Xian Wang

The anti-hyperglycemic effect of metformin is believed to be caused by its direct action on signaling processes in hepatocytes, leading to lower hepatic gluconeogenesis. Recently, metformin was reported to alter the gut microbiota community in humans, suggesting that the hyperglycemia-lowering action of the drug could be the result of modulating the population of gut microbiota. However, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of metformin remained elusive. Here, we performed metagenomic and metabolomic analysis of samples from individuals with newly diagnosed type 2 diabetes (T2D) naively treated with metformin for 3 d, which revealed that Bacteroides fragilis was decreased and the bile acid glycoursodeoxycholic acid (GUDCA) was increased in the gut. These changes were accompanied by inhibition of intestinal farnesoid X receptor (FXR) signaling. We further found that high-fat-diet (HFD)-fed mice colonized with B. fragilis were predisposed to more severe glucose intolerance, and the metabolic benefits of metformin treatment on glucose intolerance were abrogated. GUDCA was further identified as an intestinal FXR antagonist that improved various metabolic endpoints in mice with established obesity. Thus, we conclude that metformin acts in part through a B. fragilis–GUDCA–intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia. Metformin decreases the levels of Bacteroides fragilis while increasing the bile acid GUDCA to antagonize intestinal FXR and improves the metabolic health of humans and mice.

Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data.To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension.The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study.Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354).The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death.During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events.Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels.clinicaltrials.gov Identifier: NCT00794885.

Abstract N6-methyladenosine (m6A) is the most abundant mRNA modification. With the development of antibody-based sequencing technologies and the findings of m6A-related “writers”, “erasers”, and “readers”, the relationships between m6A and mRNA metabolism are emerging. The m6A modification influences almost every step of RNA metabolism that comprises mRNA processing, mRNA exporting from nucleus to cytoplasm, mRNA translation, mRNA decay, and the biogenesis of long-non-coding RNA (lncRNA) and microRNA (miRNA). Recently, more and more studies have found m6A is associated with cancer, contributing to the self-renewal of cancer stem cell, promotion of cancer cell proliferation, and resistance to radiotherapy or chemotherapy. Inhibitors of m6A-related factors have been explored, and some of them were identified to inhibit cancer progression, indicating that m6A could be a target for cancer therapy. In this review, we are trying to summarize the regulation and function of m6A in human carcinogenesis.

In order to obtain a machine understandable semantics for web resources, research on the Semantic Web tries to annotate web resources with concepts and relations from explicitly defined formal ontologies. This kind of formal annotation is usually done manually or semi-automatically. In this paper, we explore a complement approach that focuses on the "social annotations of the web" which are annotations manually made by normal web users without a pre-defined formal ontology. Compared to the formal annotations, although social annotations are coarse-grained, informal and vague, they are also more accessible to more people and better reflect the web resources' meaning from the users' point of views during their actual usage of the web resources. Using a social bookmark service as an example, we show how emergent semantics [2] can be statistically derived from the social annotations. Furthermore, we apply the derived emergent semantics to discover and search shared web bookmarks. The initial evaluation on our implementation shows that our method can effectively discover semantically related web bookmarks that current social bookmark service can not discover easily.

Single-atom catalysts (SACs) are attracting widespread interest for the catalytic oxygen reduction reaction (ORR), with Fe-Nx SACs exhibiting the most promising activity. However, Fe-based catalysts suffer serious stability issues as a result of oxidative corrosion through the Fenton reaction. Herein, using a metal-organic framework as an anchoring matrix, we for the first time obtained pyrolyzed Cr/N/C SACs for the ORR, where the atomically dispersed Cr is confirmed to have a Cr-N4 coordination structure. The Cr/N/C catalyst exhibits excellent ORR activity with an optimal half-wave potential of 0.773 V versus RHE. More excitingly, the Fenton reaction is substantially reduced and, thus, the final catalysts show superb stability. The innovative and robust active site for the ORR opens a new possibility to circumvent the stability issue of the non-noble metal ORR catalysts.

In the present paper, the following Schrödinger–Kirchhoff-type problem: (1.1)−(a+b∫RN|∇u|2dx)Δu+V(x)u=f(x,u),inRN is studied and four new existence results for nontrivial solutions and a sequence of high energy solutions for problem (1.1) are obtained by using a symmetric Mountain Pass Theorem.

In this Communication, we present the integration of synergetic designs into high-quality, well-defined Cu1.94S–ZnxCd1–xS heteronanorods (0 ≤ x ≤ 1) for enhanced photocatalytic hydrogen evolution. These heteronanorods possess two light absorbers, intimate heterointerfaces, tunable band gaps over a wide range, and uniform one-dimensional morphology. As verified by experimental and density functional theory studies, these heteronanorods with continuous composition adjustment fully exploit the benefits of both interfacial charge separation and optimized band alignments. Even without any cocatalysts, Cu1.94S–Zn0.23Cd0.77S heteronanorods exhibit efficient hydrogen production activity (7735 μmol h–1 g–1) under visible-light irradiation (λ > 420 nm), representing a 59-fold enhancement compared with the pristine CdS catalyst. Meanwhile, deposition of a Pt cocatalyst on the Cu1.94S–ZnxCd1–xS surface substantially enhances the hydrogen production performance (13 533 μmol h–1 g–1) with an apparent quantum efficiency of 26.4% at 420 nm, opening up opportunities to promote the overall photocatalytic performance using rationally designed nanostructures.

MicroRNAs (miRNAs) are a group of small noncoding RNAs (ncRNAs) that posttranscriptionally regulate gene expression by targeting their corresponding messenger RNAs (mRNAs). Dysregulated miRNAs have been considered as a new type of ‘‘oncomiRs’’ or ‘‘tumor suppressors,” playing essential roles in cancer initiation and progression. Using genome-wide detection methods, ubiquitously aberrant expression profiles of miRNAs have been identified in a broad array of human cancers, showing great potential as novel diagnostic and prognostic biomarkers of cancer with high specificity and sensitivity. The detectable miRNAs in tissue, blood, and other body fluids with high stability provide an abundant source for miRNA-based biomarkers in human cancers. Despite the fact that an increasing number of potential miRNA biomarkers have been reported, the transition of miRNAs-based biomarkers from bench to bedside still necessitates addressing several challenges. In this review, we will summarize our current understanding of miRNAs as potential biomarkers in human cancers.

Abstract Although progress has been made to improve photocatalytic CO 2 reduction under visible light ( λ >400 nm), the development of photocatalysts that can work under a longer wavelength ( λ >600 nm) remains a challenge. Now, a heterogeneous photocatalyst system consisting of a ruthenium complex and a monolayer nickel‐alumina layered double hydroxide (NiAl‐LDH), which act as light‐harvesting and catalytic units for selective photoreduction of CO 2 and H 2 O into CH 4 and CO under irradiation with λ >400 nm. By precisely tuning the irradiation wavelength, the selectivity of CH 4 can be improved to 70.3 %, and the H 2 evolution reaction can be completely suppressed under irradiation with λ >600 nm. The photogenerated electrons matching the energy levels of photosensitizer and m‐NiAl‐LDH only localized at the defect state, providing a driving force of 0.313 eV to overcome the Gibbs free energy barrier of CO 2 reduction to CH 4 (0.127 eV), rather than that for H 2 evolution (0.425 eV).

Abstract Water electrolysis is an emerging energy conversion technology, which is significant for efficient hydrogen (H 2 ) production. Based on the high‐activity transition metal ions and metal alloys of ultrastable bifunctional catalyst, the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) are the key to achieving the energy conversion method by overall water splitting (OWS). This study reports that the Co‐based coordination polymer (ZIF‐67) anchoring on an indium–organic framework (InOF‐1) composite (InOF‐1@ZIF‐67) is treated followed by carbonization and phosphorization to successfully obtain CoP nanoparticles–embedded carbon nanotubes and nitrogen‐doped carbon materials (CoP‐InNC@CNT). As HER and OER electrocatalysts, it is demonstrated that CoP‐InNC@CNT simultaneously exhibit high HER performance (overpotential of 153 mV in 0.5 m H 2 SO 4 and 159 mV in 1.0 m KOH) and OER performance (overpotential of 270 mV in 1.0 m KOH) activities to reach the current density of 10 mA cm −2 . In addition, these CoP‐InNC@CNT rods, as a cathode and an anode, can display an excellent OWS performance with η 10 = 1.58 V and better stability, which shows the satisfying electrocatalyst for the OWS compared to control materials. This method ensures the tight and uniform growth of the fast nucleating and stable materials on substrate and can be further applied for practical electrochemical reactions.

Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand–foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Funding Jiangsu Hengrui Medicine and National Key R&D Program of China. Translations For the Chinese translation of the abstract see Supplementary Materials section.

Significance A full understanding of sensorimotor transformation during complex behaviors requires quantifying brainwide dynamics of behaving animals. Here, we characterize brainwide dynamics of individual nematodes exposed to a defined thermosensory input. We show that it is possible to uncover representations of sensory input and motor output in individual neurons of behaving animals. Panneuronal imaging in roaming animals will facilitate systems neuroscience in behaving Caenorhabditis elegans .

Persistent organic pollutants (POPs) are major environmental concern due to their persistence, long-range transportability, bio-accumulation and potentially adverse effects on living organisms. Analytical chemistry plays an essential role in the measurement of POPs and provides important information on their distribution and environmental transformations. Much effort has been devoted during the last two decades to the development of faster, safer, more reliable and more sensitive analytical techniques for these pollutants. Since the Stockholm Convention (SC) on POPs was adopted 12 years ago, analytical methods have been extensively developed. This review article introduces recent analytical techniques and applications for the determination of POPs in environmental and biota samples, and summarizes the extraction, separation and instrumental analyses of the halogenated POPs. Also, this review covers important aspects for the analyses of SC POPs (e.g. lipid determination and quality assurance/quality control (QA/QC)), and finally discusses future trends for improving the POPs analyses and for potential new POPs.

Environmentally friendly and efficient transition metal phosphide (TMP) electrocatalysts for oxygen evolution reaction (OER) are developed to meet the growing demand for clean energy. Here we report a novel and environmentally friendly strategy for the preparation of MOF-derived bimetallic phosphide embedded in the carbonaceous matrix (FeNiP/C). With 3-dimensional hollow barrel shape and high specific surface, FeNiP/C-900 performs excellent OER catalytic performance, reaching a current density of 10 mA cm−2 at an overpotential of 229 mV with a low Tafel slope of 74.5 mV dec−1. Meantime, we explore the thermal conversion mechanism of P-containing MOF and the compositional changes during heat treatment.

The search on low-cost, ultra-stable, and high-performance non-novel metal replacements to the Pt-based catalysts for oxygen reduction reaction (ORR) is of great urgency. Herein, a bottom-up method has been proposed to synthesize unique hollow N-doped carbon spheres (HNCSs) from an initial amorphous coordination polymer (CP) template-assisted route for the first time. HNCSs exhibit competitively comparable high electrocatalytic ORR activity, excellent reaction selectivity, and stronger long-term stability and negligible methanol crossover effect compared to the commercial Pt/C under the alkaline medium. Together with the other two reported carbonaceous ORR catalysts, including SCSs and NGPCs, our HNCSs possess the lowest Tafel slope of 65.7 mV dec−1 which is close to Pt/C (62.6 mV dec−1), and show much enhanced ORR activity (JL = 5.34 mA cm−2) and stability (Retention = 96.5%, Time = 10 h). This CP-templated route for hollow carbon materials will shed light on a new synthetic strategy to prepare high-performance carbon-based and/or metal-free ORR catalysts.

Autophagy is a dynamic and highly regulated process of self-digestion responsible for cell survival and reaction to oxidative stress. As oxidative stress is increased in uremia and is associated with vascular calcification, we studied the role of autophagy in vascular calcification induced by phosphate. In an in vitro phosphate-induced calcification model of vascular smooth muscle cells (VSMCs) and in an in vivo model of chronic renal failure, autophagy was inhibited by the superoxide dismutase mimic MnTMPyP, superoxide dismutase-2 overexpression, and by knockdown of the sodium-dependent phosphate cotransporter Pit1. Although phosphate-induced VSMC apoptosis was reduced by an inhibitor of autophagy (3-methyladenine) and knockdown of autophagy protein 5, calcium deposition in VSMCs was increased during inhibition of autophagy, even with the apoptosis inhibitor Z-VAD-FMK. An inducer of autophagy, valproic acid, decreased calcification. Furthermore, 3-methyladenine significantly promoted phosphate-induced matrix vesicle release with increased alkaline phosphatase activity. Thus, autophagy may be an endogenous protective mechanism counteracting phosphate-induced vascular calcification by reducing matrix vesicle release. Therapeutic agents influencing the autophagic response may be of benefit to treat aging or disease-related vascular calcification and osteoporosis.

Vehicular ad hoc networks (VANETs) can significantly improve traffic safety and efficiency. The basic idea is to allow vehicles to send traffic information to roadside units (RSUs) or other vehicles. Vehicles have to be prevented from some attacks on their privacy and misuse of their private data. For this reason, security and privacy preservation issues are important prerequisites for VANETs. The identity-based batch verification (IBV) scheme has been recently proposed to make VANETs more secure and efficient for practical use. In this paper, we point out that the current IBV scheme has some security risks. We introduce an improved scheme that can satisfy the security and privacy desired by vehicles. The proposed IBV scheme provides the provable security in the random oracle model. In addition, the batch verification of the proposed scheme needs only a small constant number of pairing and point multiplication computations, independent of the number of messages. We show the efficiency advantages of the proposed scheme through performance evaluations in terms of computation delay and transmission overhead. Moreover, the extensive simulation is conducted to verify the efficiency and applicability of the proposed scheme in the real-world road environment and vehicular traffic.

Abstract Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer with the absence of targeted therapy, resulting in poor prognosis in patients. Chemotherapy remains the mainstay of treatment for TNBC; however, development of drug resistance is the main obstacle for successful treatments. In recent years, long non-coding RNA (lncRNA) has been implicated in multiple biological functions in various diseases, particularly cancers. Accumulating evidence suggested that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression is dysregulated in many human cancers and thus is a useful prognostic marker for cancer patients. Nevertheless, the mechanism of how NEAT1 confers drug resistance in TNBC is still largely unknown. We performed lncRNA profiling by the LncRNA Profiler qPCR Array Kit in normal control (NC) and breast cancers (BC) blood samples and further validated in a larger cohort of samples by qRT-PCR. Gene expression level and localization were investigated by qRT-PCR, western blotting, and immunofluorescence staining. Flow cytometric analysis was carried out to detect cancer stem cells. Functional studies were performed both in vitro and in vivo xenograft model. Among 90 lncRNAs, NEAT1 was highly expressed in the blood samples of breast cancer patients than in NC. In particular, the expression of NEAT1 was higher in TNBC tissues than other subgroups. Functional studies revealed that NEAT1 conferred oncogenic role by regulating apoptosis and cell cycle progression in TNBC cells. We identified that knockdown of NEAT1 sensitized cells to chemotherapy, indicating the involvement in chemoresistance. Importantly, shNEAT1 reduced stem cell populations such as CD44+/CD24−, ALDH+, and SOX2+, implicating that NEAT1 was closely related to cancer stemness in TNBC. Our data highlighted the roles of NEAT1 chemoresistance and cancer stemness, suggesting that it could be used as a new clinical therapeutic target for treating TNBC patients especially those with drug resistance.

Abstract The growing understanding of RNA functions and their crucial roles in diseases promotes the application of various RNAs to selectively function on hitherto “undruggable” proteins, transcripts and genes, thus potentially broadening the therapeutic targets. Several RNA-based medications have been approved for clinical use, while others are still under investigation or preclinical trials. Various techniques have been explored to promote RNA intracellular trafficking and metabolic stability, despite significant challenges in developing RNA-based therapeutics. In this review, the mechanisms of action, challenges, solutions, and clinical application of RNA-based therapeutics have been comprehensively summarized.

The physical and mechanical properties of cellular materials not only depend on the constituent materials but also on the microstructures. Here we show that, when the cellular materials are constructed by self-repeated representative volume elements, their effective elastic tensor can be obtained by a fast Fourier transform-based homogenization method. Numerical examples confirm that the bulk modulus of cellular material with the topology of triply periodic minimal surfaces such as Diamond, Gyroid, Neovius, and Schwarz P surfaces can approach to the upper Hashin-Shtrikman bound. However, the high values of their Young's modulus are obtained at the cost of low shear modulus and vice versa. Such conflicting behavior suggests that these two individual moduli may complement each other in a hybrid structure via combining different surfaces in cellular material. It is envisaged that our approach will enable the creation of ideal isotropic materials with large Young's modulus, shear modulus, and bulk modulus.

Carbon nanotubes (CNTs) have long been known as a class of one-dimensional carbon nanomaterials with sp2-hybridized structures that can be constructed with a very large length-to-diameter ratio, which is significantly larger than that of any other carbon nanomaterials. It is well known that CNTs exhibit many excellent properties in mechanics, electricity, chemistry, optics, etc., and are widely used in various fields, thus attracting scientists' attention. In this context, the development of new strategies for optimizing and synthesizing CNTs has far-reaching significance and demand. On the other hand, most metal-organic frameworks (MOFs) are microporous crystals constructed from ordered and uniform metal ions/clusters and organic linkers to obtain crystalline solids with potential porosity. Using MOF materials as precursors, hierarchical CNT-based composite materials, which are difficult to synthesize through the traditional catalyst-assisted chemical vapor deposition method, can be conveniently synthesized by thermal treatment at high temperature. In the process of converting MOFs into CNTs, MOF crystals are used as both catalysts and carbon sources, which are necessary for the growth of CNTs, and they are also used as templates and/or carriers for additional catalysts. Therefore, there are various possibilities for the thermal conversion of MOFs into CNT-based composite materials. In this review, we mainly summarize the two aspects of catalysts and synthetic strategies for MOF-derived CNT-based composite materials. Despite the rapid development in this area, there is still much space for exploration. In order to accurately control the synthesis of CNTs, we should deeply explore the thermal conversion process and mechanism for the conversion of MOFs into CNTs.

Abstract Chemoresistance remains the uppermost disincentive for cancer treatment on account of many genetic and epigenetic alterations. Long non-coding RNAs (lncRNAs) are emerging players in promoting cancer initiation and progression. However, the regulation and function in chemoresistance are largely unknown. Herein, we identified ARHGAP5-AS1 as a lncRNA upregulated in chemoresistant gastric cancer cells and its knockdown reversed chemoresistance. Meanwhile, high ARHGAP5-AS1 expression was associated with poor prognosis of gastric cancer patients. Intriguingly, its abundance is affected by autophagy and SQSTM1 is responsible for transporting ARHGAP5-AS1 to autophagosomes. Inhibition of autophagy in chemoresistant cells, thus, resulted in the upregulation of ARHGAP5-AS1. In turn, it activated the transcription of ARHGAP5 in the nucleus by directly interacting with ARHGAP5 promoter. Interestingly, ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m 6 A modification of ARHGAP5 mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. In summary, impaired autophagic degradation of lncRNA ARHGAP5-AS1 in chemoresistant cancer cells promoted chemoresistance. It can activate the transcription of ARHGAP5 in the nucleus and stimulate m 6 A modification of ARHGAP5 mRNA to stabilize ARHGAP5 mRNA in the cytoplasm by recruiting METTL3. Therefore, targeting ARHGAP5-AS1/ARHGAP5 axis might be a promising strategy to overcome chemoresistance in gastric cancer.

The metabolic syndrome (MetS) epidemic is associated with economic development, lifestyle transition and dysbiosis of gut microbiota, but these associations are rarely studied at the population scale. Here, we utilised the Guangdong Gut Microbiome Project (GGMP), the largest Eastern population-based gut microbiome dataset covering individuals with different economic statuses, to investigate the relationships between the gut microbiome and host physiology, diet, geography, physical activity and socioeconomic status.At the population level, 529 OTUs were significantly associated with MetS. OTUs from Proteobacteria and Firmicutes (other than Ruminococcaceae) were mainly positively associated with MetS, whereas those from Bacteroidetes and Ruminococcaceae were negatively associated with MetS. Two hundred fourteen OTUs were significantly associated with host economic status (140 positive and 74 negative associations), and 157 of these OTUs were also MetS associated. A microbial MetS index was formulated to represent the overall gut dysbiosis of MetS. The values of this index were significantly higher in MetS subjects regardless of their economic status or geographical location. The index values did not increase with increasing personal economic status, although the prevalence of MetS was significantly higher in people of higher economic status. With increased economic status, the study population tended to consume more fruits and vegetables and fewer grains, whereas meat consumption was unchanged. Sedentary time was significantly and positively associated with higher economic status. The MetS index showed an additive effect with sedentary lifestyle, as the prevalence of MetS in individuals with high MetS index values and unhealthy lifestyles was significantly higher than that in the rest of the population.The gut microbiome is associated with MetS and economic status. A prolonged sedentary lifestyle, rather than Westernised dietary patterns, was the most notable lifestyle change in our Eastern population along with economic development. Moreover, gut dysbiosis and a Western lifestyle had an additive effect on increasing MetS prevalence.

Amino acid transporters mediate substrates across cellular membranes and their fine-tuned regulations are critical to cellular metabolism, growth, and death. As the functional component of system Xc-, which imports extracellular cystine with intracellular glutamate release at a ratio of 1:1, SLC7A11 has diverse functional roles in regulating many pathophysiological processes such as cellular redox homeostasis, ferroptosis, and drug resistance in cancer. Notably, accumulated evidence demonstrated that SLC7A11 is overexpressed in many types of cancers and is associated with patients' poor prognosis. As a result, SLC7A11 becomes a new potential target for cancer therapy. In this review, we first briefly introduce the structure and function of SLC7A11, then discuss its pathological role in cancer. We next summarize current available data of how SLC7A11 is subjected to fine regulations at multiple levels. We further describe the potential inhibitors of the SLC7A11 and their roles in human cancer cells. Finally, we propose novel insights for future perspectives on the modulation of SLC7A11, as well as possible targeted strategies for SLC7A11-based anti-cancer therapies.

Automatically generating radiology reports can improve current clinical practice in diagnostic radiology. On one hand, it can relieve radiologists from the heavy burden of report writing; On the other hand, it can remind radiologists of abnormalities and avoid the misdiagnosis and missed diagnosis. Yet, this task remains a challenging job for data-driven neural networks, due to the serious visual and textual data biases. To this end, we propose a Posterior-and-Prior Knowledge Exploring-and-Distilling approach (PPKED) to imitate the working patterns of radiologists, who will first examine the abnormal regions and assign the disease topic tags to the abnormal regions, and then rely on the years of prior medical knowledge and prior working experience accumulations to write reports. Thus, the PPKED includes three modules: Posterior Knowledge Explorer (PoKE), Prior Knowledge Explorer (PrKE) and Multi-domain Knowledge Distiller (MKD). In detail, PoKE explores the posterior knowledge, which provides explicit abnormal visual regions to alleviate visual data bias; PrKE explores the prior knowledge from the prior medical knowledge graph (medical knowledge) and prior radiology reports (working experience) to alleviate textual data bias. The explored knowledge is distilled by the MKD to generate the final reports. Evaluated on MIMIC-CXR and IU-Xray datasets, our method is able to outperform previous state-of-the-art models on these two datasets.

Metabolic reprogramming is a hallmark of cancer. Mammalian genome is characterized by pervasive transcription, generating abundant non-coding RNAs (ncRNAs). Long non-coding RNAs (lncRNAs) are freshly discovered functional ncRNAs exerting extensive regulatory impact through diverse mechanisms. Emerging studies have revealed widespread roles of lncRNAs in the regulation of various cellular activities, including metabolic pathways. In this review, we summarize the latest advances regarding the regulatory roles of lncRNAs in cancer metabolism, particularly their roles in mitochondrial function, glucose, glutamine, and lipid metabolism. Moreover, we discuss the clinical application and challenges of targeting lncRNAs in cancer metabolism. Understanding the complex and special behavior of lncRNAs will allow a better depiction of cancer metabolic networks and permit the development of lncRNA-based clinical therapies by targeting cancer metabolism.

Reasonable design of the porous metal-organic frameworks (MOFs) to convert a burgeoning carbon-based catalysts with high oxygen reduction reaction (ORR) activity are still challenging in energy conversion, storage and transport. Herein, Fe7C3-doped in-situ grown carbon nanotubes and N-doped hollow carbon (Fex[email protected]) are prepared by using a simple and robust preparation method, which is used cubic ZIF-8-derived zinc oxide cubes as a template for secondary MOFs re-growth followed by the final carbonization. In the 0.1 M KOH, the as-pyrolyzed Fe0.1[email protected] electrocatalyst displays the value of half-wave potential is 0.92 V and the value of diffusion-limited current density is 6.08 mA cm−2, respectively, which are close to the corresponding electrochemical values of the standard commercial Pt/C (0.89 V and 5.89 mA cm−2). Meanwhile, the material has passed relevant tests on its long-term stability and methanol tolerance in alkaline media, showing that it has excellent ORR activity and efficient stability under electrocatalysis. Furthermore, the Fe0.1[email protected] materials catalyze a Zn-air battery that delivers a performed peak power density of 105.9 mW cm−2. The impressive catalytic activity of Fe0.1[email protected] stems from the effective synergy between efficient Fe and N co-doping, large specific surface area, and high electrical conductivity. This preparation route for carbon nanomaterials will provide a new synthetic strategy to synthesize high-performance non-noble metal carbon-based ORR catalysts for practical energy-related applications.

Exploring excellent microwave absorbing materials (MAMs) to manage the electromagnetic (EM) radiation and interference is still a grand challenge nowadays. In this work, NiFe Prussian blue analogues (NiFe-PBA) embedded in polyacrylonitrile (PAN) fibers is prepared by electrospinning, and the derived NiFe nanoparticles embedded in nitrogen doped carbon fibers ([email protected]) were synthesized followed a heat treatment process. Among the samples, the minimum reflection loss is −39.7 dB at 11.5 GHz with a small thickness of 2 mm and the broadest effective absorption bandwidth (EAB) is 4.6 GHz with a small thickness of only 1.45 mm. The excellent microwave absorption is attribute to the synergistic effect of suitable impedance matching and intrinsic strong attenuation capability. The quantity of NiFe-PBA embedded in PAN fiber-like precursors could effectively regulate the EM parameters of [email protected] by adjusting the conductivity and magnetic properties. It is believed that this work would opened up a way for designing novel light-weight, ultrathin-thickness, broadband, strong microwave attenuation capability of magnetic carbon-based MAMs.

Proton exchange membrane (PEM) water electrolysis shows advantages including high current density, high efficiency, and compact configuration but suffers from the scarcity and high price of iridium (Ir)-based anodic catalysts. Herein, insoluble niobium (Nb)-incorporated RuO2 with a high valence state was designed as an Ir-free catalyst for active and stable acidic oxygen evolution reaction (OER). Nb0.1Ru0.9O2 exhibited a low overpotential (204 mV) and superb stability with an ultralow degradation rate (25 μV/h) over a 360-h durability test at 200 mA cm−2, which is only 1/100th of the decay rates of other Ru-based catalysts measured at 10 mA cm−2. The PEM electrolyzer with Nb0.1Ru0.9O2 as an anode survived from a 100-h operation at 300 mA cm−2. The strengthened adsorption of oxygen intermediates to active Ru sites reduced the OER energy barrier, while the enhanced electron transfer to Ru by Nb doping and formation of Nb5+ during the OER process extended catalyst’s durability.

Magnesium phosphate cement (MPC) is a new cementing material with great development potential and excellent properties. In addition to traditional cement, MPC also has the characteristics of ceramics, refractory materials, and biological materials. The MPC materials can be applied especially in architecture and other fields such as wall spraying, structure repair, solid waste curing, biomedical engineering, and 3D printing. Nowadays, MPC materials are being used in more updated, cutting-edge applications. This paper mainly summarizes the research progress of MPC in terms of material properties and applications in various fields in recent years, analyzes the research results of various scholars, and discusses the future research direction and current problems to be solved.

The incidence of kidney stones in the United States is currently unknown. Here, we assessed the incidence of kidney stones using recent, nationally representative data.We used the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018. During this time participants were asked, "Have you ever had a kidney stone?" and "In the past 12 months, have you passed a kidney stone?" Demographics analyzed include age, race, gender, body mass index, history of smoking, diabetes, hypertension, hypercholesterolemia and gout. Multivariable models were used to assess the independent impact of subject characteristics on kidney stone prevalence and incidence.Data were available on 10,521 participants older than age 20. The prevalence of kidney stones was 11.0% (95% CI 10.1-12.0). The 12-month incidence of kidney stones was 2.1% (95% CI 1.5-2.7), or 2,054 stones per 100,000 adults. We identified significant relationships between stone incidence and subject age, body mass index, race and history of hypertension.Here we find a substantially higher 12-month incidence of kidney stones than previous reports. We also validate known risk factors for stone prevalence as associated with incidence. The remarkable incidence and prevalence of stones is concerning and has implications for disease prevention and allocation of medical resources.

Developing high-performance microwave absorbing materials is still a challenge to address the electromagnetic pollution. Interfacial engineering to heighten interfacial polarization plays a key role in microwave absorption. In this work, Multiple interfacial magnetic carbon nanotubes encapsulated hydrangea-like NiMo/MoC/N-doped carbon were prepared via carbothermic reduction. The phase structure and electromagnetic properties can be regulated by thermal treatment temperature. Dielectric loss mechanisms were analyzed deeply by Debye relaxation theory. The results indicated the composites exhibit excellent microwave absorption properties. Reflection loss (RL) less than −20 dB can be achieved in the frequency range of 3.76–17.52 GHz with the absorber thickness varied from 1.3 mm to 5.0 mm when the thermal treatment temperature was 700 °C. The strongest RL value reach to −70.1 dB at 14.2 GHz with the absorber thickness of only 1.52 mm when the thermal treatment temperature is 800 °C. The radar cross section (RCS) reduction calculated through computer simulation technology is used to analyze the microwave absorption capability in the actual far field. The RCS reduction is 17.05 dBm2 when the scattering angle is 0°. This work provided a novel approach for realizing the multi-interface absorbers for high-performance microwave absorption.

Abstract Background Chemoresistance to cisplatin (DDP) remains a major challenge in advanced gastric cancer (GC) treatment. Although accumulating evidence suggests an association between dysregulation of long non‐coding RNAs (lncRNAs) and chemoresistance, the regulatory functions and complexities of lncRNAs in modulating DDP‐based chemotherapy in GC remain under‐investigated. This study was designed to explore the critical chemoresistance‐related lncRNAs in GC and identify novel therapeutic targets for patients with chemoresistant GC. Methods Chemoresistance‐related lncRNAs were identified through microarray and verified through a quantitative real‐time polymerase chain reaction (qRT‐PCR). Proteins bound by lncRNAs were identified through a human proteome array and validated through RNA immunoprecipitation (RIP) and RNA pull‐down assays. Co‐immunoprecipitation and ubiquitination assays were performed to explore the molecular mechanisms of the Musashi2 (MSI2) post‐modification. The effects of LINC00942 (LNC942) and MSI2 on DDP‐based chemotherapy were investigated through MTS, apoptosis assays and xenograft tumour formation in vivo. Results LNC942 was found to be up‐regulated in chemoresistant GC cells, and its high expression was positively correlated with the poor prognosis of patients with GC. Functional studies indicated that LNC942 confers chemoresistance to GC cells by impairing apoptosis and inducing stemness. Mechanically, LNC942 up‐regulated the MSI2 expression by preventing its interaction with SCF β‐TRCP E3 ubiquitin ligase, eventually inhibiting ubiquitination. Then, LNC942 stabilized c‐Myc mRNA in an N6‐methyladenosine (m 6 A)‐dependent manner. As a potential m 6 A recognition protein, MSI2 stabilized c‐Myc mRNA with m 6 A modifications. Moreover, inhibition of the LNC942‐MSI2‐c‐Myc axis was found to restore chemosensitivity both in vitro and in vivo. Conclusions These results uncover a chemoresistant accelerating function of LNC942 in GC, and disrupting the LNC942‐MSI2‐c‐Myc axis could be a novel therapeutic strategy for GC patients undergoing chemoresistance.

Abstract Hollow carbon materials are regarded as crucial support materials in catalysis and electrochemical energy storage on account of their unique porous structure and electrical properties. Herein, an indium‐based organic framework of InOF‐1 can be thermally carbonized under inert argon to form indium particles through the redox reaction between nanosized indium oxide and carbon matrix. In particular, a type of porous hollow carbon nanostraw (HCNS) is in situ obtained by combining the fusion and removal of indium within the decarboxylation process. The as‐synthesized HCNS, which possesses more charge active sites, short and quick electron, and ion transport pathways, has become an excellent carrier for electrochemically active species such as iodine with its unique internal cavity and interconnected porous structure on the tube wall. Furthermore, the assembled zinc‐iodine batteries (ZIBs) provide a high capacity of 234.1 mAh g −1 at 1 A g −1 , which ensures that the adsorption and dissolution of iodine species in the electrolyte reach a rapid equilibrium. The rate and cycle performance of the HCNS‐based ZIBs are greatly improved, thereby exhibiting an excellent capacity retention rate. It shows a better electrochemical exchange capacity than typical unidirectional carbon nanotubes, making HCNS an ideal cathode material for a new generation of high‐performance batteries.

High-performance microwave absorption materials are considered to be an effective solution to the increasing electromagnetic pollution. In this work, Ti3C2Tx [email protected] double hydroxide (NiFe-LDH) derived multi-interfacial FeNi3/[email protected] carbon (NC)@magnetic multiwalled carbon nanotube composites were prepared by a hydrothermal process and subsequent carbothermal reduction. The phase compositions, morphology, defects and electromagnetic parameters of the composites can be regulated by the thermal treatment temperature. The reflection loss value of the composite with a thickness of only 1.6 mm can reach − 43.75 dB when the heat treatment temperature is 900 °C, and the effective absorption bandwidth is 5.5 GHz with a thickness of 2.12 mm when the heat treatment temperature is 700 °C. The synergistic effects among the associated dielectric loss, magnetic loss and the impedance matching of the samples are also systematically investigated. This work provides a new perspective and an effective approach for acquiring MXene hybrids derived high-performance microwave absorbing materials.

Abstract Introduction Cuproptosis and ferroptosis are the two newly defined metal-related regulated cell death. However, the crosstalk between cuproptosis and ferroptosis is obscure. Materials and methods We analyzed the effect of ferroptosis inducers on copper ionophores-induced cell death through CCK-8 assay. Cuproptosis was studied using immunofluorescence and protein soluble-insoluble fraction isolation. GSH assay, qRT-PCR and western blot were adopted to explore the machinery of ferroptosis inducers enhanced cuproptosis. And mouse xenograft model was built to detect the synergy effect of elesclomol-Cu and sorafenib in vivo. Results Herein we found that ferroptosis inducers sorafenib and erastin could enhance cuproptosis in primary liver cancer cells by increasing copper dependent lipoylated protein aggregation. Mechanically, sorafenib and erastin upregulated protein lipoylation via suppressing mitochondrial matrix-related proteases mediated ferredoxin 1 (FDX1) protein degradation, and reduced intracellular copper chelator glutathione (GSH) synthesis through inhibiting cystine importing. Discussion/Conclusion Our findings proposed that combination of ferroptosis inducers and copper ionophores to co-targeting ferroptosis and cuproptosis could be a novel therapeutic strategy for primary liver cancer.

Due to their small sizes, microrobots are advantageous for accessing hard-to-reach spaces for delivery and measurement. However, their small sizes also bring challenges in on-board powering, thus usually requiring actuation by external energy. Microrobots actuated by external energy have been applied to the fields of physics, biology, medical science, and engineering. Among these actuation sources, light and magnetic fields show advantages in high precision and high biocompatibility. This paper reviews the recent advances in the design, actuation, and applications of microrobots driven by light and magnetic fields. For light-driven microrobots, we summarized the uses of optical tweezers, optoelectronic tweezers, and heat-mediated optical manipulation techniques. For magnetically driven microrobots, we summarized the uses of torque-driven microrobots, force-driven microrobots, and shape-deformable microrobots. Then, we compared the two types of field-driven microrobots and reviewed their advantages and disadvantages. The paper concludes with an outlook for the joint use of optical and magnetic field actuation in microrobots.

The global epidemic of diabetes has brought heavy pressure on public health. New effective anti-diabetes strategies are urgently needed. Trigonelline is the main component of fenugreek, which has been proved to have a good therapeutic effect on diabetes and diabetic complications. Trigonelline achieves amelioration of diabetes, the mechanisms of which include the modulation of insulin secretion, a reduction in oxidative stress, and the improvement of glucose tolerance and insulin resistance. Besides, trigonelline has been reported to be a neuroprotective agent against many neurologic diseases including Alzheimer's disease, Parkinson's disease, stroke, and depression. Concerning the potential therapeutic effects of trigonelline, comprehensive clinical trials are warranted to evaluate this valuable molecule.

The metalloprotease ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 7) is a novel locus associated with human coronary atherosclerosis. ADAMTS-7 deletion protects against atherosclerosis and vascular restenosis in rodents.We designed 3 potential vaccines consisting of distinct B cell epitopic peptides derived from ADAMTS-7 and conjugated with the carrier protein KLH (keyhole limpet hemocyanin) as well as aluminum hydroxide as an adjuvant. Arterial ligation or wire injury was used to induce neointima in mice, whereas ApoE-/- and LDLR-/- (LDLR [low-density lipoprotein receptor]) mice fed a high-fat diet were applied to assess atherosclerosis. In addition, coronary stent implantation was performed on vaccine-immunized Bama miniature pigs, followed by optical coherence tomography to evaluate coronary intimal hyperplasia.A vaccine, ATS7vac, was screened out from 3 candidates to effectively inhibit intimal thickening in murine carotid artery ligation models after vaccination. As well, immunization with ATS7vac alleviated neointima formation in murine wire injury models and mitigated atherosclerotic lesions in both hyperlipidemic ApoE-/- and LDLR-/- mice without lowering lipid levels. Preclinically, ATS7vac markedly impeded intimal hyperplasia in swine stented coronary arteries, but without significant immune-related organ injuries. Mechanistically, ATS7vac vaccination produced specific antibodies against ADAMTS-7, which markedly repressed ADAMTS-7-mediated COMP (cartilage oligomeric matrix protein) and TSP-1 (thrombospondin-1) degradation and subsequently inhibited vascular smooth muscle cell migration but promoted re-endothelialization.ATS7vac is a novel atherosclerosis vaccine that also alleviates in-stent restenosis. The application of ATS7vac would be a complementary therapeutic avenue to the current lipid-lowering strategy for atherosclerotic disease.

TM-Nx is becoming a comforting catalytic center for sustainable and green ammonia synthesis under ambient conditions, resulting in increasing interest in single-atom catalysts (SACs) for the electrochemical nitrogen reduction reaction (NRR). However, given the poor activity and unsatisfactory selectivity of existing catalysts, it remains a long-standing challenge to design efficient catalysts for nitrogen fixation. Currently, the two-dimensional (2D) graphitic carbon-nitride substrate provides abundant and evenly distributed holes for stably supporting transition-metal atoms, which presents a fascinating prospect for overcoming this challenge and promoting single-atom NRR. An emerging holey graphitic carbon-nitride skeleton with a C10N3 stoichiometric ratio (g-C10N3) from a supercell of graphene is constructed, which provides outstanding electric conductivity for achieving high-efficiency NRR due to the Dirac band dispersion. Herein, a high-throughput first-principles calculation is carried out to evaluate the feasibility of π–d conjugated SACs resulting from a single TM atom anchored on g-C10N3 (TM = Sc–Au) for NRR. We find that W metal embedded in g-C10N3 (W@g-C10N3) can compromise the ability to adsorb the key target reaction species (N2H and NH2), hence acquiring an optimal NRR behavior among 27 TM-candidates. Our calculations demonstrate that W@g-C10N3 shows a well-suppressed HER ability and, impressively, a low energy cost of −0.46 V. Additionally, all-around descriptors are proposed to uncover the fundamental mechanism of NRR activity, among which a 3D volcano plot (limiting potential, screening strategy, and electron origin) uncovers the NRR activity trend, achieving a quick and high-efficiency prescreening for numerous candidates. Overall, the strategy of the structure- and activity-based TM-Nx-containing unit design will offer useful insight for further theoretical and experimental attempts.

Metal-nitrogen-carbon materials are the most promising platinum replacement catalysts for oxygen reduction reaction. However, lacking an efficient approach to improve durability—i.e., to cope with the attack by in situ formed radicals, leaching of central ions, etc.—has limited these catalysts from widespread application. Herein we present a novel, dual-metal, single-atom catalyst design (Fe,Ce-N-C) to confront the formidable deactivation issue of the best-performing yet unstable Fe-N-C catalysts. Cerium single sites are revealed as efficient chemical catalysts to catalyze the H2O2 disproportionation into O2, leading to increased 4e selectivity. Moreover, rather than Fe single sites that catalyze the formation of reactive ·OH and ·OOH species, these cerium single sites act proactively to eliminate in situ-generated radicals. The final Fe,Ce-N-C catalyst represents excellent durability exceeding that of Fe-N-C. This work opens a new path to alleviate the degradation of Fe-N-C catalysts in an acidic medium.

Recent years have witnessed the rapid accumulation of massive electronic medical records, which highly support intelligent medical services such as drug recommendation. However, although there are multiple interaction types between drugs, e.g., synergism and antagonism, which can influence the effect of a drug package significantly, prior arts generally neglect the interaction between drugs or consider only a single type of interaction. Moreover, most existing studies generally formulate the problem of package recommendation as getting a personalized scoring function for users, despite the limits of discriminative models to achieve satisfactory performance in practical applications. To this end, in this article, we propose a novel end-to-end Drug Package Generation (DPG) framework, which develops a new generative model for drug package recommendation that considers the interaction effects between drugs that are affected by patient conditions. Specifically, we propose to formulate the drug package generation as a sequence generation process. Along this line, we first initialize the drug interaction graph based on medical records and domain knowledge. Then, we design a novel message-passing neural network to capture the drug interaction, as well as a drug package generator based on a recurrent neural network. In detail, a mask layer is utilized to capture the impact of patient condition, and the deep reinforcement learning technique is leveraged to reduce the dependence on the drug order. Finally, extensive experiments on a real-world dataset from a first-rate hospital demonstrate the effectiveness of our DPG framework compared with several competitive baseline methods.

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease.

The boom of product review websites, blogs and forums on the web has attracted many research efforts on opinion mining. Recently, there was a growing interest in the finer-grained opinion mining, which detects opinions on different review features as opposed to the whole review level. The researches on feature-level opinion mining mainly rely on identifying the explicit relatedness between product feature words and opinion words in reviews. However, the sentiment relatedness between the two objects is usually complicated. For many cases, product feature words are implied by the opinion words in reviews. The detection of such hidden sentiment association is still a big challenge in opinion mining. Especially, it is an even harder task of feature-level opinion mining on Chinese reviews due to the nature of Chinese language. In this paper, we propose a novel mutual reinforcement approach to deal with the feature-level opinion mining problem. More specially, 1) the approach clusters product features and opinion words simultaneously and iteratively by fusing both their content information and sentiment link information. 2) under the same framework, based on the product feature categories and opinion word groups, we construct the sentiment association set between the two groups of data objects by identifying their strongest n sentiment links. Moreover, knowledge from multi-source is incorporated to enhance clustering in the procedure. Based on the pre-constructed association set, our approach can largely predict opinions relating to different product features, even for the case without the explicit appearance of product feature words in reviews. Thus it provides a more accurate opinion evaluation. The experimental results demonstrate that our method outperforms the state-of-art algorithms.

The migration of vascular smooth muscle cells (VSMCs) plays an essential role during the development of atherosclerosis and restenosis. Extensive studies have implicated the importance of extracellular matrix (ECM)-degrading proteinases in VSMC migration. A recently described family of proteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), is capable of degrading vascular ECM proteins. Here, we sought to determine whether ADAMTS-7 is involved in VSMC migration and neointima formation in response to vascular injury. ADAMTS-7 protein accumulated preferentially in neointima of the carotid artery wall after balloon injury. In primary VSMCs, ADAMTS-7 level was enhanced by the proinflammatory cytokine tumor necrosis factor alpha and growth factor platelet-derived growth factor-BB. ADAMTS-7 overexpression greatly accelerated and small interfering RNA knockdown markedly retarded VSMC migration/invasion in vitro. In addition, luminal delivery of ADAMTS-7 adenovirus to carotid arteries exacerbated intimal thickening nearly sixfold 7 days after injury. Conversely, perivascular administration of ADAMTS-7 small interfering RNA but not scramble small interfering RNA to injured arteries attenuated intimal thickening by 50% at 14 days after injury. Furthermore, ADAMTS-7 mediated degradation of the vascular ECM cartilage oligomeric matrix protein (COMP) in injured vessels. Replenishing COMP circumvented the promigratory effect of ADAMTS-7 on VSMCs. Enforced expression of COMP significantly suppressed VSMC migration and neointima formation postinjury, which indicates that ADAMTS-7 facilitated intimal hyperplasia through degradation of inhibitory matrix protein COMP. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.

Hyperphosphatemia is the major risk factor associated with vascular calcification (VC) in end-stage renal disease. As oxidative stress is increased in uremia, we studied the role of mitochondrial reactive oxygen species (ROS) and nuclear factor-κB signaling in phosphate-induced VC. In an in vitro calcification model (β-glycerophosphate (BGP) induction) using bovine aortic smooth muscle cells, the production of intracellular and mitochondrial ROS, or superoxide anion, was stimulated by increased mitochondrial membrane potential. This effect was blocked by the superoxide dismutase (SOD) mimic MnTMPyP, a respiratory chain inhibitor rotenone, or a protonophore. Calcium deposition and the switch of smooth muscle cells from a contractile to an osteogenic phenotype were decreased when mitochondrial ROS generation was inhibited by the respiratory chain inhibitor, MnTMPyP, or the overexpression of SOD1 and SOD2 and uncoupling protein 2. The phosphorylation of IkKβ, IκBα degradation, and p65 nuclear translocation were increased by BGP but reversed when mitochondrial ROS production was blocked by protonophore or MnTMPyP. Knockdown of endogenous p65 or overexpression of IκBα reduced calcium deposition in the cultured cells. Furthermore, in a rat model of dietary adenine-induced chronic renal failure, MnTMPyP reduced aortic ROS levels, p65 activation, and calcium deposition. Thus, mitochondrial ROS-mediated p65 nuclear translocation is involved in phosphate-induced VC.

A broadband metamaterial absorber (MA) based on lumped elements is presented, which is composed of the dielectric substrate sandwiched with metal split-coin resonators (SCR) welded with lumped elements and continuous metal film. We simulated, fabricated, and measured the lumped elements MA. Compared with the single SCR structure MA, the composite MA loaded with lumped elements has a wider absorptivity and works in a lower frequency. The experiment results show that the bandwidth of absorption of 90% is about 1.5 GHz and the full width at half maximum (FWHM) can be up to 50%, the absorptivity is also nearly unchanged for different polarizations. The further simulations of the absorptivity of composite MA with different lumped resistances and capacitances indicate that there exist optimal values for lumped resistances and capacitances, where the absorptivity is the highest and the bandwidth is the widest.

Homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are major chemokines for leukocyte trafficking and have been identified in atheromatous plaques. MCP-1 and IL-8 have been found to express mainly by macrophages in human lesion. We undertook this study to determine whether Hcy could induce the secretion of chemokines from human monocytes and, if so, to explore the mediating mechanism. We found that clinically relevant levels of Hcy (10 to 1000 micromol/L) increased the protein secretion and mRNA expression as well as activity of MCP-1 and IL-8 in cultured primary human monocytes. These effects of Hcy were primarily mediated by reactive oxygen species (ROS) through NAD(P)H oxidase, because Hcy could upregulate the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers, or NAD(P)H oxidase abolished Hcy-induced ROS production and MCP-1 and IL-8 secretion in these cells. Furthermore, the inhibitors of mitogen-activated protein kinase (p38 and extracellular signal-regulated kinase 1/2) and nuclear factor-kappaB or the activator of peroxisome proliferator-activated receptor gamma (PPARgamma) significantly decreased Hcy-induced MCP-1 and IL-8 secretion in these cells. These data indicate that pathophysiological levels of Hcy can alter human monocyte function by upregulating MCP-1 and IL-8 expression and secretion via enhanced formation of intracellular ROS originated from NAD(P)H oxidase source via calmodulin or protein kinase C signaling pathways and that Hcy-induced ROS subsequently activates mitogen-activated protein kinase (p38 and ERK1/2) and nuclear factor-kappaB in a PPARgamma activator-sensitive manner. Thus, activation of PPARgamma may become a therapeutic target for preventing Hcy-induced proatherogenic effects.

Endothelial activation is implicated in atherogenesis and diabetes. The role of peroxisome proliferator-activated receptor-delta (PPAR-delta) in endothelial activation remains poorly understood. In this study, we investigated the anti-inflammatory effect of PPAR-delta and the mechanism involved.In human umbilical vein endothelial cells (HUVECs), the synthetic PPAR-delta ligands GW0742 and GW501516 significantly inhibited tumor necrosis factor (TNF)-alpha-induced expression of vascular cell adhesion molecule-1 and E-selectin (assayed by real-time RT-PCR and Northern blotting), as well as the ensuing endothelial-leukocyte adhesion. Activation of PPAR-delta upregulated the expression of antioxidant genes superoxide dismutase 1, catalase, and thioredoxin and decreased reactive oxygen species production in ECs. Chromatin immunoprecipitation assays showed that GW0742 switched the association of BCL-6, a transcription repressor, from PPAR-delta to the vascular cell adhesion molecule (VCAM)-1 promoter. Small interfering RNA reduced endogenous PPAR-delta expression but potentiated the suppressive effect of GW0742 on EC activation, which suggests that the nonliganded PPAR-delta may have an opposite effect.We have demonstrated that ligand activation of PPAR-delta in ECs has a potent antiinflammatory effect, probably via a binary mechanism involving the induction of antioxidative genes and the release of nuclear corepressors. PPAR-delta agonists may have a potential for treating inflammatory diseases such as atherosclerosis and diabetes.

In this paper, we concern with a class of Kirchhoff-type problems in RN. By using the Fountain Theorem we obtain three existence results of infinitely many radial solutions for the problem.

A new non-fullerene small molecule with an acceptor-donor-acceptor (A-D-A) structure, FDNCTF, incorporating fluorenedicyclopentathiophene as core and naphthyl-fused indanone as end groups, was designed and synthesized. Compared with the previous molecule FDICTF with the phenyl-fused indanone as the end groups, the extended π-conjugation at the end group has only little impact on its molecular orbital energy levels, and thus, the open-circuit voltage (Voc) of its solar cell devices has been kept high. However, its light absorption and mobility, together with the short-current density (Jsc) and the fill factor (FF), of its devices have been all improved simultaneously. Through morphology, transient absorption, and theoretical studies, it is believed that these favorable changes are caused by (1) the appropriately enhanced molecular interaction between donor/acceptor which makes the charge separation at the interface more efficient, and (2) enhanced light absorption and more ordered packing at solid state, all due to the extended end-group conjugation of this molecule. With these, the solar cells with FDNCTF as the acceptor and a wide band gap polymer PBDB-T as the donor demonstrated a high power conversion efficiency (PCE) of 11.2% with an enhanced Jsc and a maintained high Voc, and significantly improved FF of 72.7% compared with that of the devices of FDICTF with the phenyl-fused indanone as the end groups. These results indicate that the unexplored conjugation size of the end group plays a critical role for the performance of their solar cell devices.

Primary nonalcoholic fatty liver disease is one of the most common forms of chronic liver diseases and is associated with insulin-resistant states such as diabetes and obesity. Recent work has revealed potential implications of peroxisome proliferator-activated receptor-delta (PPARdelta) in lipid homeostasis and insulin resistance. In this study, we examined the effect of PPARdelta on sterol regulatory element-binding protein-1 (SREBP-1), a pivotal transcription factor controlling lipogenesis in hepatocytes. Treatment with GW0742, the PPARdelta agonist, or overexpression of PPARdelta markedly reduced intracellular lipid accumulation. GW0742 and PPARdelta overexpression in hepatocytes induced the expression of insulin-induced gene-1 (Insig-1), an endoplasmic reticulum protein braking SREBP activation, at both the mRNA and the protein levels. PPARdelta inhibited the proteolytic processing of SREBP-1 into the mature active form, thereby suppressing the expression of the lipogenic genes fatty acid synthase, stearyl CoA desaturase-1, and acetyl coenzyme A carboxylase. Our results revealed a direct binding of PPARdelta to a noncanonical peroxisome proliferator responsive element motif upstream of the transcription initiation site of human Insig-1. The disruption of this site diminished the induction of Insig-1, which suggested that Insig-1 is a direct PPARdelta target gene in hepatocytes. Knockdown of endogenous Insig-1 attenuated the suppressive effect of GW0742 on SREBP-1 and its target genes, indicating PPARdelta inhibited SREBP-1 activation via induction of Insig-1. Furthermore, overexpression of PPARdelta by intravenous infection with the PPARdelta adenovirus induced the expression of Insig-1, suppressed SREBP-1 activation, and, consequently, ameliorated hepatic steatosis in obese db/db mice.Our study reveals a novel mechanism by which PPARdelta regulates lipogenesis, suggesting potential therapeutic applications of PPARdelta modulators in obesity and type 2 diabetes, as well as related steatotic liver diseases.

In the present paper, we use variational methods to prove two existence results of positive solutions of the following Kirchhoff type problems {−(a+b∫Ω|∇u|2)Δu=f(x,u),in Ω;u=0,on ∂Ω. One deals with the asymptotic behaviors of f near zero and infinity and the other deals with 4-superlinear of f at infinity.

Vascular calcification is a major risk factor of cardiovascular mortality, particularly for patients with end-stage renal disease and diabetes. Although chronic inflammation is one of the etiologic factors, the underlying mechanism is not fully understood. To clarify this, we studied how nuclear factor-kappa B (NF-κB) induction, a mediator of inflammation, might promote vascular calcification. Activation of NF-κB by tumor necrosis factor (TNF) promoted inorganic phosphate-induced calcification in human aortic smooth muscle cells. Pyrophosphate (an inhibitor of calcification) efflux to the extracellular matrix was suppressed along with the decreased expression of ankylosis protein homolog (ANKH), a transmembrane protein that controls pyrophosphate efflux of cells. The restoration of ANKH expression in these cells overcame the decreased pyrophosphate efflux and calcification. Tristetraprolin, a downstream product of NF-κB activation, may mediate destabilization of ANKH mRNA as its knockdown by shRNA increased ANKH expression and decreased calcification. Furthermore, a rat chronic renal failure model, with increased serum TNF levels, activated NF-κB and decreased ANKH levels. In contrast, the inhibition of NF-κB maintained ANKH expression and attenuated vascular calcification both in vivo and in vitro. Both human calcified atherosclerotic lesions and arteries from patients with chronic kidney disease had activated NF-κB and decreased ANKH expression. Thus, TNF-activated NF-κB promotes inflammation-accelerated vascular calcification by inhibiting ankylosis protein homolog expression and consequent pyrophosphate secretion.

ADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, was recently identified to be significantly associated genomewide with coronary artery disease. However, the mechanisms that link ADAMTS-7 and coronary artery disease risk remain elusive. We have previously demonstrated that ADAMTS-7 promotes vascular smooth muscle cell migration and postinjury neointima formation via degradation of a matrix protein cartilage oligomeric matrix protein. Because delayed endothelium repair renders neointima and atherosclerosis plaque formation after vessel injury, we examined whether ADAMTS-7 also inhibits re-endothelialization.Wire injury of the carotid artery and Evans blue staining were performed in Adamts7(-/-) and wild-type mice. Adamts-7 deficiency greatly promoted re-endothelialization at 3, 5, and 7 days after injury. Consequently, Adamts-7 deficiency substantially ameliorated neointima formation in mice at days 14 and 28 after injury in comparison with the wild type. In vitro studies further indicated that ADAMTS-7 inhibited both endothelial cell proliferation and migration. Surprisingly, cartilage oligomeric matrix protein deficiency did not affect endothelial cell proliferation/migration and re-endothelialization in mice. In a further examination of other potential vascular substrates of ADAMTS-7, a label-free liquid chromatography-tandem mass spectrometry secretome analysis revealed thrombospondin-1 as a potential ADAMTS-7 target. The subsequent studies showed that ADAMTS-7 was directly associated with thrombospondin-1 by its C terminus and degraded thrombospondin-1 in vivo and in vitro. The inhibitory effect of ADAMTS-7 on postinjury endothelium recovery was circumvented in Tsp1(-/-) mice.Our study revealed a novel mechanism by which ADAMTS-7 affects neointima formation. Thus, ADAMTS-7 is a promising treatment target for postinjury vascular intima hyperplasia.

Characterizing the genetic alterations leading to the more aggressive forms of oestrogen receptor-positive (ER+) breast cancers is of critical significance in breast cancer management. Here we identify recurrent rearrangements between the oestrogen receptor gene ESR1 and its neighbour CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal B tumours, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1-CCDC170-positive tumours. These fusions encode amino-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity and enhanced xenograft tumour formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signalling and enhance cell motility. Together, this study identifies neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer.

Previously, we reported that polyploid giant cancer cells (PGCCs) induced by cobalt chloride (CoCl2) could have generated daughter cells with strong invasiveness and migration capabilities via asymmetric divisions. This study compared the expression of epithelial-mesenchymal transition (EMT)-related proteins, including E-cadherin, N-cadherin, and vimentin, between PGCCs and their daughter cells, and control breast cancer cell lines MCF-7 and MDA-MB-231. The clinicopathological significance of EMT-related protein expression in human breast cancer was analyzed.Western blot was used to compare the expression levels of E-cadherin, N-cadherin, and vimentin in breast cancer lines MCF-7 and MDA-MB-231, between PGCCs with budding daughter cells and control breast cancer cells. Furthermore, 167 paraffin-embedded breast tumor tissue samples were analyzed, including samples obtained from 52 patients with primary breast cancer with lymph node metastasis (group I) and their corresponding lymph node metastatic tumors (group II), 52 patients with primary breast cancer without metastasis (group III), and 11 patients with benign breast lesions (group IV). The number of PGCCs was compared among these four groups.The number of PGCCs increased with the malignant grade of breast tumor. Group IIhad the highest number of PGCCs and the differences among group I, II, III and IV had statistically significance (P =0.000). In addition, the expression of E-cadherin (P = 0.000), N-cadherin (P = 0.000), and vimentin (P = 0.000) was significantly different among the four groups. Group II exhibited the highest expression levels of N-cadherin and vimentin and the lowest expression levels of E-cadherin.These data suggest that the number of PGCCs and the EMT-related proteins E-cadherin, N-cadherin, and vimentin may be valuable biomarkers to assess metastasis in patients with breast cancer.

Sketch-based face recognition is an interesting task in vision and multimedia research, yet it is quite challenging due to the great difference between face photos and sketches. In this paper, we propose a novel approach for photo-sketch generation, aiming to automatically transform face photos into detail-preserving personal sketches. Unlike the traditional models synthesizing sketches based on a dictionary of exemplars, we develop a fully convolutional network to learn the end-to-end photo-sketch mapping. Our approach takes whole face photos as inputs and directly generates the corresponding sketch images with efficient inference and learning, in which the architecture is stacked by only convolutional kernels of very small sizes. To well capture the person identity during the photo-sketch transformation, we define our optimization objective in the form of joint generative discriminative minimization. In particular, a discriminative regularization term is incorporated into the photo-sketch generation, enhancing the discriminability of the generated person sketches against other individuals. Extensive experiments on several standard benchmarks suggest that our approach outperforms other state-of-the-arts in both photo sketch generation and face sketch verification.

HBV infection continues to be an important worldwide cause of morbidity and mortality. Patients with chronic hepatitis B can be successfully treated using nucleoside/nucleotide analogues. However, drug-resistant HBV mutants frequently arise, leading to treatment failure and progression to liver disease. Here, we report the effects of GLS4, a non-nucleosidic inhibitor that exhibits a novel and highly specific anti-HBV activity.The median inhibitory concentrations (IC(50)s) of GLS4 on HBV were measured by Southern blotting. HBV capsid and core protein levels were detected by immunoblotting. To determine the antiviral activity of GLS4 against adefovir dipivoxil (ADV)-resistant HBV mutants, HepG2 cells transiently transfected with PUC-HBV1.2 plasmids that contained one of three major ADV-resistant mutations (rtA181T, rtA181V and rtN236T) were treated with GLS4. Intracellular HBV replicative intermediates were detected by Southern blotting. The effect on the in vitro assembly of HBV capsid protein was examined using dynamic light scattering and electron microscopy.The IC(50) of GLS4 was 0.012 μM, which is significantly lower than that of lamivudine (0.325 μM). Immunoblot analysis of HepG2.2.15 cells and transiently transfected HepG2 cells indicated that GLS4 treatment interfered with the formation of core particles (assembly). The ADV-resistant HBV mutant strains were also sensitive to GLS4. Upon examining the in vitro assembly of HBV core protein 149 by electron microscopy, increased aberrant particles were observed after GLS4 treatment.GLS4 is a new and unique potential anti-HBV agent that possesses a different mechanism of action than existing therapeutic drugs.

Vascular smooth muscle cells (VSMCs) switching from a contractile/differentiated to a synthetic/dedifferentiated phenotype has an essential role in atherosclerosis, postangioplastic restenosis and hypertension. However, how normal VSMCs maintain the differentiated state is less understood.We aimed to indentify the effect of cartilage oligomeric matrix protein (COMP), a normal vascular extracellular matrix, on modulation of VSMCs phenotype.We demonstrated that COMP was associated positively with the expression of VSMC differentiation marker genes during phenotype transition. Knockdown of COMP by small interfering (si)RNA favored dedifferentiation. Conversely, adenoviral overexpression of COMP markedly suppressed platelet-derived growth factor-BB-elicited VSMC dedifferentiation, characterized by altered VSMC morphology, actin fiber organization, focal adhesion assembly, and the expression of phenotype-dependent markers. Whereas alpha(7) integrin coimmunoprecipitated with COMP in normal rat VSMCs and vessels, neutralizing antibody or siRNA against alpha(7) integrin inhibited VSMC adhesion to COMP, which indicated that alpha(7)beta(1) integrin is a potential receptor for COMP. As well, blocking or interference by siRNA of alpha(7) integrin completely abolished the effect of COMP on conserving the contractile phenotype. In accordance, ectopic adenoviral overexpression of COMP greatly retarded VSMC phenotype switching, rescued contractility of carotid artery ring, and inhibited neointima formation in balloon-injured rats.Our data suggest that COMP is essential for maintaining a VSMC contractile phenotype and the protective effects of COMP are mainly mediated through interaction with alpha(7)beta(1) integrin. Investigations to identify the factors affecting the expression and integrity of COMP may provide a novel therapeutic target for vascular disorders.

Vascular calcification significantly increases cardiovascular morbidity and mortality. We recently reported that the deficiency of cartilage oligomeric matrix protein (COMP) leads to vascular mineralization. We characterized the COMP-degrading metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7). Here, we tested whether ADAMTS-7 facilitates vascular calcification.ADAMTS-7 expression was markedly upregulated in calcifying rat vascular smooth muscle cells (VSMCs) in vitro, calcified arteries of rats with chronic renal failure in vivo, and radial arteries of uraemic patients. Silencing of ADAMTS-7 markedly reduced COMP degradation and ameliorated VSMC calcification, whereas ectopic expression of ADAMTS-7 greatly enhanced COMP degradation and exacerbated mineralization. The transcriptional activity of ADAMTS-7 promoter was not altered by high phosphate. We used bioinformatics and quantitative polymerase chain reaction analysis to demonstrate that high-phosphate upregulated ADAMTS-7 mRNA and protein via miR-29a/b repression, which directly targeted the 3' untranslated region of ADAMTS-7 in VSMCs. MicroRNA (MiR)-29a/b mimic markedly inhibited but miR-29a/b inhibitor greatly enhanced high-phosphate-induced ADAMTS-7 expression, COMP degradation, and subsequent VSMC calcification. ADAMTS-7 silencing significantly diminished miR-29a/b repression-exaggerated VSMC calcification.Our data reveal a novel mechanism by which ADAMTS-7 upregulation by miR-29a/b repression mediates vascular calcification, which may shed light on preventing cardiovascular morbidity and mortality.

The ZnS nanoflower architectures reach a high visible light photocatalytic hydrogen production activity with the deposition of a small portion of CuS nanoparticles.

The epidermal growth factor receptor (EGFR) is a kind of receptor tyrosine kinase (RTK) that plays a critical role in the initiation and development of malignant tumors via modulating downstream signaling pathways. In non-small cell lung cancer (NSCLC), the activating mutations located in the tyrosine kinase domains of EGFR have been demonstrated in multiple researches as the "Achilles' heel" of this deadly disease since they could be well-targeted by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, it's still too early to celebrate since the first-generation EGFR-TKIs such as gefitinib and erlotinib have only achieved limited clinical benefits and acquired resistance to this kind of drugs occurred inevitably in almost all the NSCLC patients. In order to make the most of EGFR-TKIs and develop more effective regimens for the NSCLC patients, researchers majoring in different aspects start a battle against EGFR-TKI resistance. Challenging as it is, we still progress stably and step firmly toward the final victory. This review will summarize the major mechanisms of acquired resistance to EGFR-TKIs, and then discuss the development of rationally designed molecular target drugs in accordance with each mechanism, in the hope of shedding light on the great achievements we have obtained and tough obstacles we have to overcome in the battle against this deadly disease.

Rationale: Vascular calcification is a significant contributor to cardiovascular morbidity and mortality. We recently reported that cartilage oligomeric matrix protein (COMP) is pivotal for maintaining the homeostasis of vascular smooth muscle cells (VSMCs). Whether COMP affects the process of vascular calcification is unknown. Objective: We aimed to test whether COMP modulates vascular calcification. Methods and Results: VSMC calcification in vitro was induced by calcifying media containing high inorganic phosphate or calcium. In vivo medial vessel calcification was induced in rats by 5/6 nephrectomy with a high-phosphate diet or by periadventitial application of CaCl 2 to the abdominal aorta. COMP protein level was markedly reduced in both calcified VSMCs and arteries. COMP deficiency remarkably exacerbated VSMC calcification, whereas ectopic expression of COMP greatly reduced calcification. Furthermore, COMP knockdown facilitated osteogenic markers expression by VSMCs even in the absence of calcifying media. By contrast, COMP overexpression significantly inhibited high phosphate– or high calcium–induced VSMC osteochondrogenic transition. Induction of osteogenic marker expression by COMP silencing was reversed by a soluble form of bone morphogenetic protein (BMP)-2 receptor IA, which suggests a BMP-2–dependent mechanism. Our data revealed that COMP bound directly to BMP-2 through the C terminus, inhibited BMP-2 receptor binding, and blocked BMP-2 osteogenic signaling, indicating COMP inhibits osteochondrogenic transition of VSMCs at least partially through inhibiting BMP-2. Conclusions: Our data strongly suggest that COMP is a novel inhibitor of vascular calcification. The imbalance between the effects of COMP and BMP-2 may provide new insights into the pathophysiology of vascular calcification.

Traditional auxetic lattices are featured with negative Poisson's ratio but weak stiffness. In this work, a set of auxetic lattices with enhanced stiffness are proposed by adding a strengthening rib into conventional auxetic unit cells in a direction perpendicular to the re-entrant direction. The effective mechanical properties of these variants are calculated using the fast Fourier transform-based homogenization method, which show that their Young's modulus in 2D can be improved by approximately 200% along the strengthening direction without significant sacrifice of auxetic property. However, such an enhancement is weakened in 3D as the variant of a tetrahedral cell has an approximate 100% improvement of Young's modulus only at low relative density. Though the stiffness of a variant hexahedral cell can be doubled in 3D at a wide range of relative density, its Poisson's ratio remains negative only in a narrow range of relative density. The findings in this work will offer new opportunities for the applications of auxetic materials which not only need negative Poisson's ratio but also high stiffness.

Homocysteine is a sulphur‐containing non‐proteinogenic amino acid. Hyperhomocysteinaemia (HHcy), the pathogenic elevation of plasma homocysteine as a result of an imbalance of its metabolism, is an independent risk factor for various vascular diseases, such as atherosclerosis, hypertension, vascular calcification and aneurysm. Treatments aimed at lowering plasma homocysteine via dietary supplementation with folic acids and vitamin B are more effective in preventing vascular disease where the population has a normally low folate consumption than in areas with higher dietary folate. To date, the mechanisms of HHcy‐induced vascular injury are not fully understood. HHcy increases oxidative stress and its downstream signalling pathways, resulting in vascular inflammation. HHcy also causes vascular injury via endoplasmic reticulum stress. Moreover, HHcy up‐regulates pathogenic genes and down‐regulates protective genes via DNA demethylation and methylation respectively. Homocysteinylation of proteins induced by homocysteine also contributes to vascular injury by modulating intracellular redox state and altering protein function. Furthermore, HHcy‐induced vascular injury leads to neuronal damage and disease. Also, an HHcy‐activated sympathetic system and HHcy‐injured adipose tissue also cause vascular injury, thus demonstrating the interactions between the organs injured by HHcy. Here, we have summarized the recent developments in the mechanisms of HHcy‐induced vascular injury, which are further considered as potential therapeutic targets in this condition. Linked Articles This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc

Although carbonyl iron powders (CIP) have already been used as microwave absorbing material for human health, wireless communication safety and defense stealth technology, it is difficult to implement both thin coating thickness and broadband absorption capability. Herein, core-shell structured [email protected]2@Nitrogen doped carbon (NC) microspheres were fabricated by a two-step process followed by a pyrolysis process and the yolk-shell structured [email protected]@NC microspheres were obtained by alkaline hydrothermal etching. The phase structure, micromorphology, magnetic properties, and electromagnetic parameters of yolk-shell structured [email protected]@NC microspheres were investigated by variously analytical techniques. The yolk-shell structured [email protected]@NC microspheres shown enhanced electromagnetic wave absorption properties both in effective absorption bandwidth (EAB, RL ≤ −10 dB) and absorption intensity compared with single CIP. The maximum reflection loss value is −25.7 dB at 17.2 GHz and the EAB can reach to 6.9 GHz (11.1–18 GHz) at a coating thickness of 1.7 mm for yolk-shell structured [email protected]@NC microspheres. The results indicated that the yolk-shell structured [email protected]@NC microspheres are expected to be a promising candidate as the high-performance microwave absorbing material.

Chemotherapy is the major choice for the cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts the clinical efficacy of chemotherapy. It is critical to develop novel approaches to detect and overcome drug resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both intrinsic and acquired cisplatin-resistance of gastric cancer cells. The metabolic reprogramming of cisplatin-resistant cells was characterized by increased glycolysis dependence. Inhibition of glycolysis with glucose starvation or 2-Deoxy-D-glucose (2-DG) treatment significantly reversed drug resistance. By proteomic screening, we found the increased expression of the glycolytic enzyme Enolase 1 (ENO1) in cisplatin-resistant gastric cancer cells. Depletion of ENO1 by siRNA significantly reduced glycolysis and reversed drug resistance. Moreover, the increased expression of ENO1 was attributed to the down-regulation of ENO1-targeting miR-22, rather than activated gene transcriptional or prolonged protein stability. Finally, the elevated levels of ENO1 proteins were associated with the shorter overall survival of gastric cancer patients. In conclusion, ENO1 is a novel biomarker to predict drug resistance and overall prognosis in gastric cancer. Targeting ENO1 by chemical inhibitors or up-regulating miR-22 could be valuable to overcome drug resistance.

In this paper, we study the following critical fractional Schrödinger equation: (−Δ)su+V(x)u=|u|2s*−2u+λf(x,u), x∈RN, where λ &amp;gt; 0, 0 &amp;lt; s &amp;lt; 1, N &amp;gt; 2s, 2s*=2NN−2s, (−Δ)s denotes the fractional Laplacian of order s, and f is a continuous superlinear but subcritical function. When V and f are asymptotically periodic in x, we prove that the equation has a ground state solution for large λ by the Nehari method.

Endothelial dysfunction induced by hyperhomocysteinemia (HHcy) plays a critical role in vascular pathology. However, little is known about the role of endoplasmic reticulum (ER) redox homeostasis in HHcy-induced endothelial dysfunction. Here, we show that Hcy induces ER oxidoreductin-1α (Ero1α) expression with ER stress and inflammation in human umbilical vein endothelial cells and in the arteries of HHcy mice. Hcy upregulates Ero1α expression by promoting binding of hypoxia-inducible factor 1α to the ERO1A promoter. Notably, Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the ER, therefore allosterically activating Ero1α to produce H2O2 and trigger ER oxidative stress. By contrast, the antioxidant pathway mediated by ER glutathione peroxidase 7 (GPx7) is downregulated in HHcy mice. Ero1α knockdown and GPx7 overexpression protect the endothelium from HHcy-induced ER oxidative stress and inflammation. Our work suggests that targeting ER redox homeostasis could be used as an intervention for HHcy-related vascular diseases.

Type 2 diabetes is a chronic inflammatory metabolic disease, the key point being insulin resistance. Endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of type 2 diabetes. Previously, we found that hyperhomocysteinemia (HHcy) induced insulin resistance in adipose tissue. Here, we hypothesized that HHcy induces ER stress, which in turn promotes insulin resistance. In the present study, the direct effect of Hcy on adipose ER stress was investigated by the use of primary rat adipocytes in vitro and mice with HHcy in vivo. The mechanism and the effect of G protein-coupled receptor 120 (GPR120) were also investigated. We found that phosphorylation or expression of variant ER stress markers was elevated in adipose tissue of HHcy mice. HHcy activated c-Jun N-terminal kinase (JNK), the downstream signal of ER stress in adipose tissue, and activated JNK participated in insulin resistance by inhibiting Akt activation. Furthermore, JNK activated c-Jun and p65, which in turn triggered the transcription of proinflammatory cytokines. Both in vivo and in vitro assays revealed that Hcy-promoted macrophage infiltration aggravated ER stress in adipose tissue. Chemical chaperones PBA and TUDCA could reverse Hcy-induced inflammation and restore insulin-stimulated glucose uptake and Akt activation. Activation of GPR120 reversed Hcy-induced JNK activation and prevented inflammation but not ER stress. Therefore, HHcy inhibited insulin sensitivity in adipose tissue by inducing ER stress, activating JNK to promote proinflammatory cytokine production and facilitating macrophage infiltration. These findings reveal a new mechanism of HHcy in the pathogenesis of insulin resistance. Type 2 diabetes is a chronic inflammatory metabolic disease, the key point being insulin resistance. Endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of type 2 diabetes. Previously, we found that hyperhomocysteinemia (HHcy) induced insulin resistance in adipose tissue. Here, we hypothesized that HHcy induces ER stress, which in turn promotes insulin resistance. In the present study, the direct effect of Hcy on adipose ER stress was investigated by the use of primary rat adipocytes in vitro and mice with HHcy in vivo. The mechanism and the effect of G protein-coupled receptor 120 (GPR120) were also investigated. We found that phosphorylation or expression of variant ER stress markers was elevated in adipose tissue of HHcy mice. HHcy activated c-Jun N-terminal kinase (JNK), the downstream signal of ER stress in adipose tissue, and activated JNK participated in insulin resistance by inhibiting Akt activation. Furthermore, JNK activated c-Jun and p65, which in turn triggered the transcription of proinflammatory cytokines. Both in vivo and in vitro assays revealed that Hcy-promoted macrophage infiltration aggravated ER stress in adipose tissue. Chemical chaperones PBA and TUDCA could reverse Hcy-induced inflammation and restore insulin-stimulated glucose uptake and Akt activation. Activation of GPR120 reversed Hcy-induced JNK activation and prevented inflammation but not ER stress. Therefore, HHcy inhibited insulin sensitivity in adipose tissue by inducing ER stress, activating JNK to promote proinflammatory cytokine production and facilitating macrophage infiltration. These findings reveal a new mechanism of HHcy in the pathogenesis of insulin resistance.

Abstract Deficiency or mutation in the p53 tumor suppressor gene commonly occurs in human cancer and can contribute to disease progression and chemotherapy resistance. Currently, although the pro-survival or pro-death effect of autophagy remains a controversial issue, increasing data seem to support the idea that autophagy facilitates cancer cell resistance to chemotherapy treatment. Here we report that 5-FU treatment causes aberrant autophagosome accumulation in HCT116 p53 −/− and HT-29 cancer cells. Specific inhibition of autophagy by 3-MA, CQ or small interfering RNA treatment targeting Atg5 or Beclin 1 can potentiate the re-sensitization of these resistant cancer cells to 5-FU. In further analysis, we show that JNK activation and phosphorylation of Bcl-2 are key determinants in 5-FU-induced autophagy. Inhibition of JNK by the compound SP600125 or JNK siRNA suppressed autophagy and phosphorylation of c-Jun and Bcl-2 but increased 5-FU-induced apoptosis in both HCT116 p53 −/− and HT29 cells. Taken together, our results suggest that JNK activation confers 5-FU resistance in HCT116 p53 −/− and HT29 cells by promoting autophagy as a pro-survival effect, likely via inducing Bcl-2 phosphorylation. These results provide a promising strategy to improve the efficacy of 5-FU-based chemotherapy for colorectal cancer patients harboring a p53 gene mutation.

Cells perceive the physical cues such as perturbations of extracellular matrix (ECM) stiffness, and translate these stimuli into biochemical signals controlling various aspects of cell behavior, which contribute to the physiological and pathological processes of multiple organs. In this study, we tested the hypothesis that during arterial stiffening, vascular smooth muscle cells (SMCs) sense the increase of ECM stiffness, which modulates the cellular phenotype through the regulation in DNA methyltransferases 1 (DNMT1) expression. Moreover, we hypothesized that the mechanisms involve intrinsic stiffening and deficiency in contractility of vascular SMCs. Substrate stiffening was mimicked in vitro with polyacrylamide gels. A contractile-to-synthetic phenotypic transition was induced by substrate stiffening in vascular SMCs through the down-regulation of DNMT1 expression. DNMT1 repression was also observed in the tunica media of mice aortas in an acute aortic injury model and a chronic kidney failure model, as well as in the tunica intima of human carotid arteries with calcified atherosclerotic lesions. DNMT1 inhibition facilitates arterial stiffening in vivo and promotes osteogenic transdifferentiation, calcification and cellular stiffening of vascular SMCs in vitro. These effects may be attributable, at least in part, to the role of DNMT1 in regulating the promoter activities of Transgelin (SM22α) and α-smooth muscle actin (SMA) and the functional contractility of SMCs. We conclude that DNMT1 is a critical regulator that negatively regulates arterial stiffening via maintaining the contractile phenotype of vascular SMCs. This research may facilitate elucidation of the complex crosstalk between vascular SMCs and their surrounding matrix in healthy and in pathological conditions and provide new insights into the implications for potential targeting of the phenotypic regulatory mechanisms in material-related therapeutic applications.

Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.

One-dimensional photonic crystals (1DPCs) based on ZnS/Ge for compatible stealth of infrared and visible were firstly proposed theoretically and investigated experimentally. Owing to the equal inclination interference, the designed 1DPCs structure can be fabricated with a certain color corresponding to the different responded wavelength. In addition, the average emissivity of the proposed structure can reach as low as 0.054 at infrared atmosphere window of 3–5 μm. The as-prepared structure indicates that it is feasible for 1DPC to achieve infrared-visible compatible stealth.

Particulate matter with an aerodynamic diameter less than 2.5 μM (PM2.5) is one of the major environmental pollutants in China. In this study, we carried out a metabolomics profile study on PM2.5-induced inflammation. PM2.5 from Beijing, China, was collected and given to rats through intra-tracheal instillation in vivo. Acute pulmonary injury were observed by pulmonary function assessment and H.E. staining. The lipid metabolic profile was also altered with increased phospholipid and sphingolipid metabolites in broncho-alveolar lavage fluid (BALF) after PM2.5 instillation. Organic component analysis revealed that benzo[a]pyrene (BaP) is one of the most abundant and toxic components in the PM2.5 collected on the fiber filter. In vitro, BaP was used to treat A549 cells, an alveolar type II cell line. BaP (4 μM, 24 h) induced inflammation in the cells. Metabolomics analysis revealed that BaP (4 μM, 6 h) treatment altered the cellular lipid metabolic profile with increased phospholipid metabolites and reduced sphingolipid metabolites and free fatty acids (FFAs). The proportion of ω–3 polyunsaturated fatty acid (PUFA) was also decreased. Mechanically, BaP (4 μM) increased the phospholipase A2 (PLA2) activity at 4 h as well as the mRNA level of Pla2g2a at 12 h. The pro-inflammatory effect of BaP was reversed by the cytosolic PLA2 (cPLA2) inhibitor and chelator of intracellular Ca2+. This study revealed that BaP, as a component of PM2.5, induces pulmonary injury by activating PLA2 and elevating lysophosphatidylcholine (LPC) in a Ca2+-dependent manner in the alveolar type II cells.

Inflammation may play an important role in the association between exposure to polycyclic aromatic hydrocarbons (PAHs) and atherosclerotic cardiovascular disease (ASCVD) risk. However, the underlying mechanisms remain unclear. To investigate the association of PAHs exposure with ASCVD risk and effects of mean platelet volume (MPV) or Club cell secretory protein (CC16) on the association. A total of 2022 subjects (689 men and 1333 women) were drawn from the baseline Wuhan residents of the Wuhan-Zhuhai Cohort study. Data on demography and the physical examination were obtained from each participant. Urinary monohydroxy PAH metabolites (OH-PAHs) levels were measured by a gas chromatography-mass spectrometry. We estimated the association between each OH-PAHs and the 10-year ASCVD risk or coronary heart disease (CHD) risk using logistic regression models, and further analyze the mediating effect of MPV or plasma CC16 on the association by using structural equation modeling. The results of multiple logistic regression models showed that some OH-PAHs were positively associated with ASCVD risk but not CHD risk, including 2-hydroxyfluoren (β = 1.761; 95% CI: 1.194–2.597), 9-hydroxyfluoren (β = 1.470; 95% CI: 1.139–1.898), 1-hydroxyphenanthrene (β = 1.480; 95% CI: 1.008–2.175) and ΣOH-PAHs levels (β = 1.699; 95% CI: 1.151–2.507). The analysis of structural equation modeling shows that increased MPV and increased plasma CC16 levels contributed 13.6% and 15.1%, respectively, to the association between PAHs exposure and the 10-year ASCVD risk (p < 0.05). Exposure to PAHs may increase the risk of atherosclerosis, which was partially mediated by MPV or CC16.

In this Beijing Indoor Air Purifier StudY (BIAPSY), we conducted a randomized crossover intervention trial in a panel of 35 non-smoking senior participants with free-living, with and without chronic obstructive pulmonary disease (COPD). Portable air filtration units were randomly allocated to active-(filter in) for 2weeks and sham-mode (filter out) for 2weeks in the households. We examined the differences in indoor air pollutant concentrations in 20 study homes and a suite of cardio-respiratory biomarker levels in study participants between filtration modes, with and without adjustment for potential confounders. Following active filtration, we observed significant reductions from 60±45 to 24±15μg/m3 in ten-day averages of indoor PM2.5 and reductions from 3.87±1.65 to 1.81±1.19m-1.10-5 in ten-day averages of indoor BC, compared to sham-mode filtration. The major components of indoor PM2.5, including water soluble organics, NO3-, SO42-, Zn2+, Pb2+ and K+, were also reduced significantly by 42% to 63%. However, following active filtration, we only observed significant reductions on systemic inflammation measured as of IL-8 at 58.59% (95% CI: -76.31, -27.64) in the total group of participants and 70.04% (95% CI: -83.05, -47.05) in the subset of COPD patients, with adjustments. We were not able to detect improvements on lung function, blood pressure, and heart rate variability, following short-term intervention of two-week active air filtration. In conclusion, our results showed that indoor air filtration produced clear improvement on indoor air quality, but no demonstrable changes in the cardio-respiratory outcomes of study interest observed in the seniors living with real-world air pollution exposures.

Abstract Foxp3 + regulatory T cells (Tregs) can inhibit immune responses and maintain immune tolerance by secreting immunosuppressive TGF-β1 and IL-10. However, the efficiency of Tregs become the major obstacle to their use for immunotherapy. In this study, we investigated the relevance of the C-type lectin receptor CD69 to the suppressive function. Compared to CD4 + Foxp3 + CD69 − Tregs (CD69 − Tregs), CD4 + Foxp3 + CD69 + Tregs (CD69 + Tregs) displayed stronger ability to maintain immune tolerance. CD69 + Tregs expressed higher levels of suppression-associated markers such as CTLA-4, ICOS, CD38 and GITR, and secreted higher levels of IL-10 but not TGF-β1. CD69 + Tregs from Il10 +/+ rather than Il10 −/− mice significantly inhibit the proliferation of CD4 + T cells. CD69 over-expression stimulated higher levels of IL-10 and c-Maf expression, which was compromised by silencing of STAT3 or STAT5. In addition, the direct interaction of STAT3 with the c-Maf promoter was detected in cells with CD69 over-expression. Moreover, adoptive transfer of CD69 + Tregs but not CD69 − Tregs or CD69 + Tregs deficient in IL-10 dramatically prevented the development of inflammatory bowel disease (IBD) in mice. Taken together, CD69 is important to the suppressive function of Tregs by promoting IL-10 production. CD69 + Tregs have the potential to develop new therapeutic approach for autoimmune diseases like IBD.

Citywide abnormal events, such as crimes and accidents, may result in loss of lives or properties if not handled efficiently. It is important for a wide spectrum of applications, ranging from public order maintaining, disaster control and people's activity modeling, if abnormal events can be automatically predicted before they occur. However, forecasting different categories of citywide abnormal events is very challenging as it is affected by many complex factors from different views: (i) dynamic intra-region temporal correlation; (ii) complex inter-region spatial correlations; (iii) latent cross-categorical correlations. In this paper, we develop a Multi-View and Multi-Modal Spatial-Temporal learning (MiST) framework to address the above challenges by promoting the collaboration of different views (spatial, temporal and semantic) and map the multi-modal units into the same latent space. Specifically, MiST can preserve the underlying structural information of multi-view abnormal event data and automatically learn the importance of view-specific representations, with the integration of a multi-modal pattern fusion module and a hierarchical recurrent framework. Extensive experiments on three real-world datasets, i.e., crime data and urban anomaly data, demonstrate the superior performance of our MiST method over the state-of-the-art baselines across various settings.

Skin problems not only injure physical health but also induce psychological problems, especially for patients whose faces have been damaged or even disfigured. Using smart devices, most of the people are able to obtain convenient clinical images of their face skin condition. On the other hand, the convolutional neural networks (CNNs) have achieved near or even better performance than human beings in the imaging field. Therefore, this paper studied different CNN algorithms for face skin disease classification based on the clinical images. First, from Xiangya–Derm, which is, to the best of our knowledge, China’s largest clinical image dataset of skin diseases, we established a dataset that contains 2656 face images belonging to six common skin diseases [seborrheic keratosis (SK), actinic keratosis (AK), rosacea (ROS), lupus erythematosus (LE), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)]. We performed studies using five mainstream network algorithms to classify these diseases in the dataset and compared the results. Then, we performed studies using an independent dataset of the same disease types, but from other body parts, to perform transfer learning on our models. Comparing the performances, the models that used transfer learning achieved a higher average precision and recall for almost all structures. In the test dataset, which included 388 facial images, the best model achieved 92.9%, 89.2%, and 84.3% recalls for the LE, BCC, and SK, respectively, and the mean recall and precision reached 77.0% and 70.8%.

Abstract Background Heat shock transcription factor1 (HSF1) was overexpressed to promote glutaminolysis and activate mTOR in colorectal cancer (CRC). Here, we investigated the mechanism for cancer-specific overexpression of HSF1. Methods HSF1 expression was analyzed by chromatin immunoprecipitation, qRT-PCR, immunohistochemistry staining and immunoblotting. HSF1 translation was explored by polysome profiling and nascent protein analysis. Biotin pulldown and m6A RNA immunoprecipitation were applied to investigate RNA/RNA interaction and m6A modification. The relevance of HSF1 to CRC was analyzed in APC min/+ and APC min/+ HSF1 +/− mice. Results HSF1 expression and activity were reduced after the inhibition of WNT/β-catenin signaling by pyrvinium or β-catenin knockdown, but elevated upon its activation by lithium chloride (LiCl) or β-catenin overexpression. There are much less upregulated genes in HSF1-KO MEF treated with LiCl when compared with LiCl-treated WT MEF. HSF1 protein expression was positively correlated with β-catenin expression in cell lines and primary tissues. After β-catenin depletion, HSF1 mRNA translation was impaired, accompanied by the reduction of its m6A modification and the upregulation of miR455-3p, which can interact with 3′-UTR of HSF1 mRNA to repress its translation. Interestingly, inhibition of miR455-3p rescued β-catenin depletion-induced reduction of HSF1 m6A modification and METTL3 interaction. Both the size and number of tumors were significantly reduced in APC min/+ mice when HSF1 was genetically knocked-out or chemically inhibited. Conclusions β-catenin suppresses miR455-3p generation to stimulate m6A modification and subsequent translation of HSF1 mRNA. HSF1 is important for β-catenin to promote CRC development. Targeting HSF1 could be a potential strategy for the intervention of β-catenin-driven cancers.

Abstract Semiconducting quantum dots (QDs) have recently triggered a huge interest in constructing efficient hydrogen production systems. It is well established that a large fraction of surface atoms of QDs need ligands to stabilize and avoid them from aggregating. However, the influence of the surface property of QDs on photocatalysis is rather elusive. Here, the surface regulation of CdSe QDs is investigated by surface sulfide ions (S 2− ) for photocatalytic hydrogen evolution. Structural and spectroscopic study shows that with gradual addition of S 2− , S 2− first grows into the lattice and later works as ligands on the surface of CdSe QDs. In‐depth transient spectroscopy reveals that the initial lattice S 2− accelerates electron transfer from QDs to cocatalyst, and the following ligand S 2− mainly facilitates hole transfer from QDs to the sacrificial agent. As a result, a turnover frequency (TOF) of 7950 h −1 can be achieved by the S 2− modified CdSe QDs, fourfold higher than that of original mercaptopropionic acid (MPA) capped CdSe QDs. Clearly, the simple surface S 2− modification of QDs greatly increases the photocatalytic efficiency, which provides subtle methods to design new QD material for advanced photocatalysis.

One new type of electrochemical sensors for the effective glucose detection is fabricated based on the use of CuOx@Co3O4 core-shell nanowires on Cu foam as electrocatalysts, which is synthesized through the stepwise process, including anodized nano-sized Cu(OH)2 wires, Metal-organic frameworks (MOFs)-wrapped Cu(OH)2 nanowires, and the following calcination. These as-made hierarchical composites exhibit the structural characteristics of CuOx nanowires core and Co3O4 nanoparticles shell calcinated from the terminally attached microporous ZIF-67. This type of glucose sensor compared to pure individual metal oxides exhibits higher sensitivity (27778 μA mM−1 cm-2 in the range from 0.1–1300.0 μM), lower detection limit (36 nM (S/N = 3)) and faster response time (∼1 s), also displays satisfactory selectivity, reproducibility, and long-term storage stability. Meanwhile, it achieves well-pleasing results in the detection of glucose in real human blood serum compared to commercial sensors. In addition, other four types of self-supporting MOF-derived bimetallic oxides core-shell nanowire arrays on Cu foam are also prepared by adopting the similar three-step procedure, including CuOx@Fe2O3, CuOx@NiO, CuOx@CuOx and CuOx@ZnO core-shell nanowires, demonstrating the versatility of this method. These results confirm that our as-made MOF-derived bimetallic oxide based sensor of CuOx@Co3O4 has a great potential application in the development of enzyme-free sensors for monitoring glucose.

The imbalance of intestinal microecology firstly impairs intestinal mucosa barrier and function, then further damages the functions and homeostasis of distal organs, leading to systemic diseases. Nutrients, transplantation of bacteria flora and modes of life can shape gut microbiota and intestinal mucosa barrier and mitigate stress. Current researches demonstrate that dynamic epigenetic modifications of intestinal tissue strongly mediate the crosstalk between gut microbes and gut mucosa barrier. Lactobacillus and Bifidobacterium species can synthesize folate to increase DNA methylation and mRNA N6-methyladenosine (m6A) of gut, which ensures intestinal normal development. Clostridial cluster, Anaerostipes and Eubacterium can induce histone acylation modifications by butyrate to enhance the development and immune balance of gut. Herein, we summarizes the present scientific understanding of how dietary nutrients shape gut microbiota and further regulate intestinal mucosa functions via epigenetic modifications, which will shed light on manipulation of gut microbiota by dietary nutrients, for prevention or clinical treatment of intestinal diseases.

Abstract In addition to the deregulation of gene transcriptions and post-translational protein modifications, the aberrant translation from mRNAs to proteins plays an important role in the pathogenesis of various cancers. Targeting mRNA translation are expected to become potential approaches for anticancer treatments. Protein translation is affected by many factors including translation initiation factors and RNA-binding proteins. Recently, modifications of mRNAs mainly N6-methyladenine (m 6 A) modification and noncoding RNAs, such as microRNAs and long noncoding RNAs are involved. In this review, we generally summarized the recent advances on the regulation of protein translation by the interplay between mRNA modifications and ncRNAs. By doing so, we hope this review could offer some hints for the development of novel approaches in precision therapy of human cancers.

Diabetic kidney disease (DKD) is one of the microvascular complications of diabetes mellitus and a major cause of end-stage renal disease with limited treatment options. Wogonin is a flavonoid derived from the root of Scutellaria baicalensis Georgi, which has shown a potent renoprotective effect. But the mechanisms of action in DKD are not fully elucidated. In this study, we investigated the effects of wogonin on glomerular podocytes in DKD using mouse podocyte clone 5 (MPC5) cells and diabetic mice model. MPC5 cells were treated with high glucose (30 mM). We showed that wogonin (4, 8, 16 μM) dose-dependently alleviated high glucose (HG)-induced MPC5 cell damage, accompanied by increased expression of WT-1, nephrin, and podocin proteins, and decreased expression of TNF-α, MCP-1, IL-1β as well as phosphorylated p65. Furthermore, wogonin treatment significantly inhibited HG-induced apoptosis in MPC5 cells. Wogonin reversed HG-suppressed autophagy in MPC5 cells, evidenced by increased ATG7, LC3-II, and Beclin-1 protein, and decreased p62 protein. We demonstrated that wogonin directly bound to Bcl-2 in MPC5 cells. In HG-treated MPC5 cells, knockdown of Bcl-2 abolished the beneficial effects of wogonin, whereas overexpression of Bcl-2 mimicked the protective effects of wogonin. Interestingly, we found that the expression of Bcl-2 was significantly decreased in biopsy renal tissue of diabetic nephropathy patients. In vivo experiments were conducted in STZ-induced diabetic mice, which were administered wogonin (10, 20, 40 mg · kg-1 · d-1, i.g.) every other day for 12 weeks. We showed that wogonin administration significantly alleviated albuminuria, histopathological lesions, and p65 NF-κB-mediated renal inflammatory response. Wogonin administration dose-dependently inhibited podocyte apoptosis and promoted podocyte autophagy in STZ-induced diabetic mice. This study for the first time demonstrates a novel action of wogonin in mitigating glomerulopathy and podocytes injury by regulating Bcl-2-mediated crosstalk between autophagy and apoptosis. Wogonin may be a potential therapeutic drug against DKD.

Online purchase forecasting is of great importance in e-commerce platforms, which is the basis of how to present personalized interesting product lists to individual customers. However, predicting online purchases is not trivial as it is influenced by many factors including: (i) the complex temporal pattern with hierarchical inter-correlations; (ii) arbitrary category dependencies. To address these factors, we develop a Graph Multi-Scale Pyramid Networks (GMP) framework to fully exploit users' latent behavioral patterns with both multi-scale temporal dynamics and arbitrary inter-dependencies among product categories. In GMP, we first design a multi-scale pyramid modulation network architecture which seamlessly preserves the underlying hierarchical temporal factors--governing users' purchase behaviors. Then, we employ convolution recurrent neural network to encode the categorical temporal pattern at each scale. After that, we develop a resolution-wise recalibration gating mechanism to automatically re-weight the importance of each scale-view representations. Finally, a context-graph neural network module is proposed to adaptively uncover complex dependencies among category-specific purchases. Extensive experiments on real-world e-commerce datasets demonstrate the superior performance of our method over state-of-the-art baselines across various settings.

Numerous hypotheses invoke tissue stiffness as a key parameter that regulates morphogenesis and disease progression. However, current methods are insufficient to test hypotheses that concern physical properties deep in living tissues. Here we introduce, validate, and apply a magnetic device that generates a uniform magnetic field gradient within a space that is sufficient to accommodate an organ-stage mouse embryo under live conditions. The method allows rapid, nontoxic measurement of the three-dimensional (3D) spatial distribution of viscoelastic properties within mesenchyme and epithelia. Using the device, we identify an anteriorly biased mesodermal stiffness gradient along which cells move to shape the early limb bud. The stiffness gradient corresponds to a Wnt5a-dependent domain of fibronectin expression, raising the possibility that durotaxis underlies cell movements. Three-dimensional stiffness mapping enables the generation of hypotheses and potentially the rigorous testing of mechanisms of development and disease.

In this study, multiwalled carbon nanotube (MWCNT) anchored on the surface of silica coated porous rodlike nickel ferrite (NiFe2O4@SiO2) composite was fabricated, and its structure, composition, magnetic and electromagnetic (EM) wave absorption properties were studied. High-performance EM wave absorption properties of the ternary composite can be regulated by the coating thickness and the content of the absorber. The reflection loss (RL) was optimized to −67.8 dB at the matching thickness of 1.9 mm, and the effective absorption bandwidth (RL ≤ −10 dB) was 4.5 GHz (13.5–18 GHz) at the coating thickness of only 1.5 mm with the filler loading 40 wt%. The effective bandwidth can reach 5.3 GHz (12.7–18 GHz) at the coating thickness of only 2.2 mm with the filler loading 30 wt%. The broadband absorption, thin thickness, strong absorption and adjustable absorption properties endow NiFe2O4@SiO2/MWCNT composite with extensive prospects for EM wave absorption.

Photocatalytic reduction of CO2 with H2O to syngas is an effective way for producing high value-added chemical feedstocks such as methanol and light olefins in industry. Nevertheless, the precise control of CO/H2 ratio from photocatalytic CO2 reduction reaction still poses a great challenge for the further application. Herein, we prepared a series of highly efficient heterostructure based on highly dispersed palladium supported on ultrathin CoAl-layered double hydroxide (LDH). In conjunction with a Ru-complex sensitizer, the molar ratios of CO/H2 can be tuned from 1:0.74 to 1:3 under visible-light irradiation (λ > 400 nm). More interestingly, the syngas can be obtained under light irradiation at λ > 600 nm. Structure characterization and density functional theory calculations revealed that the remarkable catalytic activity can be due to the supported palladium, which improved the charge transfer efficiency. Meanwhile, more H atoms were used to generate H2 on the supported palladium for further tunable CO/H2 ratio. This work demonstrates a new strategy for harnessing abundant solar-energy to produce syngas from a CO2 feedstock.

From single-pole magnetic tweezers to robotic magnetic-field generation systems, the development of magnetic micromanipulation systems, using electromagnets or permanent magnets, has enabled a multitude of applications for cellular and intracellular measurement and stimulation. Controlled by different configurations of magnetic-field generation systems, magnetic particles have been actuated by an external magnetic field to exert forces/torques and perform mechanical measurements on the cell membrane, cytoplasm, cytoskeleton, nucleus, intracellular motors, etc. The particles have also been controlled to generate aggregations to trigger cell signaling pathways and produce heat to cause cancer cell apoptosis for hyperthermia treatment. Magnetic micromanipulation has become an important tool in the repertoire of toolsets for cell measurement and stimulation and will continue to be used widely for further explorations of cellular/intracellular structures and their functions. Existing review papers in the literature focus on fabrication and position control of magnetic particles/structures (often termed micronanorobots) and the synthesis and functionalization of magnetic particles. Differently, this paper reviews the principles and systems of magnetic micromanipulation specifically for cellular and intracellular measurement and stimulation. Discoveries enabled by magnetic measurement and stimulation of cellular and intracellular structures are also summarized. This paper ends with discussions on future opportunities and challenges of magnetic micromanipulation in the exploration of cellular biophysics, mechanotransduction, and disease therapeutics.

In the preparation of nanomaterials, the kinetics and thermodynamics in the reaction can significantly affect the structures and phases of nanocrystals. Therefore, people are keen to adopt various synthetic strategies to accurately assemble the target nanocrystals, and reveal the underlying mechanism of the formation of specific structures. In this work, the total reaction time is adjusted to let the prepared MnCo Prussian blue analogous (MnCoPBA) crystals show four evolving morphological changes at different stages with the assistance of sodium dodecyl sulfate. Furthermore, it is clearly observed that the epitaxial growth along the (100) plane on the shell of MnCoPBA nanocrystals is favored, and the thermodynamics and kinetics in the morphology change process are analyzed in detail. Through the simple pyrolysis, MnCoPBA crystals can be successfully converted into the corresponding carbon composites, of which Mn2 Co2 C nanoparticles are evenly distributed in highly graphitized carbon matrix. Among them, PBA-III-700 performs good oxygen reduction reaction performance in alkaline solution with the half-wave potential of 0.801 V and diffusion-limited current density of 5.36 mA cm-2 , and its zinc-air battery exhibits the peak power density of 103.4 mW cm-2 competitive with commercial Pt/C.

This paper reviews the first challenge on high-dynamic range (HDR) imaging that was part of the New Trends in Image Restoration and Enhancement (NTIRE) workshop, held in conjunction with CVPR 2021. This manuscript focuses on the newly introduced dataset, the proposed methods and their results. The challenge aims at estimating a HDR image from one or multiple respective low-dynamic range (LDR) observations, which might suffer from under-or over-exposed regions and different sources of noise. The challenge is composed by two tracks: In Track 1 only a single LDR image is provided as input, whereas in Track 2 three differently-exposed LDR images with inter-frame motion are available. In both tracks, the ultimate goal is to achieve the best objective HDR reconstruction in terms of PSNR with respect to a ground-truth image, evaluated both directly and with a canonical tonemapping operation.

N6-methyladenosine (m6A), the most prevalent and reversible modification of mRNA in mammalian cells, has recently been extensively studied in epigenetic regulation. YTH family proteins, whose YTH domain can recognize and bind m6A-containing RNA, are the main "readers" of m6A modification. YTH family proteins perform different functions to determine the metabolic fate of m6A-modified RNA. The crystal structure of the YTH domain has been completely resolved, highlighting the important roles of several conserved residues of the YTH domain in the specific recognition of m6A-modified RNAs. Upstream and downstream targets have been successively revealed in different cancer types and the role of YTH family proteins has been emphasized in m6A research. This review describes the regulation of RNAs by YTH family proteins, the structural features of the YTH domain, and the connections of YTH family proteins with human cancers.

As glutamine plays a central role in cancer metabolism, inhibition of glutaminolysis has become an ideal anticancer therapeutic target.However, glutaminolysis inhibition leads to activation of autophagy, which compromises its antitumor effect.Hence, we investigated the mechanism underlying glutaminolysis inhibition-induced pro-survival autophagy.Methods: High-throughput sequencing was performed on colorectal cancer (CRC) cells before and after glutaminolysis inhibition to identify differentially expressed genes.Activating transcription factor 4 (ATF4) pathway enrichment in glutaminolysis inhibited cells was identified through gene set enrichment analysis.ATF4 expression was assessed by quantitative real-time PCR (qRT-PCR) and western blotting.The function of ATF4 on mechanistic target of rapamycin (mTOR) regulation was assessed by western blotting.Luciferase reporter assays and chromatin immunoprecipitation were used to confirm the regulation of DNA damage inducible transcript 4 (DDIT4) by ATF4.mRNA half-life assays, RNA immunoprecipitation, qRT-PCR and western blotting were performed to determine the relationship between FTO alpha-ketoglutarate dependent dioxygenase (FTO), YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2), and ATF4.ATF4 regulation of pro-survival autophagy was measured by tandem monomeric red fluorescent protein-green fluorescent protein fluorescence microscopy.Finally, the synergistic effect of autophagy and glutaminolysis inhibition was analyzed in an azoxymethane/dextran sodium sulfate mouse model.Results: The ATF4 pathway was activated in CRC cells upon glutaminolysis inhibition.Functionally, ATF4 transcriptionally upregulated DDIT4 to suppress mTOR, which induced pro-survival autophagy during glutaminolysis inhibition.Interestingly, glutaminolysis inhibition promoted ATF4 mRNA expression by abrogating N 6 -methyladenosine (m 6 A) modification and YTHDF2-mediated RNA decay.Finally, inhibition of ATF4-induced autophagy enhanced the antitumor efficacy of glutaminolysis inhibition.Conclusion: Glutaminolysis inhibition upregulated ATF4 expression in an m 6 A-dependent manner to activate pro-survival autophagy through transcriptional activation of the mTOR inhibitor DDIT4.Targeting ATF4-induced autophagy is a new strategy to synergize glutaminolysis-targeting therapies for cancer treatment.

The topological characteristics, including invariant topological orders, band inversion, and the topological edge mode (TEM) in the photonic insulators, have been widely studied. Whether people can take advantage of intriguing topological modes in simple one-dimensional systems to implement some practical applications is an issue which people are increasingly concerned about. In this work, based on a photonic dimer chain composed of ultra-subwavelength resonators, we verify experimentally that the TEM in the effective second-order parity-time (PT) system is immune to the inner disorder perturbation, and can be used to realize the long-range wireless power transfer (WPT) with high transmission efficiency. To intuitively show the TEM can be used for WPT, a power signal source is used to excite the TEM. It can be clearly seen that two LED lamps with 0.5-W at both ends of the structure are lighted up with the aid of TEMs. In addition, in order to solve the special technical problems of standby power loss and frequency tracking, we further propose that a WPT system with effective third-order PT symmetry can be constructed by using one topological interface mode and two TEMs. Inspired by the long-range WPT with TEMs in this work, it is expected to use more complex topological structures to achieve energy transmission with more functions, such as the WPT devices whose direction can be selected flexibly in the quasiperiodic or trimer topological chains.

Bergapten is a natural furocoumarin, also known as 5‐methoxypsoralen, and its medicinal value has been paid more and more attention. By sorting out the pharmacological literature of bergapten, we found that bergapten has a wide range of pharmacological effects, including neuroprotection, organ protection, anticancer, antiinflammatory, antimicrobial, and antidiabetes effects. However，bergapten has complex impacts on the hepatic metabolic enzyme. Moreover, pharmacokinetic studies showed that bergapten has higher absolute bioavailability and can cross the blood–brain barrier and has a great potential for treating brain disease, but the mechanism needs further clarification to make greater use of its ability to treat brain diseases. Furthermore, the phototoxicity of bergapten combined with ultraviolet light has always been mentioned. In view of its wide range of pharmacological activities, bergapten is expected to be a potential drug candidate for the treatment of diabetes and diabetes‐induced osteoporosis, epilepsy, Alzheimer's disease, depression, and cancer. However, further studies are needed to elucidate its molecular mechanisms and targets. The phototoxicity of bergapten as a side effect should be further avoided. On the other hand, the photoactivation of bergapten in the anticancer aspect can be better utilized.

This study was to explore effects of hot air assisted or not assisted radio frequency (RF, 27.12 MHz, 1.4 kW) heating with different electrode gaps (100 mm, 120 mm, and 140 mm) on the water-holding capacity (WHC) of myofibrillar protein (MP) gel and to understand the underlying mechanism through chemical forces, water distribution, and structure. The results showed that the MP gels heated by RF (100 mm) had the highest WHC and uniform gel network structure. As for RF with 100 mm electrode gap, the increased ionic and hydrogen bonds might be conducive to the WHC compared to water bath heating, which was verified by Low-field nuclear magnetic resonance results that the free water converted into the immobilized water. Raman spectroscopy results revealed that RF (100 mm) induced the self-assembly of β-sheet to α-helix, which conduced to the stable and ordered gel network structure.

Baicalin (BI) is an important biologically active flavonoid isolated from the root of Scutellaria radix (Huang Qin). Traditionally Scutellaria radix was the common drug of dysentery. As the main flavonoid compound, there is a distribution tendency of baicalin to the intestinal tract and it has a protective effect on the gastrointestinal tract.This review aims to compile up-to-date and comprehensive information on the efficacy of baicalin in vitro and in vivo, about treating inflammatory bowel disease. Relevant information on the therapeutic potential of baicalin against inflammatory bowel disease was collected from the Web of Science, Pubmed and so on. Additionally, a few books and magazines were also consulted to get the important information.The mechanisms of baicalin against inflammatory bowel disease mainly include anti-inflammation, antioxidant, immune regulation, maintenance of intestinal barrier, maintenance of intestinal flora balance. Also, BI can relieve parts of extraintestinal manifestations (EIMs), and prevent colorectal cancer.Baicalin determined the promising therapeutic prospects as potential supplementary medicines for the treatment of IBD.