The intrinsic reversibility and strong polarization of imine linkages, however, leads to insufficient chemical stability and optoelectronic properties. Developing COFs with improved robustness and π-delocalization is highly desirable but remains an unsettled challenge. Here we report a facile strategy that transforms imine-linked COFs into ultrastable porous aromatic frameworks by kinetically fixing the reversible imine linkage via an aza-Diels-Alder cycloaddition reaction. The as-formed, quinoline-linked COFs not only retain crystallinity and porosity, but also display dramatically enhanced chemical stability over their imine-based COF precursors, rendering them among the most robust COFs up-to-date that can withstand strong acidic, basic and redox environment. Owing to the chemical diversity of the cycloaddition reaction and structural tunability of COFs, the pores of COFs can be readily engineered to realize pre-designed surface functionality.

In mammalian cells, mitochondrial dysfunction triggers the integrated stress response, in which the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) results in the induction of the transcription factor ATF41–3. However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show that HRI is the eIF2α kinase that is necessary and sufficient for this relay. In a genome-wide CRISPR interference screen, we identified factors upstream of HRI: OMA1, a mitochondrial stress-activated protease; and DELE1, a little-characterized protein that we found was associated with the inner mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2α kinase activity of HRI. In addition, DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation. Blockade of the OMA1–DELE1–HRI pathway triggers an alternative response in which specific molecular chaperones are induced. The OMA1–DELE1–HRI pathway therefore represents a potential therapeutic target that could enable fine-tuning of the integrated stress response for beneficial outcomes in diseases that involve mitochondrial dysfunction. A genome-wide CRISPR interference screen shows that a signalling pathway involving OMA1, DELE1 and the eIF2α kinase HRI relays mitochondrial stress to the cytosol to trigger the integrated stress response.

Codon-usage bias has been observed in almost all genomes and is thought to result from selection for efficient and accurate translation of highly expressed genes. Codon usage is also implicated in the control of transcription, splicing and RNA structure. Many genes exhibit little codon-usage bias, which is thought to reflect a lack of selection for messenger RNA translation. Alternatively, however, non-optimal codon usage may be of biological importance. The rhythmic expression and the proper function of the Neurospora FREQUENCY (FRQ) protein are essential for circadian clock function. Here we show that, unlike most genes in Neurospora, frq exhibits non-optimal codon usage across its entire open reading frame. Optimization of frq codon usage abolishes both overt and molecular circadian rhythms. Codon optimization not only increases FRQ levels but, unexpectedly, also results in conformational changes in FRQ protein, altered FRQ phosphorylation profile and stability, and impaired functions in the circadian feedback loops. These results indicate that non-optimal codon usage of frq is essential for its circadian clock function. Our study provides an example of how non-optimal codon usage functions to regulate protein expression and to achieve optimal protein structure and function.

A new type of one-dimensional (1D) carbon structure, carbon nanowires (CNWs), was discovered in the cathode deposits prepared by hydrogen arc discharge evaporation of carbon rods. Observation of high-resolution transmission electron microscopy (HRTEM) indicates that a CNW consists of a multiwalled carbon nanotube (MWNT) with a long 1D linear carbon chain (C chain) inserted into its innermost tube of 0.7 nm in diameter. The characteristic Raman peaks of CNWs appeared at around $1850\text{ }\text{ }{\mathrm{c}\mathrm{m}}^{\ensuremath{-}1}$. Raman scattering and HRTEM studies show the formation of a long linear C chain involving more than 100 carbon atoms inside a MWNT. This novel 1D carbon allotrope has potential applications in nanoelectronics, nanomechanics, and nanomaterials.

The self-assembly of well-defined 2D supramolecular polymers in solution has been a challenge in supramolecular chemistry. We have designed and synthesized a rigid stacking-forbidden 1,3,5-triphenylbenzene compound that bears three 4,4'-bipyridin-1-ium (BP) units on the peripheral benzene rings. Three hydrophilic bis(2-hydroxyethyl)carbamoyl groups are introduced to the central benzene ring to suppress 1D stacking of the triangular backbone and to ensure solubility in water. Mixing the triangular preorganized molecule with cucurbit[8]uril (CB[8]) in a 2:3 molar ratio in water leads to the formation of the first solution-phase single-layer 2D supramolecular organic framework, which is stabilized by the strong complexation of CB[8] with two BP units of adjacent molecules. The periodic honeycomb 2D framework has been characterized by various (1)H NMR spectroscopy, dynamic light scattering, X-ray diffraction and scattering, scanning probe and electron microscope techniques and by comparing with the self-assembled structures of the control systems.

We wanted to identify genes that are controlled by the circadian clock in the prokaryotic cyanobacterium Synechococcus sp. strain PCC 7942. To use luciferase as a reporter to monitor gene expression, bacterial luciferase genes (luxAB) were inserted randomly into the Synechococcus genome by conjugation with Escherichia coli and subsequent homologous recombination. The resulting transformed clones were then screened for bioluminescence using a new developed cooled-CCD camera system. We screened approximately 30,000 transformed Synechococcus colonies and recovered approximately 800 clones whose bioluminescence was bright enough to be easily monitored by the screening apparatus. Unexpectedly, the bioluminescence expression patterns of almost all of these 800 colonies clearly manifested circadian rhythmicity. These rhythms exhibited a range of waveforms and amplitudes, and they also showed a variety of phase relationships. We also found bioluminescence rhythms expressed by cyanobacterial colonies in which the luciferase gene set was coupled to the promoters of several known genes. Together, these results indicate that control of gene expression by circadian clocks may be more widespread than expected thus far. Moreover, our results show that screening organisms in which promoterless luciferase genes have been inserted randomly throughout the genome by homologous recombination provides an extremely sensitive method to explore differential gene expression.

The inward rectifier K+ channel Kir2.1 mediates the potassium IK1 current in the heart. It is encoded by KCNJ2 gene that has been linked to Andersen’s syndrome. Recently, strong evidences showed that Kir2.1 channels were associated with mouse atrial fibrillation (AF), therefore we hypothesized that KCNJ2 was associated with familial AF. Thirty Chinese AF kindreds were evaluated for mutations in KCNJ2 gene. A valine-to-isoleucine mutation at position 93 (V93I) of Kir2.1 was found in all affected members in one kindred. This valine and its flanking sequence is highly conserved in Kir2.1 proteins among different species. Functional analysis of the V93I mutant demonstrated a gain-of-function consequence on the Kir2.1 current. This effect is opposed to the loss-of-function effect of previously reported mutations in Andersen’s syndrome. Kir2.1 V93I mutation may play a role in initiating and/or maintaining AF by increasing the activity of the inward rectifier K+ channel.

The Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC) is the standard method for bioorthogonal conjugation. However, current Cu(I) catalyst formulations are toxic, hindering their use in living systems. Here we report that BTTES, a tris(triazolylmethyl)amine-based ligand for Cu(I), promotes the cycloaddition reaction rapidly in living systems without apparent toxicity. This catalyst allows, for the first time, noninvasive imaging of fucosylated glycans during zebrafish early embryogenesis. We microinjected embryos with alkyne-bearing GDP-fucose at the one-cell stage and detected the metabolically incorporated unnatural sugars using the biocompatible click chemistry. Labeled glycans could be imaged in the enveloping layer of zebrafish embryos between blastula and early larval stages. This new method paves the way for rapid, noninvasive imaging of biomolecules in living organisms.

The ATP site of kinases displays remarkable conformational flexibility when accommodating chemically diverse small molecule inhibitors. The so-called activation segment, whose conformation controls catalytic activity and access to the substrate binding pocket, can undergo a large conformational change with the active state assuming a ‘DFG-in’ and an inactive state assuming a ‘DFG-out’ conformation. Compounds that preferentially bind to the DFG-out conformation are typically called ‘type II’ inhibitors in contrast to ‘type I’ inhibitors that bind to the DFG-in conformation. This review surveys the large number of type II inhibitors that have been developed and provides an analysis of their crystallographically determined binding modes. Using a small library of type II inhibitors, we demonstrate that more than 200 kinases can be targeted, suggesting that type II inhibitors may not be intrinsically more selective than type I inhibitors.

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.

The frequency(frq) gene encodes central components of the transcription/translation-based negative-feedback loop comprising the core of the Neurospora circadian oscillator; posttranscriptional regulation associated with FRQ is surprisingly complex. Alternative use of translation initiation sites gives rise to two forms of FRQ whose levels peak 4–6 hr following the peak of frq transcript. Each form of FRQ is progressively phosphorylated over the course of the day, thus providing a number of temporally distinct FRQ products. The kinetics of these regulatory processes suggest a view of the clock where relatively rapid events involving translational regulation in the synthesis of FRQ and negative feedback of FRQ on frq transcript levels are followed by slower posttranslational regulation, ultimately driving the turnover of FRQ and reactivation of the frq gene.

Limiting the rise in global mean temperatures relies on reducing carbon dioxide (CO2) emissions and on the removal of CO2 by land carbon sinks. China is currently the single largest emitter of CO2, responsible for approximately 27 per cent (2.67 petagrams of carbon per year) of global fossil fuel emissions in 20171. Understanding of Chinese land biosphere fluxes has been hampered by sparse data coverage2-4, which has resulted in a wide range of a posteriori estimates of flux. Here we present recently available data on the atmospheric mole fraction of CO2, measured from six sites across China during 2009 to 2016. Using these data, we estimate a mean Chinese land biosphere sink of -1.11 ± 0.38 petagrams of carbon per year during 2010 to 2016, equivalent to about 45 per cent of our estimate of annual Chinese anthropogenic emissions over that period. Our estimate reflects a previously underestimated land carbon sink over southwest China (Yunnan, Guizhou and Guangxi provinces) throughout the year, and over northeast China (especially Heilongjiang and Jilin provinces) during summer months. These provinces have established a pattern of rapid afforestation of progressively larger regions5,6, with provincial forest areas increasing by between 0.04 million and 0.44 million hectares per year over the past 10 to 15 years. These large-scale changes reflect the expansion of fast-growing plantation forests that contribute to timber exports and the domestic production of paper7. Space-borne observations of vegetation greenness show a large increase with time over this study period, supporting the timing and increase in the land carbon sink over these afforestation regions.

As a result of several successful applications in computer vision and image processing, sparse representation (SR) has attracted significant attention in multi-sensor image fusion. Unlike the traditional multiscale transforms (MSTs) that presume the basis functions, SR learns an over-complete dictionary from a set of training images for image fusion, and it achieves more stable and meaningful representations of the source images. By doing so, the SR-based fusion methods generally outperform the traditional MST image fusion methods in both subjective and objective tests. In addition, they are less susceptible to mis-registration among the source images, thus facilitating the practical applications. This survey paper proposes a systematic review of the SR-based multi-sensor image fusion literature, highlighting the pros and cons of each category of approaches. Specifically, we start by performing a theoretical investigation of the entire system from three key algorithmic aspects, (1) sparse representation models; (2) dictionary learning methods; and (3) activity levels and fusion rules. Subsequently, we show how the existing works address these scientific problems and design the appropriate fusion rules for each application such as multi-focus image fusion and multi-modality (e.g., infrared and visible) image fusion. At last, we carry out some experiments to evaluate the impact of these three algorithmic components on the fusion performance when dealing with different applications. This article is expected to serve as a tutorial and source of reference for researchers preparing to enter the field or who desire to employ the sparse representation theory in other fields.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets. Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.

Covalent organic frameworks (COFs) with their porous structures that are accommodative of Li salts are considered to be potential candidates for solid-state fast Li+ conductors. However, Li salts simply infiltrated in the pores of solid-state COFs tend to be present in closely associate ion pairs, resulting in slow ionic diffusion dynamics. Here we incorporate cationic skeleton into the COF structure to split the Li salt ion pair through stronger dielectric screening. It is observed that the concentration of free Li+ ions in the resulting material is drastically increased, leading to a significantly improved Li+ conductivity in the absence of any solvent (up to 2.09 × 10-4 S cm-1 at 70 °C).

Periodontitis is one of the most widespread infectious diseases in humans. It is the main cause of tooth loss and associated with a number of systemic diseases. Until now, there is no appropriate method for functional periodontal tissue regeneration. Here, we establish a novel approach of using allogeneic periodontal ligament stem cells (PDLSCs) sheet to curing periodontitis in a miniature pig periodontitis model. Significant periodontal tissue regeneration was achieved in both the autologous and the allogeneic PDLSCs transplantation group at 12 weeks post-PDLSCs transplantation. Based on clinical assessments, computed tomography (CT) scanning, and histological examination, there was no marked difference between the autologous and allogeneic PDLSCs transplantation groups. In addition, lack of immunological rejections in the animals that received the allogeneic PDLSCs transplantation was observed. Interestingly, we found that human PDLSCs fail to express human leukocyte antigen (HLA)-II DR and costimulatory molecules. PDLSCs were not able to elicit T-cell proliferation and inhibit T-cell proliferation when stimulated with mismatched major histocompatibility complex molecules. Furthermore, we found that prostaglandin E2 (PGE2) plays a crucial role in PDLSCs-mediated immunomodulation and periodontal tissue regeneration in vitro and in vivo. Our study demonstrated that PDLSCs possess low immunogenicity and marked immunosuppression via PGE2-induced T-cell anergy. We developed a standard technological procedure of using allogeneic PDLSCs to cure periodontitis in swine.

Retinoids are known to inhibit the growth of hormone-dependent but not that of hormone-independent breast cancer cells. We investigated the involvement of retinoic acid (RA) receptors (RARs) in the differential growth-inhibitory effects of retinoids and the underlying mechanism. Our data demonstrate that induction of RAR beta by RA correlates with the growth-inhibitory effect of retinoids. The hormone-independent cells acquired RA sensitivity when the RAR beta expression vector was introduced and expressed in the cells. In addition, RA sensitivity of hormone-dependent cells was inhibited by a RAR beta-selective antagonist and the expression of RAR beta antisense RNA. Introduction of RAR alpha also restored RA sensitivity in hormone-independent cells, but this restoration was accomplished by the induction of endogenous RAR beta expression. Furthermore, we show that induction of apoptosis contributes to the growth-inhibitory effect of RAR beta. Thus, RAR beta can mediate retinoid action in breast cancer cells by promoting apoptosis. Loss of RAR beta, therefore, may contribute to the tumorigenicity of human mammary epithelial cells.

Significance Codon usage bias is an essential feature of all genomes. The effects of codon usage biases on gene expression were previously thought to be mainly due to its impacts on translation. Here, we show that codon usage bias strongly correlates with protein and mRNA levels genome-wide in the filamentous fungus Neurospora , and codon usage is an important determinant of gene expression. Surprisingly, we found that the impacts of codon usage on gene expression are mainly due to effects on transcription and are largely independent of translation. Together, these results uncovered an unexpected role of codon biases in determining transcription levels by affecting chromatin structures and suggest that codon biases are results of genome adaptation to both transcription and translation machineries.

Abstract Atmospheric water harvesting (AWH)—producing fresh water via collecting moisture from air—enables sustainable water delivery without geographical and hydrologic limitations. However, the fundamental design principle to prepare materials that can convert the water vapor in the air to collectible liquid water is still mostly unknown. Here, a super moisture‐absorbent gel, which is composed of hygroscopic polypyrrole chloride penetrating in hydrophilicity‐switchable polymeric network of poly N ‐isopropylacrylamide, is shown. Based on such design, a high‐efficiency water production by AWH has been achieved in a broad range of relative humidity. The synergistic effect enabled by the molecular level integration of hygroscopic and hydrophilicity‐switchable polymers in a network architecture presents controllable interaction between the gel and water molecules, simultaneously realizing efficient vapor capturing, in situ water liquefaction, high‐density water storage and fast water releasing under different weather conditions. Being an effective method to regulate migration of water molecules, such design represents a novel strategy to improve the AWH, and it is also fundamental to other water management systems for environmental cooling, surficial moisturizing and beyond.

Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. Unexpectedly, PP242 has much weaker effects than rapamycin on the proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase (PI3K), is more immunosuppressive than PP242. These findings establish that Ph(+) transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.

Transient receptor potential V2 (TRPV2) has been proposed to be a high-threshold thermosensor. However, further elucidation of the channel properties and physiological role of TRPV2 have been hindered by the lack of selective pharmacological tools as well as by the species-dependent differences in the activation of this channel. In the present study, we have used cell-based calcium mobilization and electrophysiological assays to identify and characterize several novel cannabinoid TRPV2 agonists. Among these, cannabidiol was found to be the most robust and potent (EC(50) = 3.7 microM), followed by Delta(9)-tetrahydrocannabinol (EC(50) = 14 microM) and cannabinol (EC(50) = 77.7 microM). We also demonstrated that cannabidiol evoked a concentration-dependent release of calcitonin gene-related peptide (CGRP) from cultured rat dorsal root ganglion neurons in a cannabinoid receptor- and TRPV1-independent manner. Moreover, the cannabidiol-evoked CGRP release depended on extracellular calcium and was blocked by the nonselective TRP channel blocker, ruthenium red. We further provide evidence through the use of small interfering RNA knockdown and repetitive stimulation studies, to show that cannabidiol-evoked CGRP release is mediated, at least in part, by TRPV2. Together, these data suggest not only that TRPV2 may comprise a mechanism whereby cannabidiol exerts its clinically beneficial effects in vivo, but also that TRPV2 may constitute a viable, new drug target.

Anticancer agents are critical for the cancer treatment, but side effects and the drug resistance associated with the currently used anticancer agents create an urgent need to explore novel drugs with low side effects and high efficacy. 1,2,3-Triazole is privileged building block in the discovery of new anticancer agents, and some of its derivatives have already been applied in clinics or under clinical trials for fighting against cancers. Hybrid molecules occupy an important position in cancer control, and hybridization of 1,2,3-triazole framework with other anticancer pharmacophores may provide valuable therapeutic intervention for the treatment of cancer, especially drug-resistant cancer. This review emphasizes the recent advances in 1,2,3-triazole-containing hybrids with anticancer potential, covering articles published between 2015 and 2019, and the structure-activity relationships, together with mechanisms of action are also discussed.

On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9.We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome.All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment.Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.

Cd(<sc>ii</sc>) frameworks with amino functionalized sites show high sensitivity for the detection of Fe(<sc>iii</sc>) and antibiotics such as nitrofurazone.

Aloe-emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe-emodin exhibits many pharmacological effects, including anticancer, antivirus, anti-inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe-emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe-emodin has a poor intestinal absorption, short elimination half-life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe-emodin reported to date with an emphasis on its biological properties and mechanisms of action.

In addition to direct effect on tumor cells, the tumor-promoting activity of CCL2 has been ascribed to its role in chemoattracting tumor-associated macrophages. However it is unclear whether CCL2 also attracts other immune regulatory cells during tumor development. In this study, we confirmed the ubiquitous expression of CCR2 in myeloid suppressor cells (MSCs), a main inducer for tumor immune evasion, and identified that cancer patient-derived CCL2 mediated the migration of MSCs to tumors in vitro, which could be interdicted by antibodies neutralizing CCL2 or blocking CCR2. In mouse tumor model, the adoptively transferred CCR2−/− MSCs could not migrate to either tumor or spleen as efficiently as WT MSCs. The absence of CCL2/CCR2 signaling hindered both MSC migration and MSC-promoted tumor growth. Our data provide evidence that CCL2/CCR2 pathway plays a pivotal role in MSC migration, which is a novel mechanism through which CCL2 promotes tumor growth.

<h2>Summary</h2> A variety of small RNAs, including the Dicer-dependent miRNAs and the Dicer-independent Piwi-interacting RNAs, associate with Argonaute family proteins to regulate gene expression in diverse cellular processes. These two species of small RNA have not been found in fungi. Here, by analyzing small RNAs associated with the <i>Neurospora</i> Argonaute protein QDE-2, we show that diverse pathways generate miRNA-like small RNAs (milRNAs) and Dicer-independent small interfering RNAs (disiRNAs) in this filamentous fungus. Surprisingly, milRNAs are produced by at least four different mechanisms that use a distinct combination of factors, including Dicers, QDE-2, the exonuclease QIP, and an RNase III domain-containing protein, MRPL3. In contrast, disiRNAs originate from loci producing overlapping sense and antisense transcripts, and do not require the known RNAi components for their production. Taken together, these results uncover several pathways for small RNA production in filamentous fungi, shedding light on the diversity and evolutionary origins of eukaryotic small RNAs.

Previous studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model.MSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-β1] in brain homogenates. The immunosuppression-related factors TNF-α stimulated gene/protein 6 (TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway.The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI.

A one-step microwave-assisted polyol method was developed to fabricate green luminescent carbon dots (CDs). By using sucrose as the carbon source and diethylene glycol (DEG) as the reaction medium, the CDs were obtained within one minute under microwave irradiation. The as-prepared DEG stabilized CDs (DEG-CDs) had an average diameter about 5 nm and could be readily dispersed in water with transparent appearance in day light while emitted unique green luminescence upon a 360 nm excitation. Moreover, these green luminescent DEG-CDs could be efficiently uptaken by C6 glioma cells and exhibited a low cytotoxicity, suggesting their potentials in bio-imaging applications.

It remains unknown whether the treatment of hypertension influences the mortality of patients diagnosed with coronavirus disease 2019 (COVID-19).This is a retrospective observational study of all patients admitted with COVID-19 to Huo Shen Shan Hospital. The hospital was dedicated solely to the treatment of COVID-19 in Wuhan, China. Hypertension and the treatments were stratified according to the medical history or medications administrated prior to the infection. Among 2877 hospitalized patients, 29.5% (850/2877) had a history of hypertension. After adjustment for confounders, patients with hypertension had a two-fold increase in the relative risk of mortality as compared with patients without hypertension [4.0% vs. 1.1%, adjusted hazard ratio (HR) 2.12, 95% confidence interval (CI) 1.17-3.82, P = 0.013]. Patients with a history of hypertension but without antihypertensive treatment (n = 140) were associated with a significantly higher risk of mortality compared with those with antihypertensive treatments (n = 730) (7.9% vs. 3.2%, adjusted HR 2.17, 95% CI 1.03-4.57, P = 0.041). The mortality rates were similar between the renin-angiotensin-aldosterone system (RAAS) inhibitor (4/183) and non-RAAS inhibitor (19/527) cohorts (2.2% vs. 3.6%, adjusted HR 0.85, 95% CI 0.28-2.58, P = 0.774). However, in a study-level meta-analysis of four studies, the result showed that patients with RAAS inhibitor use tend to have a lower risk of mortality (relative risk 0.65, 95% CI 0.45-0.94, P = 0.20).While hypertension and the discontinuation of antihypertensive treatment are suspected to be related to increased risk of mortality, in this retrospective observational analysis, we did not detect any harm of RAAS inhibitors in patients infected with COVID-19. However, the results should be considered as exploratory and interpreted cautiously.

Stem cells from human exfoliated deciduous teeth (SHED) have been identified as a population of postnatal stem cells capable of differentiating into osteogenic and odontogenic cells, adipogenic cells, and neural cells. Herein we have characterized mesenchymal stem cell properties of SHED in comparison to human bone marrow mesenchymal stem cells (BMMSCs).We used in vitro stem cell analysis approaches, including flow cytometry, inductive differentiation, telomerase activity, and Western blot analysis to assess multipotent differentiation of SHED and in vivo implantation to assess tissue regeneration of SHED. In addition, we utilized systemic SHED transplantation to treat systemic lupus erythematosus (SLE)-like MRL/lpr mice.We found that SHED are capable of differentiating into osteogenic and adipogenic cells, expressing mesenchymal surface molecules (STRO-1, CD146, SSEA4, CD73, CD105, and CD166), and activating multiple signaling pathways, including TGFbeta, ERK, Akt, Wnt, and PDGF. Recently, BMMSCs were shown to possess an immunomodulatory function that leads to successful therapies for immune diseases. We examined the immunomodulatory properties of SHED in comparison to BMMSCs and found that SHED had significant effects on inhibiting T helper 17 (Th17) cells in vitro. Moreover, we found that SHED transplantation is capable of effectively reversing SLE-associated disorders in MRL/lpr mice. At the cellular level, SHED transplantation elevated the ratio of regulatory T cells (Tregs) via Th17 cells.These data suggest that SHED are an accessible and feasible mesenchymal stem cell source for treating immune disorders like SLE.

Dumbbell-like PtxPd100–x–Fe3O4 nanoparticles (NPs) were synthesized and studied for electrocatalytic reduction and sensing of H2O2. In 0.1 M phosphate buffered saline (PBS) solution, the 4–10 nm PtxPd100–x–Fe3O4 NPs showed the Pt/Pd composition-dependent catalysis with Pt48Pd52–Fe3O4 NPs having the best activity. The Pt48Pd52–Fe3O4 NPs were tested for H2O2 detection, and their H2O2 detection limit reached 5 nM, which was suitable for monitoring H2O2 generated from Raw 264.7 cells. These dumbbell-like PtPd–Fe3O4 NPs are the most sensitive probe ever reported and can be used to achieve real-time quantitative detection of H2O2 in biological environment for biological and biomedical applications.

Preorganization in a covalent organic framework leads to the generation of a more conductive mixed-valence state upon doping.

The imbalance between energy intake and expenditure is the main cause of excessive overweight and obesity. Technically, obesity is defined as the abnormal accumulation of ≥20% of body fat, over the individual's ideal body weight. The latter constitutes the maximal healthful value for an individual that is calculated based chiefly on the height, age, build and degree of muscular development. However, obesity is diagnosed by measuring the weight in relation to the height of an individual, thereby determining or calculating the body mass index. The National Institutes of Health have defined 30 kg/m2 as the limit over which an individual is qualified as obese. Accordingly, the prevalence of obesity in on the increase in children and adults worldwide, despite World Health Organization warnings. The growth of obesity and the scale of associated health issues induce serious consequences for individuals and governmental health systems. Excessive overweight remains among the most neglected public health issues worldwide, while obesity is associated with increasing risks of disability, illness and death. Cardiovascular diseases, the leading cause of mortality worldwide, particularly hypertension and diabetes, are the main illnesses associated with obesity. Nevertheless, the mechanisms underlying obesity‑associated hypertension or other associated metabolic diseases remains to be adequately investigated. In the present review, we addressed the association between obesity and cardiovascular disease, particularly the biological mechanisms linking obesity and hypertension.

Global trends in a new multi‐satellite surface soil moisture dataset were analyzed for the period 1988–2010. 27% of the area covered by the dataset showed significant trends (p = 0.05). Of these, 73% were negative and 27% positive. Subtle drying trends were found in the Southern US, central South America, central Eurasia, northern Africa and the Middle East, Mongolia and northeast China, northern Siberia, and Western Australia. The strongest wetting trends were found in southern Africa and the subarctic region. Intra‐annual analysis revealed that most trends are not uniform among seasons. The most prominent trend patterns in remotely sensed surface soil moisture were also found in GLDAS‐Noah and ERA Interim modeled surface soil moisture and GPCP precipitation, lending confidence to the obtained results. The relationship with trends in GIMMS‐NDVI appeared more complex. In areas of mutual disagreement more research is needed to identify potential deficiencies in models and/or remotely sensed products.

Semi-supervised learning has attracted a significant amount of attention in pattern recognition and machine learning. Most previous studies have focused on designing special algorithms to effectively exploit the unlabeled data in conjunction with labeled data. Our goal is to improve the classification accuracy of any given supervised learning algorithm by using the available unlabeled examples. We call this as the Semi-supervised improvement problem, to distinguish the proposed approach from the existing approaches. We design a metasemi-supervised learning algorithm that wraps around the underlying supervised algorithm and improves its performance using unlabeled data. This problem is particularly important when we need to train a supervised learning algorithm with a limited number of labeled examples and a multitude of unlabeled examples. We present a boosting framework for semi-supervised learning, termed as SemiBoost. The key advantages of the proposed semi-supervised learning approach are: 1) performance improvement of any supervised learning algorithm with a multitude of unlabeled data, 2) efficient computation by the iterative boosting algorithm, and 3) exploiting both manifold and cluster assumption in training classification models. An empirical study on 16 different data sets and text categorization demonstrates that the proposed framework improves the performance of several commonly used supervised learning algorithms, given a large number of unlabeled examples. We also show that the performance of the proposed algorithm, SemiBoost, is comparable to the state-of-the-art semi-supervised learning algorithms.

Schiff base, an important family of reaction in click chemistry, has received significant attention in the formation of self-healing hydrogels in recent years. Schiff base reversibly reacts even in mild conditions, which allows hydrogels with self-healing ability to recover their structures and functions after damages. Moreover, pH-sensitivity of the Schiff base offers the hydrogels response to biologically relevant stimuli. Different types of Schiff base can provide the hydrogels with tunable mechanical properties and chemical stabilities. In this review, we summarized the design and preparation of hydrogels based on various types of Schiff base linkages, as well as the biomedical applications of hydrogels in drug delivery, tissue regeneration, wound healing, tissue adhesives, bioprinting, and biosensors.

The interaction between malachite green (MG) and bovine serum albumin (BSA) under simulative physiological conditions was investigated by the methods of fluorescence spectroscopy, UV–vis absorption and circular dichroism (CD) spectroscopy. Fluorescence data showed that the fluorescence quenching of BSA by MG was the result of the formation of the MG–BSA complex. According to the modified Stern–Volmer equation, the effective quenching constants (Ka) between MG and BSA at four different temperatures were obtained to be 3.734 × 104, 3.264 × 104, 2.718 × 104, and 2.164 × 104 L mol−1, respectively. The enthalpy change (ΔH) and entropy change (ΔS) were calculated to be −27.25 kJ mol−1 and −11.23 J mol−1 K−1, indicating that van der Waals force and hydrogen bonds were the dominant intermolecular force in stabilizing the complex. Site marker competitive experiments indicated that the binding of MG to BSA primarily took place in sub-domain IIA. The binding distance (r) between MG and the tryptophan residue of BSA was obtained to be 4.79 nm according to Förster theory of non-radioactive energy transfer. The conformational investigation showed that the presence of MG decreased the α-helical content of BSA (from 62.6% to 55.6%) and induced the slight unfolding of the polypeptides of protein, which confirmed some micro-environmental and conformational changes of BSA molecules.

Methylmercury (MeHg+) is a strong liposoluble ion, which can be accumulated in the organs of animals and can cause prenatal nervous system and visceral damage. Therefore, the efficient and sensitive monitoring of MeHg+ in organisms is of great importance. Upconversion luminescence (UCL) detection based on rare-earth upconversion nanophosphors (UCNPs) as probes has been proved to exhibit a large anti-Stokes shift, no autofluorescence from biological samples, a remarkably deep penetration depth, and no photobleaching. In this study, a hydrophobic heptamethine cyanine dye (hCy7) modified by two long alkyl moieties and amphiphilic polymer (P-PEG)-modified nanophosphors (hCy7-UCNPs) was fabricated as a highly sensitive water-soluble probe for UCL monitoring and bioimaging of MeHg+. Further application of hCy7-UCNPs for sensing MeHg+ was confirmed by an optical titration experiment and upconversion luminescence live cell imaging. Using the ratiometric upconversion luminescence as a detection signal, which provides a built-in correction for environmental effects, the detection limit of MeHg+ for this nanosystem was as low as 0.18 ppb. Importantly, the hCy7-UCNPs nanosystem was shown to be capable of monitoring MeHg+ex vivo and in vivo by upconversion luminescence bioimaging.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

All-inorganic CsPbX3 (X = Cl, Br or I) perovskite nanocrystals have attracted extensive interest recently due to their exceptional optoelectronic properties. In an effort to improve the charge separation and transfer following efficient exciton generation in such nanocrystals, novel functional nanocomposites were synthesized by the in situ growth of CsPbBr3 perovskite nanocrystals on two-dimensional MXene nanosheets. Efficient excited state charge transfer occurs between CsPbBr3 NCs and MXene nanosheets, as indicated by significant photoluminescence (PL) quenching and much shorter PL decay lifetimes compared with pure CsPbBr3 NCs. The as-obtained CsPbBr3/MXene nanocomposites demonstrated increased photocurrent generation in response to visible light and X-ray illumination, attesting to the potential application of these heterostructure nanocomposites for photoelectric detection. The efficient charge transfer also renders the CsPbBr3/MXene nanocomposite an active photocatalyst for the reduction of CO2 to CO and CH4. This work provides a guide for exploration of perovskite materials in next-generation optoelectronics, such as photoelectric detectors or photocatalyst.

The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC). One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results. NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction. FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.

Regulatory T (Treg) cells are essential for maintenance of immune homeostasis. Here we found that hydrogen sulfide (H2S) was required for Foxp3+ Treg cell differentiation and function and that H2S deficiency led to systemic autoimmune disease. H2S maintained expression of methylcytosine dioxygenases Tet1 and Tet2 by sulfhydrating nuclear transcription factor Y subunit beta (NFYB) to facilitate its binding to Tet1 and Tet2 promoters. Transforming growth factor-β (TGF-β)-activated Smad3 and interleukin-2 (IL-2)-activated Stat5 facilitated Tet1 and Tet2 binding to Foxp3. Tet1 and Tet2 catalyzed conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in Foxp3 to establish a Treg-cell-specific hypomethylation pattern and stable Foxp3 expression. Consequently, Tet1 and Tet2 deletion led to Foxp3 hypermethylation, impaired Treg cell differentiation and function, and autoimmune disease. Thus, H2S promotes Tet1 and Tet2 expression, which are recruited to Foxp3 by TGF-β and IL-2 signaling to maintain Foxp3 demethylation and Treg-cell-associated immune homeostasis.

Human generates responses relying on semantic and functional dependencies, including coreference relation, among dialogue elements and their context.In this paper, we investigate matching a response with its multi-turn context using dependency information based entirely on attention.Our solution is inspired by the recently proposed Transformer in machine translation (Vaswani et al., 2017) and we extend the attention mechanism in two ways.First, we construct representations of text segments at different granularities solely with stacked self-attention.Second, we try to extract the truly matched segment pairs with attention across the context and response.We jointly introduce those two kinds of attention in one uniform neural network.Experiments on two large-scale multi-turn response selection tasks show that our proposed model significantly outperforms the state-of-the-art models.