A comprehensive overview of oncogenic pathways in human cancer.

Alterations of biological pathways can lead to oncogenesis. An overview of these oncogenic pathways would be highly valuable for researchers to reveal the pathogenic mechanism and develop novel therapeutic approaches for cancers. Here, we reviewed approximately 8500 literatures and documented experimentally validated cancer-pathway associations as benchmarking data set. This data resource includes 4709 manually curated relationships between 1557 paths and 49 cancers with 2427 upstream regulators in 7 species. Based on this resource, we first summarized the cancer-pathway associations and revealed some commonly deregulated pathways across tumor types. Then, we systematically analyzed these oncogenic pathways by integrating TCGA pan-cancer data sets. Multi-omics analysis showed oncogenic pathways may play different roles across tumor types under different omics contexts. We also charted the survival relevance landscape of oncogenic pathways in 26 tumor types, identified dominant omics features and found survival relevance for oncogenic pathways varied in tumor types and omics levels. Moreover, we predicted upstream regulators and constructed a hierarchical network model to understand the pathogenic mechanism of human cancers underlying oncogenic pathway context. Finally, we developed `CPAD' (freely available at http://bio-bigdata.hrbmu.edu.cn/CPAD/), an online resource for exploring oncogenic pathways in human cancers, that integrated manually curated cancer-pathway associations, TCGA pan-cancer multi-omics data sets, drug-target data, drug sensitivity and multi-omics data for cancer cell lines. In summary, our study provides a comprehensive characterization of oncogenic pathways and also presents a valuable resource for investigating the pathogenesis of human cancer.

RNAactDrug: a comprehensive database of RNAs associated with drug sensitivity from multi-omics data.

Drug sensitivity has always been at the core of individualized cancer chemotherapy. However, we have been overwhelmed by large-scale pharmacogenomic data in the era of next-generation sequencing technology, which makes it increasingly challenging for researchers, especially those without bioinformatic experience, to perform data integration, exploration and analysis. To bridge this gap, we developed RNAactDrug, a comprehensive database of RNAs associated with drug sensitivity from multi-omics data, which allows users to explore drug sensitivity and RNA molecule associations directly. It provides association data between drug sensitivity and RNA molecules including mRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) at four molecular levels (expression, copy number variation, mutation and methylation) from integrated analysis of three large-scale pharmacogenomic databases (GDSC, CellMiner and CCLE). RNAactDrug currently stores more than 4 924 200 associations of RNA molecules and drug sensitivity at four molecular levels covering more than 19 770 mRNAs, 11 119 lncRNAs, 438 miRNAs and 4155 drugs. A user-friendly interface enriched with various browsing sections augmented with advance search facility for querying the database is offered for users retrieving. RNAactDrug provides a comprehensive resource for RNA molecules acting in drug sensitivity, and it could be used to prioritize drug sensitivity-related RNA molecules, further promoting the identification of clinically actionable biomarkers in drug sensitivity and drug development more cost-efficiently by making this knowledge accessible to both basic researchers and clinical practitioners. Database URL: http://bio-bigdata.hrbmu.edu.cn/RNAactDrug.

Identification and comprehensive characterization of lncRNAs with copy number variations and their driving transcriptional perturbed subpathways reveal functional significance for cancer.

Numerous studies have shown that copy number variation (CNV) in lncRNA regions play critical roles in the initiation and progression of cancer. However, our knowledge about their functionalities is still limited. Here, we firstly provided a computational method to identify lncRNAs with copy number variation (lncRNAs-CNV) and their driving transcriptional perturbed subpathways by integrating multidimensional omics data of cancer. The high reliability and accuracy of our method have been demonstrated. Then, the method was applied to 14 cancer types, and a comprehensive characterization and analysis was performed. LncRNAs-CNV had high specificity in cancers, and those with high CNV level may perturb broad biological functions. Some core subpathways and cancer hallmarks widely perturbed by lncRNAs-CNV were revealed. Moreover, subpathways highlighted the functional diversity of lncRNAs-CNV in various cancers. Survival analysis indicated that functional lncRNAs-CNV could be candidate prognostic biomarkers for clinical applications, such as ST7-AS1, CDKN2B-AS1 and EGFR-AS1. In addition, cascade responses and a functional crosstalk model among lncRNAs-CNV, impacted genes, driving subpathways and cancer hallmarks were proposed for understanding the driving mechanism of lncRNAs-CNV. Finally, we developed a user-friendly web interface-LncCASE (http://bio-bigdata.hrbmu.edu.cn/LncCASE/) for exploring lncRNAs-CNV and their driving subpathways in various cancer types. Our study identified and systematically characterized lncRNAs-CNV and their driving subpathways and presented valuable resources for investigating the functionalities of non-coding variations and the mechanisms of tumorigenesis.

Epidermal growth factor receptor-extracellular-regulated kinase blockade upregulates TRIM32 signaling cascade and promotes neurogenesis after spinal cord injury.

Nerve regeneration is blocked after spinal cord injury (SCI) by a complex myelin-associated inhibitory (MAI) microenvironment in the lesion site; however, the underlying mechanisms are not fully understood. During the process of neural stem cell (NSC) differentiation, pathway inhibitors were added to quantitatively assess the effects on neuronal differentiation. Immunoprecipitation and lentivirus-induced overexpression were used to examine effects in vitro. In vivo, animal experiments and lineage tracing methods were used to identify nascent neurogenesis after SCI. In vitro results indicated that myelin inhibited neuronal differentiation by activating the epidermal growth factor receptor (EGFR)-extracellular-regulated kinase (ERK) signaling cascade. Subsequently, we found that tripartite motif (TRIM) 32, a neuronal fate-determining factor, was inhibited. Moreover, inhibition of EGFR-ERK promoted TRIM32 expression and enhanced neuronal differentiation in the presence of myelin. We further demonstrated that ERK interacts with TRIM32 to regulate neuronal differentiation. In vivo results indicated that EGFR-ERK blockade increased TRIM32 expression and promoted neurogenesis in the injured area, thus enhancing functional recovery after SCI. Our results showed that EGFR-ERK blockade antagonized MAI of neuronal differentiation of NSCs through regulation of TRIM32 by ERK. Collectively, these findings may provide potential new targets for SCI repair.

Neuroprotection of N-benzyl Eicosapentaenamide in Neonatal Mice Following Hypoxic-Ischemic Brain Injury.

Maca (Lepidium meyenii) has emerged as a popular functional plant food because of its medicinal properties and nutritional value. Macamides, as the exclusively active ingredients found in maca, are a unique series of non-polar, long-chain fatty acid N-benzylamides with multiple bioactivities such as antifatigue characteristics and improving reproductive health. In this study, a new kind of macamide, N-benzyl eicosapentaenamide (NB-EPA), was identified from maca. We further explore its potential neuroprotective role in hypoxic-ischemic brain injury. Our findings indicated that treatment with biosynthesized NB-EPA significantly alleviates the size of cerebral infarction and improves neurobehavioral disorders after hypoxic-ischemic brain damage in neonatal mice. NB-EPA inhibited the apoptosis of neuronal cells after ischemic challenge. NB-EPA improved neuronal cell survival and proliferation through the activation of phosphorylated AKT signaling. Of note, the protective property of NB-EPA against ischemic neuronal damage was dependent on suppression of the p53-PUMA pathway. Taken together, these findings suggest that NB-EPA may represent a new neuroprotectant for newborns with hypoxic-ischemic encephalopathy.

Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. METHODS: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia and treated with IL-33 at a dose of 0.2 µg/day i.p. for 3 days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells and cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. RESULTS: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 days after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. CONCLUSIONS: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

Superparamagnetic iron oxide nanoparticles conjugated with Aß oligomer-specific scFv antibody and class A scavenger receptor activator show therapeutic potentials for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. No disease-modifying strategy to prevent or delay AD progression currently exists. Aß oligomers (AßOs), rather than monomers or fibrils, are considered as the primary neurotoxic species. Therapeutic approaches that direct against AßOs and promote Aß clearance may have great value for AD treatment. RESULTS: We here reported a multifunctional superparamagnetic iron oxide nanoparticle conjugated with Aß oligomer-specific scFv antibody W20 and class A scavenger receptor activator XD4 (W20/XD4-SPIONs). Besides the diagnostic value, W20/XD4-SPIONs retained the anti-Aß properties of W20 and XD4 by inhibiting Aß aggregation, attenuating AßO-induced cytotoxicity and increasing microglial phagocytosis of Aß. When applied to APP/PS1 mice, W20/XD4-SPIONs significantly rescued cognitive deficits and alleviated neuropathology of AD mice. CONCLUSION: These results suggest that W20/XD4-SPIONs show therapeutic benefits for AD. In combination with the early diagnostic property, W20/XD4-SPIONs present as a promising agent for early-stage AD diagnosis and intervention.

A novel rapid modularized hepatitis B core virus-like particle-based platform for personalized cancer vaccine preparation via fixed-point coupling.

Personalized cancer vaccine which targets neoepitopes shows great promise for cancer treatment. However, rapid preparation is a critical challenge for clinical application of personalized cancer vaccine. Genetic recombination and chemical modification are a time-consuming "trial and error" pattern for making vaccines. Here we first constructed a platform for peptide vaccine preparation by inserting SpyCatcher into the major immunodominant region (MIR) of hepatitis B core protein (HBc) (1-183). The resulted recombinant protein HBc(1-183)-SpyCatcher (HBc(1-183)-S) assembled to virus-like particles (VLPs) and readily bound to SpyTag conjugated with OVA epitope peptides by just mixing, forming HBc(1-183)-S-OVA. HBc(1-183)-S-OVA VLPs effectively induced dendritic cell maturation. Our further results indicated that HBc(1-183)-S-OVA VLPs vaccination inhibited tumor growth in both prophylactic and treatment ways in E.G7-OVA tumor bearing mice by generating significant OVA-specific cytotoxic T lymphocyte responses. Our study provides a simple, rapid, efficient and universal HBc-based platform for the preparation of personalized cancer vaccine.

Identifying subpathway signatures for individualized anticancer drug response by integrating multi-omics data.

BACKGROUND: Individualized drug response prediction is vital for achieving personalized treatment of cancer and moving precision medicine forward. Large-scale multi-omics profiles provide unprecedented opportunities for precision cancer therapy. METHODS: In this study, we propose a pipeline to identify subpathway signatures for anticancer drug response of individuals by integrating the comprehensive contributions of multiple genetic and epigenetic (gene expression, copy number variation and DNA methylation) alterations. RESULTS: Totally, 46 subpathway signatures associated with individual responses to different anticancer drugs were identified based on five cancer-drug response datasets. We have validated the reliability of subpathway signatures in two independent datasets. Furthermore, we also demonstrated these multi-omics subpathway signatures could significantly improve the performance of anticancer drug response prediction. In-depth analysis of these 46 subpathway signatures uncovered the essential roles of three omics types and the functional associations underlying different anticancer drug responses. Patient stratification based on subpathway signatures involved in anticancer drug response identified subtypes with different clinical outcomes, implying their potential roles as prognostic biomarkers. In addition, a landscape of subpathways associated with cellular responses to 191 anticancer drugs from CellMiner was provided and the mechanism similarity of drug action was accurately unclosed based on these subpathways. Finally, we constructed a user-friendly web interface-CancerDAP ( http://bio-bigdata.hrbmu.edu.cn/CancerDAP/ ) available to explore 2751 subpathways relevant with 191 anticancer drugs response. CONCLUSIONS: Taken together, our study identified and systematically characterized subpathway signatures for individualized anticancer drug response prediction, which may promote the precise treatment of cancer and the study for molecular mechanisms of drug actions.

Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5.

Epidemiological and clinical studies have increasingly shown that fine particulate matter (PM2.5) is associated with cardiovascular morbidity and mortality, which share the common feature of PM2.5-induced vascular inflammation; however, the underlying mechanisms of how PM2.5 triggers increased inflammatory response in vascular endothelial cells are not well understood. After treating mouse aortic endothelial cells (MAECs) with different concentrations of PM2.5, we assessed interleukin (IL)-6 and four and a half LIM domains 2 (FHL2) expression in cell supernatant by enzyme-linked immunosorbent assay and Western blot, respectively, as well as activation of nuclear factor (NF)-κB and immune-response signaling pathways. Additionally, changes in pathway activation, IL-6 expression, and autophagy were evaluated under PM2.5 exposure, following FHL2 knockdown with small interfering RNA. Our results indicated that PM2.5 exposure induced FHL2 expression and IL-6 secretion, as well as activation of pathways associated with immune response. Additionally, following FHL2 knockdown, the activation of NF-κB-related pathways and IL-6 secretion was inhibited under PM2.5 exposure, although the Akt- and p38-signaling pathways were not affected. Furthermore, PM2.5 exposure induced autophagy, whereas autophagy inhibition eventually inhibited PM2.5-induced FHL2 expression. These findings suggested a novel link between autophagy induced FHL2 upregulation and IL-6 production in MAECs under PM2.5 exposure.

[Application of ICP-MS and ICP-AES for Studying on Source Apportionment of PM2.5 during Haze Weather in Urban Beijing].

To investigate the characteristics of chemical constitute and pollution sources of aerosol fine particulate matter during haze-fog day in Beijing in winter 2013. The samples of PM2.5 were collected in Beijing from January to February, 2013. The technique of ICP-MS and ICP-AES coupled with procedure of bathing-ultrasonic extraction was applied to determine the concentration of 40 elements in the aerosol samples to analyze the characteristics of elements distribution statistically. The absolute principal factor method was used to apportion the pollution sources of PM2.5 during the haze weather in Beijing city in winter 2013. The results showed that during the period of sampling, the volume concentration of Li, Mn, Pb, S etc. obeyed normal distribution approximately, and according to National Ambient Air Quality Standard issued by Ministry of Environmental Protection of the People's Republic of China, the geometric mean concentration of As was twice the annual limit of standard reference, while Pb of some aerosol samples beyond the annual limit of standard reference respectively. The mass fraction of Fe, Zn, Pb, Ti accounted for over 0.1%, while that of Mn, Cu, As, Se etc. 0.01%. These elements were primary inorganic pollutants, and especially the hazards and sources of As and Pb should be concerned. There were 6 main pollution sources were chosen by the factor analysis method, including industrial dust and human beings activities, biomass combustion and building dust, soil and sand dusts, fossil fuel, electronic waste and metal smelting, with the variance contribution rate of 40.3%, 27.0%, 9.1%, 4.9%, 4.8% and 4.6% respectively. ICP-MS and ICP-AES can be applied to analyzing multi-elements in PM2.5 accurately and quickly to facilitate source apportionment, and it indicated that the relevant pollution sources should be considered and the effect of regional transferring of haze pollution sources should be taken into account, and specific measures should be taken for control.

Synthesis of 6/5/3-Fused Tricyclic Scaffolds via Multistep Cascade Cyclization of α-Aryl Vinylsulfoniums with para-Quinamines and para-Quinols.

Herein, we present a straightforward approach to access hydroindoline-5-one-based 6/5/3-fused polycyclic ring structures through multistep cascade reactions involving α-aryl vinylsulfoniums and para-quinamines. The reactions proceed smoothly under mild conditions to deliver the desired products in generally good isolated yields. This protocol is also applicable to the cascade cycloaddition reactions of α-aryl vinylsulfoniums and para-quinols, effectively generating complex tricyclic scaffolds. In addition, the scale-up synthesis and further derivatizations demonstrate the potential synthetic application of the protocol.

Salidroside Ameliorates Lung Injury Induced by PM 2.5by Regulating SIRT1-PGC-1α in Mice.

Objective: This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Methods: Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Results: Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1ɑ, and an increase in the protein expressions of IL-6, IL-1ß, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway. Conclusion: SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5-induced lung injury.

Transient receptor potential vanilloid 2 (TRPV2), a potential novel biomarker in childhood asthma.

BACKGROUND: The presence of transient receptor potential vanilloid 2 (TRPV2) in human peripheral blood cells may suggest a role under pathological conditions. The aim of this study was to explore the relationship between the expression profile of TRPV2 gene and childhood asthma in the north of China. The effects of allergens exposure on the expression of TRPV2 gene were also investigated. METHODS: Sixty asthmatics children confirmed by physician diagnosis and 60 healthy children as a control group were recruited. Serum total IgE and specific IgE were measured. Using quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), TRPV2 was detected in total RNA extracted from peripheral blood lymphocytes. Student's t-test and chi-square test were used to analyze the relationship between TRPV2 transcript and different parameter variables on susceptibility of childhood asthma. Multiple logistic regression was used to analyze the associations between TRPV2 gene and allergens. RESULTS: The expression level of TRPV2 gene was increased 2.6 times in asthmatic children compared with controls (p < .01). The up-regulation of TRPV2 gene and sensitization to one of three the allergens-spring pollen, dust mite, and dog and cat hair-were correlated with childhood asthma. In addition, the hypersensitivity to spring pollen, cockroach, and dust mite and up-regulation of TRPV2 gene expression may be the risk factors for the childhood asthma in Beijing. CONCLUSIONS: The increased expression of TRPV2 gene in peripheral lymphocytes is closely correlated with childhood asthma in the north of China. This study provides a potential new biomarker of childhood asthma and lays the basis for further clarification of the pathogenesis underlying asthma.

[Assessment of haze-related human health risks for four Chinese cities during extreme haze in January 2013].

OBJECTIVE: To evaluate the human health risks (premature death risk as an indicator) in Beijing, Shanghai, Guangzhou and Xi'an during extreme haze in January 2013. METHODS: The daily average particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5) concentrations of Beijing, Shanghai, Guangzhou and Xi'an in January 2013 were collected and their characteristics explored. The populations and mortality rate of four cities in 2010 were collected from the statistical yearbook, the exposure-response relationships selected from the reference and then the premature death calculated according to the proportion risk model of Poisson regression. RESULTS: In January 2013, the 24 h mean concentrations of PM2.5 in Beijing, Shanghai, Guangzhou and Xi'an were (240 ± 165) , (83 ± 27), (94 ± 49) and (210 ± 98) µg/m(3) respectively and they were all above the secondary level of Ambient Air Quality Standards (GB 3095-2012). The 24 h mean concentrations of PM2.5 in Beijing and Xi'an were much higher than those in Shanghai and Guangzhou. Approximately 86.4% (19/22) , 58.1% (18/31), 54.8% (17/31) and 93.5% (29/31) of 24 h mean PM2.5 concentrations in Beijing, Shanghai, Guangzhou and Xi'an respectively exceeded the secondary level of Ambient Air Quality Standards (GB 3095-2012). The number of premature death due to the exposure to haze were 725 (95%CI: 457-977) for Beijing, 296 (95%CI: 96-502) for Shanghai, 310 (95%CI: 189-434) for Guangzhou and 85 (95%CI: 21-141) for Xi'an respectively in January 2013. CONCLUSION: The PM2.5 pollutions of four cities in January 2013 were serious enough to pose elevated risks of human health.

[Epidemiological survey of children asthma prevalence in Beijing urban area].

OBJECTIVE: To explore the prevalence, diagnosis and management of childhood asthma in Beijing urban area. METHODS: Multi-stage, stratified and random cluster sampling was used to recruit children born during November 1, 1995 to October 31, 2010 from Beijing or other provinces but residing in Beijing for over half a year. The same screening questionnaires for the third national epidemiological survey of children's asthma were distributed to parents of children at schools, kindergartens and communities during October 2010 to March 2011. Asthmatic children were picked among the screening-positive children based on on-the-spot inquiries, physical examinations, medical records and supporting test results. Further survey of asthmatics was carried out to investigate the diagnosis and treatment status of childhood asthma and other associated allergic diseases. All data required double entry by Epi-Info 3.5.3 software and were processed by SPSS 19.0. RESULTS: Among a total of 14 085 questionnaires, 13 513 were completed with a response rate of 95.94%. And 497 (3.68%) children were diagnosed with typical (n = 451, 3.34%) and cough variant (n = 46, 0.34%) asthma. Among them, 40.64% (202/497) were newly diagnosed and 59.36% (295/497) had been previously diagnosed with asthma. The prevalence of asthma was higher in boys than in girls (4.80% (345/1790) vs 2.40% (152/6323), χ(2) = 54.446, P < 0.01). The asthma prevalence of preschoolers (3 - < 7 years old) was the highest (5.05% (180/3563)). In the past two years, the symptoms of 69.42% (345/497) children persisted and the current two-year prevalence of asthma was 2.55% (345/13513). Among the 295 children with previous asthma, only 46.44% (137/295) received inhaled corticosteroids according to the Global Initiative for Asthma (GINA) and 82.37% (243/295) of them used antibiotics. CONCLUSIONS: The prevalence of asthma is 3.68% in children under 14 years old in Beijing urban area and it varies in children with different genders and ages. A considerable number of children are not diagnosed or treated properly. And the management of asthma requires further improvement.

[Chemical constituents from the aerial part of Stauntonia obovatifoliola Hayata subsp. urophylla].

OBJECTIVE: To study the chemical constituents of the aerial part of Stauntonia obovatifoliola. METHODS: The chemical constituents of ethyl acetate fraction were isolated and purified by several chromatography. Their structures were elucidated by their physiochemical properties and spectral methods. RESULTS: Six known compounds were isolated and identified as lupeone(1), lupeol(2), stigmasterol(3),3beta-O-acetyloleanolic acid(4), resinone(5) and daucosterol(6). CONCLUSION: Compounds 1-6 are isolated from this plant for the first time.

Vaginal reconstruction with a double-sided biomembrane-a preclinical experimental study on large animals.

Tissue engineering techniques bring the promise of vaginal reconstruction with low invasiveness and fewer complications. However, existing biomaterial scaffolds remain limited in efficient vaginal recovery, focusing only on regenerating an epithelial layer, but muscle layers are missing or abnormal. The lack of a multi-tissue hierarchical structure in the reconstructed vagina leads to shrinking, stenosis, and fibrosis. Here, an acellular matrix named a double-sided biomembrane (DBM) is demonstrated for vaginal recovery. The regeneration of epithelial and muscle layers is achieved simultaneously since the smooth side of the DBM is helpful for guiding epithelial cell growth, while its loose and porous side guides muscle cell growth. In addition, the DBM demonstrates excellent mechanical properties similar to vaginal tissue, and hydrophilicity. Therefore, neovaginas were observed in the fourth and twelfth weeks after DBMs were transplanted to repair full-thickness vaginal defects (4 cm) that we established in large animals. The DBMs can effectively promote rapid epithelialization, the formation of large muscle bundles, higher rates of angiogenesis, and the restoration of physiological function in a neovagina. That is, the injured vagina achieves nearly complete recovery in anatomy and function, similar to a normal vagina. These preclinical results indicate that the DBM has prospects for vaginal injury repair.

Artificial intelligence in psychiatry research, diagnosis, and therapy.

Psychiatric disorders are now responsible for the largest proportion of the global burden of disease, and even more challenges have been seen during the COVID-19 pandemic. Artificial intelligence (AI) is commonly used to facilitate the early detection of disease, understand disease progression, and discover new treatments in the fields of both physical and mental health. The present review provides a broad overview of AI methodology and its applications in data acquisition and processing, feature extraction and characterization, psychiatric disorder classification, potential biomarker detection, real-time monitoring, and interventions in psychiatric disorders. We also comprehensively summarize AI applications with regard to the early warning, diagnosis, prognosis, and treatment of specific psychiatric disorders, including depression, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, addiction, sleep disorders, and Alzheimer's disease. The advantages and disadvantages of AI in psychiatry are clarified. We foresee a new wave of research opportunities to facilitate and improve AI technology and its long-term implications in psychiatry during and after the COVID-19 era.

Fc effector of anti-Aß antibody induces synapse loss and cognitive deficits in Alzheimer's disease-like mouse model.

Passive immunotherapy is one of the most promising interventions for Alzheimer's disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aß-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aß, antibody, and complement. Notably, anti-Aß antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aß-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aß-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.