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Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment., (© 2024. The Author(s).)

Endothelins and their receptors, ET A and ET B , play vital roles in maintaining vascular homeostasis. Therapeutically targeting endothelin receptors, particularly through ET A antagonists, has shown efficacy in treating pulmonary arterial hypertension (PAH) and other cardiovascular- and renal-related diseases. Here we present cryo-electron microscopy structures of ET A in complex with two PAH drugs, macitentan and ambrisentan, along with zibotentan, a selective ET A antagonist, respectively. Notably, a specialized anti-ET A antibody facilitated the structural elucidation. These structures, together with the active-state structures of ET-1-bound ET A and ET B , and the agonist BQ3020-bound ET B , in complex with G q , unveil the molecular basis of agonist/antagonist binding modes in endothelin receptors. Key residues that confer antagonist selectivity to endothelin receptors were identified along with the activation mechanism of ET A . Furthermore, our results suggest that ECL2 in ET A can serve as an epitope for antibody-mediated receptor antagonism. Collectively, these insights establish a robust theoretical framework for the rational design of small-molecule drugs and antibodies with selective activity against endothelin receptors., (© 2024. The Author(s).)

Hypersonic vehicles and aircraft engine blades face complex and harsh environments such as high heat flow density and high temperature, and they are generally narrow curved spaces, making it impossible to actually install them for testing. Thin-film heat flux sensors (HFSs) have the advantages of small size, fast response, and in-situ fabrication, but they are prone to reach thermal equilibrium and thus fail during testing. In our manuscript, an ITO-In 2 O 3 thick film heat flux sensor (HFS) is designed, and a high-temperature heat flux test system is built to simulate the working condition of a blade subjected to heat flow impact. The simulation and test results show that the test performance of the thick-film HFS is improved by optimizing the structure and parameters. Under the condition of no water cooling, the designed HFS can realize short-time heat flux monitoring at 1450 °C and long-term stable monitoring at 1300 °C and below. With a maximum output thermopotential of 17.8 mV and an average test sensitivity of 0.035 mV/(kW/m 2 ), the designed HFS has superior high-temperature resistance that cannot be achieved by other existing thin (thick) film HFSs. Therefore, the designed HFS has great potential for application in harsh environments such as aerospace, weaponry, and industrial metallurgy., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2024.)

Cellular senescence (CS) is closely related to tumor progression. However, the studies about CS genes across human cancers have not explored the relationship between cancer senescence signature and telomere length. Additionally, single-cell analyses have not revealed the evolutionary trends of malignant cells and immune cells at the CS level. We defined a CS-associated signature, called "senescence signature", and found that patients with higher senescence signature had worse prognosis. Higher senescence signature was related to older age, higher genomic instability, longer telomeres, increased lymphocytic infiltration, higher pro-tumor immune infiltrates (Treg cells and MDSCs), and could predict responses to immune checkpoint inhibitor therapy. Single-cell analysis further reveals malignant cells and immune cells share a consistent evolutionary trend at the CS level. MAPK signaling pathway and apoptotic processes may play a key role in CS, and senescence signature may effectively predict sensitivity of MEK1/2 inhibitors, ERK1/2 inhibitors and BCL-2 family inhibitors. We also developed a new CS prediction model of cancer survival and established a portal website to apply this model ( https://bio-pub.shinyapps.io/cs_nomo/ )., (© 2024. The Author(s).)

Bitter taste receptors, particularly TAS2R14, play central roles in discerning a wide array of bitter substances, ranging from dietary components to pharmaceutical agents 1,2 . TAS2R14 is also widely expressed in extragustatory tissues, suggesting its extra roles in diverse physiological processes and potential therapeutic applications 3 . Here we present cryogenic electron microscopy structures of TAS2R14 in complex with aristolochic acid, flufenamic acid and compound 28.1, coupling with different G-protein subtypes. Uniquely, a cholesterol molecule is observed occupying what is typically an orthosteric site in class A G-protein-coupled receptors. The three potent agonists bind, individually, to the intracellular pockets, suggesting a distinct activation mechanism for this receptor. Comprehensive structural analysis, combined with mutagenesis and molecular dynamic simulation studies, elucidate the broad-spectrum ligand recognition and activation of the receptor by means of intricate multiple ligand-binding sites. Our study also uncovers the specific coupling modes of TAS2R14 with gustducin and G i1 proteins. These findings should be instrumental in advancing knowledge of bitter taste perception and its broader implications in sensory biology and drug discovery., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Janus group-III chalcogenide monolayers and based heterostructures with breaking vertical structural symmetry offer additional prospects in the upcoming high-performance photoelectric devices. We studied the geometrical, electronic, and photoelectric properties of Janus group-III chalcogenide monolayers and heterostructures. The most energy favorable stacking design of ten vertical heterostructures are considered. The results showed that the Janus Se-In-Ga-S and S-In-Ga-Se monolayers exhibit semiconducting characteristics with the band gaps of 1.295 eV and 1.752 eV, respectively. Furthermore, the different stacking configurations and surface termination at interface can realize the transition of band alignment between type I and type II due to the interlayer coupling. Moreover, we systematically investigated the photoelectric properties of Janus group-III chalcogenide heterostructures and predicated an optimized power conversion efficiency of 16.2%. These findings can aid in comprehending the customized characteristics of Janus group-III chalcogenide heterostructures, offering theoretical guidance for creating innovative photoelectric devices., (© 2024. The Author(s).)

Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For comparison, we have included transcriptomics datasets from cells treated with type I and type II human interferon. Raw multi-omics data and metadata were deposited in public repositories, and we provide a central location linking the raw data with experimental metadata and ready-to-use, quality-controlled, statistically processed multi-omics datasets not previously available in any public repository. This compendium of infection-induced host response data for reuse will be useful for those endeavouring to understand viral disease pathophysiology and network biology., (© 2024. Battelle Memorial Institute.)

The implementation of an intelligent road network system requires many sensors for acquiring data from roads, bridges, and vehicles, thereby enabling comprehensive monitoring and regulation of road networks. Given this large number of required sensors, the sensors must be cost-effective, dependable, and environmentally friendly. Here, we show a laser upgrading strategy for coal tar, a low-value byproduct of coal distillation, to manufacture flexible strain-gauge sensors with maximum gauge factors of 15.20 and 254.17 for tension and compression respectively. Furthermore, we completely designed the supporting processes of sensor placement, data acquisition, processing, wireless communication, and information decoding to demonstrate the application of our sensors in traffic and bridge vibration monitoring. Our novel strategy of using lasers to upgrade coal tar for use as a sensor not only achieves the goal of turning waste into a resource but also provides an approach to satisfy large-scale application requirements for enabling intelligent road networks., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2024.)

Traffic time series anomaly detection has been intensively studied for years because of its potential applications in intelligent transportation. However, classical traffic anomaly detection methods often overlook the evolving dynamic associations between road network nodes, which leads to challenges in capturing the long-term temporal correlations, spatial characteristics, and abnormal node behaviors in datasets with high periodicity and trends, such as morning peak travel periods. In this paper, we propose a mirror temporal graph autoencoder (MTGAE) framework to explore anomalies and capture unseen nodes and the spatiotemporal correlation between nodes in the traffic network. Specifically, we propose the mirror temporal convolutional module to enhance feature extraction capabilities and capture hidden node-to-node features in the traffic network. Morever, we propose the graph convolutional gate recurrent unit cell (GCGRU CELL) module. This module uses Gaussian kernel functions to map data into a high-dimensional space, and enables the identification of anomalous information and potential anomalies within the complex interdependencies of the traffic network, based on prior knowledge and input data. We compared our work with several other advanced deep-learning anomaly detection models. Experimental results on the NYC dataset illustrate that our model works best compared to other models for traffic anomaly detection., (© 2024. The Author(s).)

During the process of wound healing, fibroblasts migrate to the wound site and perform essential functions in promoting cell proliferation, as well as synthesizing and secreting the extracellular matrix (ECM). However, in diabetic wounds, senescent fibroblasts exhibit impaired proliferative capacity and fail to synthesize essential ECM components. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating cellular senescence and fibroblast function. However, its specific role in diabetic wounds remains poorly understood. In this study, we conducted a series of in vivo and in vitro experiments using STZ-induced diabetic mice and human dermal fibroblasts. We evaluated cellular senescence markers, including SA-β-gal, P53, P16, P21, and PAI-1, as well as senescence-associated secretory phenotype (SASP) factors. Finally, we observed that PDK4 increased in normal wound healing, but its expression was insufficient in diabetic wounds. Significantly, the overexpression of PDK4 demonstrated the potential to accelerate diabetic wound healing and improve the senescence phenotype both in vivo and in vitro. Furthermore, our study elucidated the underlying mechanism by which PDK4 improved the senescent phenotype through the enhancement of glycolysis and regulation of YAP and JNK pathway. The effect was dependent on metabolic reprogramming and subsequent reduction of reactive oxygen species (ROS), which was mediated by PDK4. Overall, our findings highlight the potential of PDK4 as a promising therapeutic target for addressing diabetic wounds., (© 2023. The Author(s).)

Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA., (© 2023. The Author(s).)

Despite a wealth of research linking the triglyceride glucose index (TyG index) to metabolic diseases. However, little evidence links the TyG index to all-cause or CVD mortality in middle-aged and elderly individuals with type 2 diabetes (T2D). This study analyzed data from 2998 patients with T2D who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. The TyG index and mortality in middle-aged and elderly T2D patients were investigated using Cox regression models. The nonlinear association between the TyG index and mortality can be understood with the help of a restricted cubic spline (RCS). During a median follow-up period of 82 months, 883 fatalities were observed from all causes and 265 from CVD. The TyG index was found to have a U-shaped relationship with all-cause and CVD mortality in T2D, with cutoffs of 8.95 and 9, respectively, according to the RCS. After controlling for other factors, an increase of 1 unit in the TyG index was related to an increase of 33% in all-cause mortality and 50% in CVD mortality when TyG was ≥ 8.95 and 9. When TyG < 8.95 and 9, with the change in the TyG index, the change in all-cause and CVD death was insignificant. Patients with T2D who are middle-aged or older, especially elderly patients, have higher TyG levels associated with increased mortality. In middle-aged and elderly patients with T2D, the TyG index may predict the probability of death from any cause and death from CVD., (© 2023. Springer Nature Limited.)

This paper presents a surface acoustic wave (SAW) sensor based on coplanar integrated Langasite (LGS) that is fabricated using wet etching, high-temperature bonding, and ion beam etching (IBE) processes. The miniaturized multiparameter temperature‒pressure-humidity (TPH) sensor used the MXene@MoS 2 @Go (MMG) composite to widen the humidity detection range and improve the humidity sensitivity, including a fast response time (3.18 s) and recovery time (0.94 s). The TPH sensor was shown to operate steadily between 25-700 °C, 0-700 kPa, and 10-98% RH. Coupling issues among multiple parameters in complex environments were addressed by decoupling the Δf-temperature coupling factor to improve the accuracy. Therefore, this work can be applied to simultaneous measurements of several environmental parameters in challenging conditions., Competing Interests: Competing interestsThe authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (© Aerospace Information Research Institute, Chinese Academy of Sciences 2023.)

A novel newsvendor model-based framework for regional industrial water resources allocation that considers uncertainties in water supply and demand was proposed in this study. This framework generates optimal water allocation schemes while minimizing total costs. The total cost of water allocation consists of the allocated water cost, the opportunity loss for not meeting water demand, and the loss of the penalty for exceeding water demand. The uncertainties in water demand and supply are expressed by cumulative distribution functions. The optimal water allocation for each water use sector is determined by the water price, the unit loss of the penalty and opportunity loss, and the cumulative distribution functions. The model was then applied to monthly water allocation for domestic, industrial, and agricultural water use in two counties of Huizhou City, China, whose water supply mainly depends on Baipenzhu Reservoir. The water demand for each water use sector and the monthly reservoir inflow showed good fits with the uniform and P-III distributions, respectively. The water demand satisfied ratio for each water use sector was stable and increased for the optimal water allocation scheme from the newsvendor model-based framework, and the costs were lower compared with the actual water allocation scheme. The novel framework is characterized by less severe water shortages, lower costs, and greater similarity to actual water use compared with the traditional deterministic multi-objective analysis model, and demonstrates strong robustness in the advantages of lower released surplus water and higher water demand satisfied ratio. This novel framework yields the optimal water allocation for each water use sector by integrating the properties of the market (i.e., determining the opportunity loss for not meeting water demand) with the government (i.e., determining the water price and the loss of the penalty for exceeding water demand) under the strictest water resources management systems., (© 2023. Springer Nature Limited.)

Drought stress can severely affect sugarcane growth and yield. The objective of this research was to identify candidate genes in sugarcane tillering seedlings in response to drought stress. We performed a comparative phenotypic, physiological and transcriptomic analysis of tiller seedlings of drought-stressed and well-watered "Guire 2" sugarcane, in a time-course experiment (5 days, 9 days and 15 days). Physiological examination reviewed that SOD, proline, soluble sugars, and soluble proteins accumulated in large amounts in tiller seedlings under different intensities of drought stress, while MDA levels remained at a stable level, indicating that the accumulation of osmoregulatory substances and the enhancement of antioxidant enzyme activities helped to limit further damage caused by drought stress. RNA-seq and weighted gene co-expression network analysis (WGCNA) were performed to identify genes and modules associated with sugarcane tillering seedlings in response to drought stress. Drought stress induced huge down-regulated in gene expression profiles, most of down-regulated genes were mainly associated with photosynthesis, sugar metabolism and fatty acid synthesis. We obtained four gene co-expression modules significantly associated with the physiological changes under drought stress (three modules positively correlated, one module negatively correlated), and found that LSG1-2, ERF1-2, SHKA, TIL, HSP18.1, HSP24.1, HSP16.1 and HSFA6A may play essential regulatory roles as hub genes in increasing SOD, Pro, soluble sugar or soluble protein contents. In addition, one module was found mostly involved in tiller stem diameter, among which members of the BHLH148 were important nodes. These results provide new insights into the mechanisms by which sugarcane tillering seedlings respond to drought stress., (© 2023. Springer Nature Limited.)

Doping of perovskite semiconductors 1 and passivation of their grain boundaries 2 remain challenging but essential for advancing high-efficiency perovskite solar cells. Particularly, it is crucial to build perovskite/indium tin oxide (ITO) Schottky contact based inverted devices without predepositing a layer of hole-transport material 3-5 . Here we report a dimethylacridine-based molecular doping process used to construct a well-matched p-perovskite/ITO contact, along with all-round passivation of grain boundaries, achieving a certified power conversion efficiency (PCE) of 25.39%. The molecules are shown to be extruded from the precursor solution to the grain boundaries and the bottom of the film surface in the chlorobenzene-quenched crystallization process, which we call a molecule-extrusion process. The core coordination complex between the deprotonated phosphonic acid group of the molecule and lead polyiodide of perovskite is responsible for both mechanical absorption and electronic charge transfer, and leads to p-type doping of the perovskite film. We created an efficient device with a PCE of 25.86% (reverse scan) and that maintained 96.6% of initial PCE after 1,000 h of light soaking., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Strategies to degrade steroid receptors and their alternative splicing isoforms are critical for disease management. Here we report that celastrol recruited the ubiquitin ligase UBE3A and degraded androgen receptor (AR), AR-v7, and glucocorticoid receptor (GR) to suppress prostate cancer development. UBE3A was not an optimal endogenous AR ubiquitin ligase in mice and patients, but celastrol promoted the interaction between UBE3A and AR. Multiple domains of AR, including the DNA binding domain (DBD), were implicated into the UBE3A-AR interaction. Sharing a conserved DBD, GR, AR-v7, and other steroid receptors were recognized and degraded by UBE3A after celastrol treatment. Thus, celastrol suppressed prostate cancer cell proliferation more potently than enzalutamide. Modifying the carboxyl group of celastrol improved its anti-tumor activity. Together, our findings revealed that celastrol might be a potential molecular glue to enhance the interaction between UBE3A and steroid receptors to degrade multiple steroid receptors and splicing isoforms in prostate cancer, paving a way for further drug optimization and disease treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations., (© 2022. The Author(s).)

Molecular oxygen (O 2 ) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs., (© 2022. The Author(s).)

Click-through rate prediction, which aims to predict the probability of the user clicking on an item, is critical to online advertising. How to capture the user evolving interests from the user behavior sequence is an important issue in CTR prediction. However, most existing models ignore the factor that the sequence is composed of sessions, and user behavior can be divided into different sessions according to the occurring time. The user behaviors are highly correlated in each session and are not relevant across sessions. We propose an effective model for CTR prediction, named Session Interest Model via Self-Attention (SISA). First, we divide the user sequential behavior into session layer. A self-attention mechanism with bias coding is used to model each session. Since different session interest may be related to each other or follow a sequential pattern, next, we utilize gated recurrent unit (GRU) to capture the interaction and evolution of user different historical session interests in session interest extractor module. Then, we use the local activation and GRU to aggregate their target ad to form the final representation of the behavior sequence in session interest interacting module. Experimental results show that the SISA model performs better than other models., (© 2022. The Author(s).)

New neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate functional adult-born neurons, neural progenitor cells proliferate to expand the precursor cell pool and differentiate into neurons. Newly generated cells then undergo postmitotic maturation to migrate to their final destination and develop elaborate dendritic branching, which allows them to receive input signals. Little is known about factors that regulate neuronal differentiation, migration, and dendrite maturation during adult hippocampal neurogenesis. Here, we show that the transcriptional repressor protein capicua (CIC) exhibits dynamic expression in the adult dentate gyrus. Conditional deletion of Cic from the mouse dentate gyrus compromises the adult neural progenitor cell pool without altering their proliferative potential. We further demonstrate that the loss of Cic impedes neuronal lineage development and disrupts dendritic arborization and migration of adult-born neurons. Our study uncovers a previously unrecognized role of CIC in neurogenesis of the adult dentate gyrus.

The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system 1 . These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties 2-4 . Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.

The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system) 1 . It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation 2 . However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G i protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu-G i structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs.

Radish (Raphanus sativus) is an important vegetable worldwide that exhibits different flesh and skin colors. The anthocyanins responsible for the red and purple coloring in radishes possess nutritional value and pharmaceutical potential. To explore the structural and regulatory networks related to anthocyanin biosynthesis and identify key genes, we performed comparative transcriptome analyses of the skin and flesh of six colored radish accessions. The transcript profiles showed that each accession had a species-specific transcript profile. For radish pigmentation accumulation, the expression levels of anthocyanin biosynthetic genes (RsTT4, RsC4H, RsTT7, RsCCOAMT, RsDFR, and RsLDOX) were significantly upregulated in the red- and purple-colored accessions, but were downregulated or absent in the white and black accessions. The correlation test, combined with metabolome (PCC > 0.95), revealed five structural genes (RsTT4, RsDFR, RsCCOAMT, RsF3H, and RsBG8L) and three transcription factors (RsTT8-1, RsTT8-2, and RsPAR1) to be significantly correlated with flavonoids in the skin of the taproot. Four structural genes (RsBG8L, RsDFR, RsCCOAMT, and RsLDOX) and nine transcription factors (RsTT8-1, RsTT8-2, RsMYB24L, RsbHLH57, RsPAR2L, RsbHLH113L, RsOGR3L, RsMYB24, and RsMYB34L) were found to be significantly correlated with metabolites in the flesh of the taproot. This study provides a foundation for future studies on the gene functions and genetic diversity of radish pigmentation and should aid in the cultivation of new valuable radish varieties.

The purpose of this study was focused on the mechanisms of the cross-resistance to tetracycline (TET), piperacillin Sodium (PIP), and gentamicin (GEN) in Staphylococcus aureus (SA) mediated by Rhizoma Coptidis extracts (RCE). The selected strains were exposed continuously to RCE at the sublethal concentrations for 12 days, respectively. The susceptibility change of the drug-exposed strains was determined by analysis of the minimum inhibitory concentration. The 16S rDNA sequencing method was used to identify the RCE-exposed strain. Then the expression of resistant genes in the selected isolates was analyzed by transcriptome sequencing. The results indicated that RCE could trigger the preferential cross-resistance to TET, PIP, and GEN in SA. The correlative resistant genes to the three kinds of antibiotics were upregulated in the RCE-exposed strain, and the mRNA levels of the resistant genes determined by RT-qPCR were consistent with those from the transcriptome analysis. It was suggested from these results that the antibacterial Traditional Chinese Medicines might be a significant factor of causing the bacterial antibiotic-resistance.

Phenology is an important indicator of global climate change. Revealing the spatiotemporal characteristics of crop phenology is vital for ameliorating the adverse effects of climate change and guiding regional agricultural production. This study evaluated the spatiotemporal variability of soybean's phenological stages and key growth periods, and assessed their sensitivity to key climatic factors, utilizing a long-term dataset (1992-2018) of soybean phenology and associated meteorological data collected at 51 stations across China. The results showed that (1) during the soybean growing seasons from 1992 to 2018, the average temperature (0.34 ± 0.09 ℃ decade -1 ) and cumulative precipitation (6.66 ± 0.93 mm decade -1 ) increased, but cumulative sunshine hours (- 33.98 ± 1.05 h decade -1 ) decreased. (2) On a national scale, dates of sowing, emergence, trifoliate, anthesis, and podding of soybean were delayed, while the maturity date showed an advancing trend. The vegetative growth period (- 0.52 ± 0.24 days decade -1 ) and whole growth period (- 1.32 ± 0.30 days decade -1 ) of soybean were shortened, but the reproductive growth period (0.05 ± 0.26 days decade -1 ) was slightly extended. Trends in soybean phenological stages and key growth periods diverged in regions. Soybean phenological stages were delayed in Huang-Huai-Hai soybean zone, whereas advanced in southern soybean zone. Moreover, the key growth periods were greatly shortened in northern soybean zone. (3) In general, the sensitivity of soybean key growth periods to temperature was negative, whereas those to precipitation and sunshine hours differed among regions. In particular, most phenological stages were negatively sensitive to sunshine hours. Our results will provide scientific support for decision-making in agricultural production practices.

The exact mechanism of myocardial hypertrophy has not been completely elucidated. NOD-like receptor protein 3 (NLRP3) and the pyroptotic cascade play a critical role in cardiac hypertrophy and inflammation. The myokine irisin can inhibit NLRP3 activation, although its exact mechanism of action is unknown. In this study, we induced cardiac hypertrophy in a mouse model via aortic constriction (TAC) to further explore the pathological role of NLRP3 inflammasome-mediated pyroptosis and the potential therapeutic effects of irisin. Cardiac hypertrophy significantly increased the percentage of apoptotic cells and upregulated IL-1β, cleaved caspase-1, and GSDMD-N that lie downstream of the NLRP3 inflammasome. Subsequently, irisin was co-administered to the TAC mice or angiotensin II (Ang-II)-treated cardiomyocytes to observe whether it could attenuate pyroptosis and cardiac hypertrophy. We established a direct association between pyroptosis and cardiac hypertrophy and found that pharmacological or genetic inhibition of NLRP3 attenuated cardiac hypertrophy. Furthermore, ectopic overexpression of NLRP3 abrogated the cardioprotective effects of irisin. To summarize, pyroptosis is a pathological factor in cardiac hypertrophy, and irisin is a promising therapeutic agent that inhibits NLRP3-mediated pyroptosis of cardiomyocytes.

Mosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2-7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917-1923 and 1931-1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7-29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917-1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.

Duodenal dysbiosis may be potential infection risks in patients with severe acute pancreatitis (SAP). Acid-suppression drugs (ACDs) are widely used in SAP patients in Asian countries. However, the impact of ACDs on duodenal microbiota during the early phase of SAP is still unknown. This randomized controlled clinical trial evaluated the impacts of esomeprazole (Eso), one of ACDs on duodenal microbiota during the first week of SAP with duodenal aspirates culture and 16sRNA Illumina sequencing analysis. 66 patients were randomized as 1:1 ratio into Eso group (Eso 40 mg/day) and Eso-N group (no Eso). The occurrence of duodenal bacterial overgrowth (DBO) was significantly higher in Eso group (about 85%) than that in Eso-N group (about 42%). The duodenal microbiota of the SAP patients shifted away from that of the normal control. There were differences between the Eso-N and Eso groups including enriched abundances of the class Negativicutes, order Selenomonadales and genus Veillonella. Acid suppression significantly increased incidence of Candida oesophagitis (CE) by 8-folds but did not increase other infectious events. In conclusion, acid suppression greatly increased the occurrence of DBO, duodenal dysbiosis and CE during the first week of SAP. Restrictive use of acid-suppressing medications might be helpful to reduce CE and potential risk of pancreatic infection in SAP patients.Trial registration: Chictr.org, ChiCTR-IPR-16008301, Registered April 18 2016, http://www.chictr.org.cn/showproj.aspx?proj=14089 .

Growing evidences suggest that the fibroblast growth factor/FGF receptor (FGF/FGFR) signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment, differentiation, proliferation, and apoptosis of various types of cells. In this review, we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development, injury repair, and the pathophysiology of spectrum of diseases, which is a consequence of FGF signaling dysregulation, including cancers and chronic kidney disease (CKD). In this context, the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.

Acute lung injury (ALI) is a life-threatening disorder with high rates of morbidity and mortality. Reactive oxygen species and epithelial apoptosis are involved in the pathogenesis of acute lung injury. Ferroptosis, an iron-dependent non-apoptotic form of cell death, mediates its effects in part by promoting the accumulation of reactive oxygen species. The inhibition of ferroptosis decreases clinical symptoms in experimental models of ischemia/reperfusion-induced renal failure and heart injury. This study investigated the roles of inhibitor of apoptosis-stimulating protein of p53 (iASPP) and Nrf2 in ferroptosis and their potential therapeutic effects in intestinal ischemia/reperfusion-induced acute lung injury. Intestinal ischemia/reperfusion-induced ALI was induced in wild-type and Nrf2 -/- mice. The mice were treated with erastin followed by liproxstatin-1. Ferroptosis-related factors in mice with ischemia/reperfusion-induced acute lung injury or in mouse lung epithelial-2 cells with hypoxia/regeneration (HR)-induced ALI were measured by western blotting, real-time PCR, and immunofluorescence. Ferroptosis contributed to intestinal ischemia/reperfusion-induced ALI in vivo. iASPP inhibited ferroptosis and alleviated intestinal ischemia/reperfusion-induced acute lung injury, and iASPP-mediated protection against ischemia/reperfusion-induced ALI was dependent on Nrf2 signaling. HR-induced acute lung injury enhanced ferroptosis in vitro in mouse lung epithelial-2 cells, and ferroptosis was modulated after the enhancement of intestinal ischemia/reperfusion in Nrf2 -/- mice. iASPP mediated its protective effects against acute lung injury through the Nrf2/HIF-1/TF signaling pathway. Ferroptosis contributes to intestinal ischemia/reperfusion-induced ALI, and iASPP treatment inhibits ferroptosis in part via Nrf2. These findings indicate the therapeutic potential of iASPP for treating ischemia/reperfusion-induced ALI.

We investigated the heritability of educational attainment and how it differed between birth cohorts and cultural-geographic regions. A classical twin design was applied to pooled data from 28 cohorts representing 16 countries and including 193,518 twins with information on educational attainment at 25 years of age or older. Genetic factors explained the major part of individual differences in educational attainment (heritability: a 2  = 0.43; 0.41-0.44), but also environmental variation shared by co-twins was substantial (c 2  = 0.31; 0.30-0.33). The proportions of educational variation explained by genetic and shared environmental factors did not differ between Europe, North America and Australia, and East Asia. When restricted to twins 30 years or older to confirm finalized education, the heritability was higher in the older cohorts born in 1900-1949 (a 2  = 0.44; 0.41-0.46) than in the later cohorts born in 1950-1989 (a 2  = 0.38; 0.36-0.40), with a corresponding lower influence of common environmental factors (c 2  = 0.31; 0.29-0.33 and c 2  = 0.34; 0.32-0.36, respectively). In conclusion, both genetic and environmental factors shared by co-twins have an important influence on individual differences in educational attainment. The effect of genetic factors on educational attainment has decreased from the cohorts born before to those born after the 1950s.

Endometrial cancer is one of the most prevalent tumors of the female reproductive system causing serious health effects to women worldwide. Although numerous studies, including analysis of gene expression profile and cellular microenvironment have been reported in this field, pathogenesis of this disease remains unclear. In this study, we performed a system bioinformatics analysis of endometrial cancer using the Gene Expression Omnibus (GEO) datasets (GSE17025, GSE63678, and GSE115810) to identify the core genes. In addition, exosomes derived from endometrial cancer cells were also isolated and identified. First, we analyzed the differentially expressed genes (DEGs) between endometrial cancer tissues and normal tissues in clinic samples. We found that HAND2-AS1, PEG3, OGN, SFRP4, and OSR2 were co-expressed across all 3 datasets. Pathways analysis showed that several pathways associated with endometrial cancer, including "p53 signaling pathway", "Glutathione metabolism", "Cell cycle", and etc. Next, we selected DEGs with highly significant fold change and co-expressed across the 3 datasets and validated them in the TCGA database using Gene Expression Profiling Interactive Analysis (GEPIA). Finally, we performed a survival analysis and identified four genes (TOP2A, ASPM, EFEMP1, and FOXL2) that play key roles in endometrial cancer. We found up-regulation of TOP2A and ASPM in endometrial cancer tissues or cells, while EFEMP1 and FOXL2 were down-regulated. Furthermore, we isolated exosomes from the culturing supernatants of endometrial cancer cells (Ishikawa and HEC-1-A) and found that miR-133a, which regulates expression of FOXL2, were present in exosomes and that they could be delivered to normal endometrial cells. The common DEGs, pathways, and exosomal miRNAs identified in this study might play an important role in progression as well as diagnosis of endometrial cancer. In conclusion, our results provide insights into the pathogenesis and risk assessment of endometrial cancer. Even so, further studies are required to elucidate on the precise mechanism of action of these genes in endometrial cancer.

Soil water retention curve (SWRC) plays an important role in simulating soil water movement and assessing soil water holding capacity and availability. Comparison of fitness between different models to determine the best SWRC model of specific regions is required. In this study, three popular models, van Genuchten, Brooks Corey and Gardner model, were selected for comparing in a degraded alpine meadow region on the eastern Tibetan Plateau. Fitness, error distribution along with key parameters were compared. For each soil horizon, the soil moisture content at all soil water potentials decreased consistently with degradation, thereby integrally moving the SWRCs of all soil depths downward with degradation. The differences in SWRCs across various degradation degrees diminished along with soil depth and soil water potential. The Adj.r 2 values of van Genuchten, Brooks Corey and Gardner models ranged in 0.971-0.995, 0.958-0.997, and 0.688-0.909, respectively. The van Genuchten and Brooks Corey models significantly (p < 0.05) outperformed the Gardner model, and have no significant differences in fitness. The fitness of all three models showed no significant changes with degradation. Regardless of degradation degree and soil depth, the fitting error of van Genuchten and Brooks Corey models was mainly distributed in the higher (from -100 hPa to -500 hPa) and lower (below -10000 hPa) potential sections. With regard to the parameters of van Genuchten and Brooks Corey models, the field capacity (θs), and permanent wilting moisture were highly coherent with Adj.r 2 values of higher than 0.98, while the curve shape parameter (θr), and air entry pressure of the Brooks Corey model were much lower than those of the van Genuchten model with Adj.r 2 values of lower than 0.91. The SWRCs with varying degrees of degradation are best fitted by both van Genuchten and Brooks Corey models but cannot be fitted by Gardner model. Soil water holding capacity decreased with degradation especially in the top soil (0 cm to 30 cm), but the curve shape of all SWRCs did not change significantly with degradation.

Previously, we successfully prepared a monoclonal antibody (mAb) named 2E4, that directly recognizes the major envelope protein B2L of the orf virus (ORFV), but there is little information about its epitope. Here, we meticulously mapped the 2E4 epitope through combinatorial programs and identified the functional binding domain and a key amino acid residue. Briefly, the simulated epitope peptide closely resembles 84 VDVQSKDKDADELR 97 located at the N-terminus of B2L, strongly suggesting that the epitope is conformationally or spatially structure-dependent. Subsequently, we combined these findings with the results from the antigenicity prediction of B2L to design three truncated fragments of B2L (F1, F2 and F3) selected using 2E4, and only the F1 fragment was found to be eligible for the advanced stage. Alanine-scanning mutagenesis suggested that the D 94 residue is structurally crucial for the 2E4 epitope. The other participating residues, including K 61 , E 62 , and D 92 , together with D 94 were responsible for enabling 2E4 binding and served as factors that synergistically enabled binding to the whole 2E4 epitope. In this paper, we describe, for the first time, the architecture of an ORFV conformational epitope, and it is also expected that mAb 2E4 and its epitope can be used for applications relating to orf control.

Ankle arthrodesis and total ankle arthroplasty are the two primary surgeries for treatment of end-stage degenerative ankle arthritis. The biomechanical effects of them on the inner foot are insufficient to identify which is superior. This study compared biomechanical parameters among a foot treated by ankle arthrodesis, a foot treated by total ankle arthroplasty, and an intact foot using computational analysis. Validated finite element models of the three feet were developed and used to simulate the stance phase of gait. The results showed total ankle arthroplasty provides a more stable plantar pressure distribution than ankle arthrodesis. The highest contact pressure, 3.17 MPa, occurred in the medial cuneonavicular joint in the total ankle arthroplasty foot. Neither of the surgeries resulted in contact pressure increase in the subtalar joint. The peak stress in the metatarsal bones was increased in both surgical models, especially the second and third metatarsals. This study enables us to get visual to the biomechanics inside of an intact foot, and feet treated by total ankle arthroplasty and ankle arthrodesis during walking.

Environmental stresses such as extreme temperatures, dehydration and food deprivation may have distinct consequences for different age-classes and for males and females across species. Here we investigate a natural population of the model organism Drosophila melanogaster. Males and females at ages 3, 19 and 35 days were tested for stress resistance; i.e. the ability of flies to cope with starvation and both cold and hot temperatures. Further, we tested a measure of metabolic efficiency, namely mitochondrial DNA copy number (mtDNA CN) in both sexes at all three age-classes. We hypothesize that stress resistance is reduced at old age and more so in males, and that mtDNA CN is a biomarker for sex- and age-dependent reductions in the ability to cope with harsh environments. We show that: (1) males exhibit reduced starvation tolerance at old age, whereas older females are better in coping with periods without food compared to younger females, (2) heat tolerance decreases with increasing age in males but not in females, (3) cold tolerance is reduced at old age in both sexes, and (4) old males have reduced mtDNA CN whereas mtDNA CN slightly increases with age in females. In conclusion, our data provide strong evidence for trait and sex specific consequences of aging with females generally being better at coping with environmental stress at old age. The reduced mtDNA CN in old males suggests reduced metabolic efficiency and this may partly explain why males are less stress tolerant at old age than females. We suggest that mtDNA CN might be a suitable biomarker for physiological robustness. Our findings likely extend to other taxa than Drosophila and therefore we discuss the observations in relation to aging and sex specific lifespan across species.

Recent studies have shown that transforming microglia phenotype from pro-inflammation of M1 phenotype to anti-inflammation and tissue-repairing M2 phenotype may be an effective therapeutic strategy for preventing ischemic stroke brain injury. Isosteviol Sodium (STV-Na) has shown promise as a neuroprotective agent in cerebral ischemia model, although its effect on microglial polarization and chronic recovery after stroke is not clear. Here, we demonstrated that STV-Na treatment significantly reduced cerebral ischemic damage at both acute and chronic time points. STV-Na has a profound regulatory effect on microglia response after stroke. It can promote M2 polarization and inhibit microglia-mediated inflammation (M1) response following stroke in vivo and in vitro. Furthermore, we also found that Growth Arrest-Specific 5 (GAS5) altered OGD/R-induced microglial activation by increasing Notch1 expression via miR-146a-5p, the mRNA level of GAS5 and the protein level of Notch1 in vivo and in vitro, were discovered that both downgraded with STV-Na. Taken together, the present study demonstrated that STV-Na exerted neuroprotective effects by modulating microglia/macrophage polarization in ischemic stroke via the GAS5/miR-146a-5p sponge. These findings provide new evidence that targeting STV-Na could be a treatment for the prevention of stroke-related brain damage.

Background visual scenes in which faces are perceived provide contextual information for facial expression processing. One type of background information, the language context, has a vital influence on facial expression processing. The current study is aimed to investigate the effect of the language context on facial expression processing by recording event-related potentials (ERPs). Experiment one adopted the facial expression categorization task to investigate the effects of different language contexts on emotional and non-emotional facial processing. Experiment two adopted the task-irrelevant paradigm to investigate whether the language context effect on facial expression processing was mandatory. The results found that (1) the language context affected facial expression processing. Facial expression processing was promoted when the language context was emotionally congruent with faces. Moreover, the language context had an evoking effect on neutral faces. To be detailed, neutral facial expressions were evoked to be judged as positive in the positive language context while as negative in the negative language context. (2) The language context effect still affected facial expression processing in a task-irrelevant paradigm. When the language context was emotionally incongruent with facial expressions, larger N170 and LPP amplitudes were elicited, indicating the inhibition of incongruent emotions. These findings prove that the language context effect on facial expression processing is mandatory.

The detection of ammonia (NH 3 ) in low concentrations is very important in the chemical industry and for human health. In this paper, we present reduced graphene oxide (RGO) decorated with silver nanoparticles (AgNPs) as a sensing material for NH 3 . A simple, environmentally friendly, and cost-efficient green approach for the preparation of the sensing material is proposed. X-ray diffraction (XRD), Raman spectroscopy, and field emission scanning electron microscopy (FE-SEM) were used to analyze the crystalline structure, material composition, and surface appearance characteristics of the sensing material. By combining the material with a commercial near-field communication (NFC) tag, a wireless gas sensor was built. The enhanced NH 3 -sensing performance is mainly due to the synergistic effect between Ag and RGO. More specifically, AgNPs enhanced the adsorption capacity of RGO for NH 3 electrons. The excellent performance of the sensor shows that it has potential for applications in food safety, environment, and human health monitoring.

China has two populations of Lentinula edodes sensu lato as follows: L. edodes sensu stricto and an unexcavated morphological species respectively designated as A and B. In a previous study, we found that the nuclear types of the two populations are distinct and that both have two branches (A1, A2, B1 and B2) based on the internal transcribed spacer 2 (ITS2) sequence. In this paper, their mitogenome types were studied by resequencing 20 of the strains. The results show that the mitogenome type (mt) of ITS2-A1 was mt-A1, that of ITS2-A2 was mt-A2, and those of ITS2-B1 and ITS2-B2 were mt-B. The strains with heterozygous ITS2 types had one mitogenome type, and some strains possessed a recombinant mitogenome. This indicated that there may be frequent genetic exchanges between the two populations and both nuclear and mitochondrial markers were necessary to identify the strains of L. edodes sensu lato. In addition, by screening SNP diversity and comparing four complete mitogenomes among mt-A1, mt-A2 and mt-B, the cob, cox3, nad2, nad3, nad4, nad5, rps3 and rrnS genes could be used to identify mt-A and mt-B and that the cox1, nad1 and rrnL genes could be used to identify mt-A1, mt-A2 and mt-B.

Genetic interaction is a crucial issue in the understanding of functional pathways underlying complex diseases. However, detecting such interaction effects is challenging in terms of both methodology and statistical power. We address this issue by introducing a disease-concordant twin-case-only design, which applies to both monozygotic and dizygotic twins. To investigate the power, we conducted a computer simulation study by setting a series of parameter schemes with different minor allele frequencies and relative risks. Results from the simulation study reveals that the disease-concordant twin-case-only design largely reduces sample size required for sufficient power compared to the ordinary case-only design for detecting gene-gene interaction using unrelated individuals. Sample sizes for dizygotic and monozygotic twins were roughly 1/2 and 1/4 of sample sizes in the ordinary case-only design. Since dizygotic twins are genetically similar as siblings, the enriched power for dizygotic twins also applies to affected siblings, which could help to largely extend the application of the powerful twin-case-only design. In summary, our simulation reveals high value of disease-concordant twins and siblings in efficiently detecting gene-by-gene interactions.

We propose a flexible wireless pressure sensor, which uses a graphene/polydimethylsiloxane (GR/PDMS) sponge as the dielectric layer. The sponge is sandwiched between two surfaces of a folded flexible printed circuit with patterned Cu as the antenna and electrode. By adjusting graphene and NH 4 HCO 3 concentrations, a composite with 20% concentration of NH 4 HCO 3 and 2% concentration of graphene as the dielectric layer is obtained, which exhibits high sensitivity (2.2 MHz/kPa), wide operating range (0-500 kPa), rapid response time (~7 ms), low detection limit (5 Pa), and good stability, recoverability, and repeatability. In addition, the sensor is sensitive to finger bending and facial muscle movements for smile and frown, that are transmitted using wireless electromagnetic coupling; therefore, it has potential for a wide range of applications such as intelligent robots, bionic-electronic skin and wearable electronic devices.

Hepatocellular carcinoma (HCC) is a typical hypervascular solid tumor. Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. Hsp90β promotes endothelial cell-dependent angiogenesis in HCC. However, the relationship between Hsp90β and VM formation is unclear. In this study, we found that Hsp90β is positively correlated with VM and EMT marker proteins in HCC tissues and promotes tube formation, cell migration, and invasion in vitro. Hsp90β interacts with Twist1 and promotes its deubiquitination and stabilization to nuclear translocation and enhances the VE-cadherin promoter activity. Results of in vitro analysis indicate that Hsp90β enhances the tumor VM in tumor-burdened mice, and the Hsp90 inhibitor NVP-BEP800 suppresses VM formation by releasing Hsp90β and Twist1 interaction. This study provides a potential antitumor therapy for inhibiting VM by targeting Hsp90β in HCC.

Neurobiology is regulated by miRNA. Here circulating plasma miRNAs were assayed on a 754 miRNA OpenArray platform using 90 monozygotic elderly twins (73-95 year of age) and associated with mini mental state examination (MMSE) and a five-component cognitive score (CCS) in an explorative study. Both ordinary individual and twin-pair analyses were performed with level of cognitive scores. Candidate miRNAs were further associated with cognitive decline over 10 years using up to six repeated assessments. A total of 278 miRNAs were expressed in plasma from at least ten participants and 23 miRNAs were nominally associated (i.e., at an uncorrected p < 0.05) with CCS or MMSE in the paired analyses. Generally, elderly individuals with poor cognitive function had increase miRNA expression compared with equivalent individuals who performed better on the cognitive scale. Three miRNAs, miR-151a-3p, miR-212-3p and miR-1274b were associated with CCS both in the paired and the individual analysis. Four miRNAs found to be associated with CCS in cross-sectional analysis were also found to show an association in longitudinal analysis such that increase miRNA expression was associated with steeper cognitive decline. We propose a shared biological path underlies dementia and normative cognitive aging.

In 2015, an unexpected multiple outbreak of dengue occurred in Guangdong, China. In total, 1,699 cases were reported, of which 1,627 cases were verified to have DENV infections by nucleic acid or NS1 protein, including 44 DENV-1, 1126 DENV-2, 18 DENV-3 and 6 DENV-4, and the other cases were confirmed by NS1 ELISA. Phylogenetic analyses of DENV-1 isolates identified two genotypes (I and V). The predominant DENV-2 outbreak isolates were the Cosmopolitan genotypes, which likely originated from Malaysia. The DENV-3 isolates were assigned into genotype I and genotype III. All 6 DENV-4 isolates from imported cases were likely originally from Cambodia, Thailand and the Philippines. The entomological surveillance showed a moderate risk for the BI index in Chaozhou and Foshan and a low risk in Guangzhou. The imported cases were mostly detected in Guangzhou and Foshan. Surprisingly, the most serious outbreak occurred in Chaozhou, but not in Guangzhou or Foshan. A combined analyses demonstrated the multiple geographical origins of this outbreak, and highlight the detection of suspected cases after the alerting of imported cases, early implementation of control policies and reinforce the vector surveillance strategies were the key points in the chain of prevention and control of dengue epidemics.

Advanced modified polyacrylonitrile (PAN) membrane with high adsorption property for heavy metal ions was designed and fabricated for the first time. The introduced diazoresin-ethylenediaminetetraacetic acid (DR-EDTA) layer could effectively absorb the metal ion, such as Cu 2+ , Pb 2+ , Hg 2+ in the waste water. The effects of layers, metal ion concentration, pH, temperature and cycle time were investigated. The results showed that the adsorption isotherms for Cu 2+ were well fitted by Langmuir model. The maximum adsorption capacity of the modified membrane for Cu 2+ was approximately 47.6 mg/g. In addition, the prepared PAN-(DR-EDTA) 3 membrane could be regenerated more than 720 h based on their adsorption/desorption cycles. The results demonstrated that the modified PAN membrane could be used as effective adsorbents for heavy metal removal from waste water.