Genetic regulation of human brain proteome reveals proteins implicated in psychiatric disorders.

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate <5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Dissecting the genetic and causal relationship between sleep-related traits and common brain disorders.

BACKGROUND: There is a profound connection between abnormal sleep patterns and brain disorders, suggesting a shared influential association. However, the shared genetic basis and potential causal relationships between sleep-related traits and brain disorders are yet to be fully elucidated. METHODS: Utilizing linkage disequilibrium score regression (LDSC) and bidirectional two-sample univariable Mendelian Randomization (UVMR) analyses with large-scale GWAS datasets, we investigated the genetic correlations and causal associations across six sleep traits and 24 prevalent brain disorders. Additionally, a multivariable Mendelian Randomization (MVMR) analysis evaluated the cumulative effects of various sleep traits on each brain disorder, complemented by genetic loci characterization to pinpoint pertinent genes and pathways. RESULTS: LDSC analysis identified significant genetic correlations in 66 out of 144 (45.8 %) pairs between sleep-related traits and brain disorders, with the most pronounced correlations observed in psychiatric disorders (66 %, 48/72). UVMR analysis identified 29 causal relationships (FDR<0.05) between sleep traits and brain disorders, with 19 associations newly discovered according to our knowledge. Notably, major depression, attention-deficit/hyperactivity disorder, bipolar disorder, cannabis use disorder, and anorexia nervosa showed bidirectional causal relations with sleep traits, especially insomnia's marked influence on major depression (IVW beta 0.468, FDR = 5.24E-09). MVMR analysis revealed a nuanced interplay among various sleep traits and their impact on brain disorders. Genetic loci characterization underscored potential genes, such as HOXB2, while further enrichment analyses illuminated the importance of synaptic processes in these relationships. CONCLUSIONS: This study provides compelling evidence for the causal relationships and shared genetic backgrounds between common sleep-related traits and brain disorders.

Lapatinib combined with doxorubicin causes dose-dependent cardiotoxicity partially through activating the p38MAPK signaling pathway in zebrafish embryos.

Because of its enhanced antitumor efficacy, lapatinib (LAP) is commonly used clinically in combination with the anthracycline drug doxorubicin (DOX) to treat metastatic breast cancer. While it is well recognized that this combination chemotherapy can lead to an increased risk of cardiotoxicity in adult women, its potential cardiotoxicity in the fetus during pregnancy remains understudied. Here, we aimed to examine the combination of LAP chemotherapy and DOX-induced cardiotoxicity in the fetus using a zebrafish embryonic system and investigate the underlying pathologic mechanisms. First, we examined the dose-dependent cardiotoxicity of combined LAP and DOX exposure in zebrafish embryos, which mostly manifested as pericardial edema, bradycardia, cardiac function decline and reduced survival. Second, we revealed that a significant increase in oxidative stress concurrent with activated MAPK signaling, as indicated by increased protein expression of phosphorylated p38 and Jnk, was a notable pathophysiological event after combined LAP and DOX exposure. Third, we showed that inhibiting MAPK signaling by pharmacological treatment with the p38MAPK inhibitor SB203580 or genetic ablation of the map2k6 gene could significantly alleviate combined LAP and DOX exposure-induced cardiotoxicity. Thus, we provided both pharmacologic and genetic evidence to suggest that inhibiting MAPK signaling could exert cardioprotective effects. These findings have implications for understanding the potential cardiotoxicity induced by LAP and DOX combinational chemotherapy in the fetus during pregnancy, which could be leveraged for the development of new therapeutic strategies.

Discrepancies in breast cancer guideline recommendations despite similar Cochrane systematic review conclusions.

AIM: This study aims to describe the citation patterns of Cochrane systematic reviews (CSR) in guidelines for managing breast cancer. METHODS: We searched for systematic reviews on breast cancer in The Cochrane Library from the date of inception to November 15, 2023, and identified guidelines that cited them. We described how systematic reviews were cited by the guidelines in each database and each year. Additionally, we presented the relationships between the conclusions of the systematic reviews and guideline recommendations and compared the consistency of the recommendations on the same topic across different guidelines. RESULTS: A total of 64 systematic reviews and 228 guidelines were included in this study. The average number of the 64 systematic reviews cited by the guidelines was 5.91. We found that the guideline recommendations were irrelevant or inconsistent with the conclusions of the systematic reviews in 56 (38.36%) cited entries. We grouped recommendations on the same topic across different guidelines into one group, of which only 5 groups (15.15%) had completely consistent recommendations, and the other 28 groups (84.85%) had inconsistent recommendations. CONCLUSION: The average number of citations for CSR on breast cancer in the guidelines was 5.91. There were also situations in which the guideline recommendations were inconsistent with the conclusions of the included systematic reviews, and recommendations on the same topic across different guidelines were inconsistent.

Enhancement of Nutrient Composition and Non-Volatile Flavor Substances in Muscle Tissue of Red Drum (Sciaenops ocellatus) Through Inland Low Salinity Saline-Alkaline Water Culture.

The red drum (Sciaenops ocellatus), a globally significant marine aquaculture species, boasts formidable osmoregulatory capabilities and remarkable adaptability to low salinity, making it an ideal candidate for commercial cultivation in inland low salinity saline-alkaline waters. However, studies on the fundamental nutritional composition and flavor quality of S. ocellatus in these inland low salinity saline-alkaline waters remain unreported. This study delves into the impact of inland low salinity saline-alkaline environments on the basic nutritional components and nonvolatile flavor substances (including free amino acids and free nucleotides) in the muscle tissue of S. ocellatus. The findings reveal that redfish cultivated in these conditions exhibit a significant increase in the crude fat, ash, and protein content in their dorsal muscle tissue, coupled with a decrease in moisture content (p < 0.05), indicating an enhancement in the nutritional value of the dorsal muscle tissue. Furthermore, this cultivation environment significantly elevates the content of free amino acids in the muscle tissue (p < 0.05), particularly those contributing to umami and sweet tastes, while reducing the relative content of bitter amino acids. Although the total content of free nucleotides decreased, the equivalent umami concentration (EUC) in the muscle tissue markedly increased (p < 0.05) due to the synergistic effect of umami amino acids and flavor nucleotides, enhancing the umami taste characteristics. Therefore, inland low salinity saline-alkaline aquaculture not only elevates the nutritional value of S. ocellatus muscle tissue but also improves its umami flavor characteristics. This discovery opens new perspectives for further research into the impact of inland low salinity saline-alkaline environments on the flavor properties of marine animals.

The impact of common variants on gene expression in the human brain: from RNA to protein to schizophrenia risk.

Background: The impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding in valuable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood. Results: We quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort. Together with transcriptomics and proteomics data from the same cohort, we performed cis-Quantitative Trait Locus (QTL) mapping and identified 3,253 expression QTLs (eQTLs), 1,344 ribosome occupancy QTLs (rQTLs), and 657 protein QTLs (pQTLs) out of 7,458 genes quantitated in all three omics types from 185 samples. Of the eQTLs identified, only 34% have their effects propagated to the protein level. Further analysis on the effect size of prefrontal cortex eQTLs identified from an independent dataset showed clear post-transcriptional attenuation of eQTL effects. To investigate the biological relevance of the attenuated eQTLs, we identified 70 expression-specific QTLs (esQTLs), 51 ribosome-occupancy-specific QTLs (rsQTLs), and 107 protein-specific QTLs (psQTLs). Five of these omics-specific QTLs showed strong colocalization with SCZ GWAS signals, three of them are esQTLs. The limited number of GWAS colocalization discoveries from omics-specific QTLs and the apparent prevalence of eQTL attenuation prompted us to take a complementary approach to investigate the functional relevance of attenuated eQTLs. Using S-PrediXcan we identified 74 SCZ risk genes, 34% of which were novel, and 67% of these risk genes were replicated in a MR-Egger test. Notably, 52 out of 74 risk genes were identified using eQTL data and 70% of these SCZ-risk-gene-driving eQTLs show little to no evidence of driving corresponding variations at the protein level. Conclusion: The effect of eQTLs on gene expression in the prefrontal cortex is commonly attenuated post-transcriptionally. Many of the attenuated eQTLs still correlate with SCZ GWAS signal. Further investigation is needed to elucidate a mechanistic link between attenuated eQTLs and SCZ disease risk.

The shared microbiome in mud crab (Scylla paramamosain) of Sanmen Bay, China: core gut microbiome.

Introduction: The mud crab, Scylla paramamosain, holds great commercial significance as a marine crustacean widely cultivated in the Indo-Pacific region. Understanding the core gut microbiota of aquatic animals is crucial for their overall health and growth, yet the core gut microbiota of mud crab remains poorly characterized. Methods: In this study, we gathered gut samples from mud crabs across five locations within Sanmen Bay, China. Through the utilization of high-throughput sequencing, we delved into the composition of the gut microbial community and identified the core gut microbiome of mud crab. Results: Our results demonstrate that the gut microbial diversity of mud crab did not exhibit significant variation among the five sampling sites, although there were some differences in community richness. At the phylum level, we identified 35 representative phyla, with Firmicutes, Proteobacteria, Bacteroidota, and Campilobacterota as the dominant phyla. Among the 815 representative genera, we discovered 19 core genera, which accounted for 65.45% of the total sequences. These core genera were distributed across 6 phyla, and among them, Photobacterium exhibited the highest average relative abundance. Discussion: Photobacterium has probiotic activity and may play a crucial role in enhancing the immune response of the host and maintaining the diversity of the gut microbiota. Moreover, we observed a positive correlation between the relative abundance of core genera and the stability of the gut microbial community. Furthermore, our findings revealed distinct differences in gut microbial composition and specific taxa between the sexes of mud crab. These differences subsequently influenced the functionality of the gut microbial community. Overall, our investigation sheds light on the core gut microbiota of mud crab, emphasizing the importance of core gut microbial communities in maintaining the health and growth of these commercially significant marine crustaceans.

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Evidence mapping of clinical practice guidelines recommendations and quality for depression in children and adolescents.

This study systematically reviewed the clinical practice guidelines (CPGs) for depression in children and adolescents and assessed the quality and recommendation consistency of those CPGs. Evidence mapping was presented to illustrate the research trends and identify gaps to guide future research. Literature on CPGs for depression was systematically collected from PubMed, Embase, Web of Science, guideline databases, and psychiatric association/ society websites. The basic information, recommendations, methodological quality, and reporting quality of CPGs were extracted, and the supporting evidence strength for the included CPGs was analyzed in Excel. Four appraisers independently assessed the eligible CPGs using AGREE II instrument and the RIGHT checklist. All recommendations from the CPGs were summarized and analyzed, and the evidence mapping bubble charts were plotted in Excel. After excluding 15,184 records, 12 depression CPGs were eventually proved eligible, six of which were of high quality and six medium quality. A total of 39 major recommendations were summarized, 35 of which were supported by high-quality CPGs. Although direct comparisons are challenging due to differences in grading schemes and research quality, most CPGs share many pivotal recommendations that can help guide clinical practice. However, the evidence for some clinical problems is still lacking. Thus, more research is necessary on the screening and treatment of children and adolescents to put forward more evidence-based and high-quality recommendations.

Quality and clinical applicability of recommendations for incontinence-associated dermatitis: A systematic review of guidelines and consensus statements.

AIMS AND OBJECTIVES: The aim of this study was to assess methodological quality of all currently available guidelines and consensus statements for IAD using the Appraisal of Guidelines, Research and Evaluation (AGREE) II and the AGREE Recommendation Excellence (AGREE-REX) instruments. BACKGROUND: Globally, incontinence-associated dermatitis (IAD) is a significant health challenge. IAD is a complex healthcare problem that reduces quality of life of patients, increases healthcare costs and prolongs hospital stays. Several guidelines and consensus statements are available for IAD. However, the quality of these guidelines and consensus statements remains unclear. DESIGN: A systematic review of guidelines and consensus statements. METHODS: Our study was undertaken using PRISMA guidelines. We searched seven electronic databases. Guidelines and consensus statements had to be published in English, Chinese or German languages. Five independent reviewers assessed the methodological quality of guidelines and consensus statements using the AGREE II and AGREE-REX instruments. Mean with standard deviation (SD) and median with interquartile range (IQR) were calculated for descriptive analyses. We generated bubble plots to describe the assessment results of each domain of each guideline and consensus statement. RESULTS: We included ten guidelines and consensus statements. The NICE guidelines, obtained the highest scores, fulfilled 86.11%-98.61% of criteria in AGREE II and 76.67%-91.11% for AGREE-REX. In the domains 'Stakeholder Involvement' (4.39 ± 1.64), 'Rigor of Development' (3.38 ± 1.86), 'Applicability' (3.62 ± 1.64), 'Editorial Independence' (3.91 ± 2.56) and 'Values and Preferences' (2.98 ± 1.41), the remaining guidelines and consensus statements showed deficiencies. CONCLUSIONS: Altogether, this study demonstrated that the currently available guidelines and consensus statements for IAD have room for methodological improvement. NICE guidelines on faecal incontinence and urinary incontinence have better quality. Remaining guidelines and consensus statements showed substantial methodological weaknesses, especially the domains of 'Stakeholder Involvement', 'Rigor of Development', 'Applicability', 'Editorial independence' and 'Values and Preferences'. This study was registered on INPLASY. (Registration number: INPLASY202190078). RELEVANCE TO CLINICAL PRACTICE: The currently available guidelines and consensus statements on IAD have room for methodological improvement.

Cognitive behavior therapy for insomnia in cancer patients: a systematic review and network meta-analysis.

OBJECTIVE: The aim of this study was to examine the most effective delivery format of cognitive behavioral therapy for insomnia (CBT-I) on insomnia in cancer patients. METHODS: We searched five databases up to February 2021 for randomized clinical trials that compared CBT-I with inactive or active controls for insomnia in cancer patients. Outcomes were insomnia severity, sleep efficiency, sleep onset latency (SOL), wake after sleep onset (WASO), and total sleep time (TST). Pairwise meta-analyses and frequentist network meta-analyses with the random-effects model were applied for data analyses. RESULTS: Sixteen unique trials including 1523 participants met inclusion criteria. Compared with inactive control, CBT-I could significantly reduce insomnia severity (mean differences [MD] = -4.98 points, 95% confidence interval [CI]: -5.82 to -4.14), SOL (MD = -12.29 min, 95%CI: -16.48 to -8.09), and WASO (MD = -16.58 min, 95%CI: -22.00 to -11.15), while increasing sleep efficiency (MD = 7.62%, 95%CI: 5.82% to 9.41%) at postintervention. Compared with active control, CBT-I could significantly reduce insomnia severity (MD = -2.75 points, 95%CI: -4.28 to -1.21), SOL (MD = -13.56 min, 95%CI: -18.93 to -8.18), and WASO (MD = -6.99 min, 95%CI: -11.65 to -2.32) at postintervention. These effects diminished in short-term follow-up and almost disappeared in long-term follow-up. Most of the results were rated as "moderate" to "low" certainty of evidence. Network meta-analysis showed that group CBT-I had an increase in sleep efficiency of 10.61%, an increase in TST of 21.98 min, a reduction in SOL of 14.65 min, and a reduction in WASO of 24.30 min, compared with inactive control at postintervention, with effects sustained at short-term follow-up. CONCLUSIONS: CBT-I is effective for the management of insomnia in cancer patients postintervention, with diminished effects in short-term follow-up. Group CBT-I is the preferred choice based on postintervention and short-term effects. The low quality of evidence and limited sample size demonstrate the need for robust evidence from high-quality, large-scale trials providing long-term follow-up data.

Establishing a core outcome set for neurogenic bladder trials: study protocol for a scoping review and Delphi surveys.

BACKGROUND: Neurogenic bladder (NGB) is a chronic and disabling condition with a high prevalence rate, which can cause economic burden on patients and their families and reduce the quality of life of patients. Researchers have carried out a large number of clinical trials on the effectiveness and safety of different interventions for the treatment of NGB. The published clinical trials of NGB generally suffered from inconsistent and irregular reporting of outcome indicators. To facilitate future research studies of NGB, a core outcome set (COS) is required, which helps translate the results into high-quality evidence. METHODS AND ANALYSIS: This mixed-method project has four phases instrument: in phase 1, a scoping review of the literature to identify outcomes that have been reported in clinical trials and systematic reviews of clinical trials of interventions for NGB; in phase 2, a qualitative component using interviews to obtain the views of NGB patients, families, and their caregivers; in phase 3, Delphi survey among stakeholders to prioritize the core outcomes; and in phase 4, a face-to-face consensus meeting to discuss and agree on the final NBG COS. CONCLUSIONS: We will develop a COS that should be reported in future clinical trials of NGB. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials (COMET) Initiative database registration: http://www.comet-initiative.org/studies/details/1985 . Registered on 02 January 2022. INPLASY  INPLASY202210007.

Comparative efficacy and acceptability of cognitive behavioral therapy delivery formats for insomnia in adults: A systematic review and network meta-analysis.

This review compared the efficacy and acceptability of different delivery formats for cognitive behavioral therapy for insomnia (CBT-I) in insomnia. We searched five databases for randomized clinical trials that compared one CBT-I delivery format against another format or control conditions for insomnia in adults. We used pairwise meta-analyses and frequentist network meta-analyses with the random-effects model to synthesize data. A total of 61 unique trials including 11,571 participants compared six CBT-I delivery formats with four control conditions. At post-intervention, with low to high certainty evidence, individual, group, guided self-help, digital assisted, and unguided self-help CBT-I could significantly increase sleep efficiency and total sleep time (TST) and reduce sleep onset latency (SOL), wake after sleep onset (WASO), and insomnia severity compared with treatment as usual (MD range for sleep efficiency: 7.81%-12.45%; MD range for TST: 16.14-33.96 min; MD range for SOL: -22.42 to -13.81 min; MD range for WASO: -40.84 to -19.48 min; MD range for insomnia severity: -6.40 to -3.93) and waitlist (MD range for sleep efficiency: 7.68%-12.32%; MD range for TST: 12.67-30.49 min; MD range for SOL: -19.07 to -10.46 min; MD range for WASO: -47.10 to -19.15 min; MD range for insomnia severity: -7.59 to -5.07). The effects of different CBT-I formats persisted at short-term follow-up (4 wk-6 mo). Individual, group, and digital assisted CBT-I delivery formats would be the more appropriate choices for insomnia in adults, based on post-intervention and short-term effects. Further trials are needed to investigate the long-term effects of different CBT-I formats.

Deep Single-Cell-Type Proteome Profiling of Mouse Brain by Nonsurgical AAV-Mediated Proximity Labeling.

Proteome profiling is a powerful tool in biological and biomedical studies, starting with samples at bulk, single-cell, or single-cell-type levels. Reliable methods for extracting specific cell-type proteomes are in need, especially for the cells (e.g., neurons) that cannot be readily isolated. Here, we present an innovative proximity labeling (PL) strategy for single-cell-type proteomics of mouse brain, in which TurboID (an engineered biotin ligase) is used to label almost all proteins in a specific cell type. This strategy bypasses the requirement of cell isolation and includes five major steps: (i) constructing recombinant adeno-associated viruses (AAVs) to express TurboID driven by cell-type-specific promoters, (ii) delivering the AAV to mouse brains by direct intravenous injection, (iii) enhancing PL labeling by biotin administration, (iv) purifying biotinylated proteins, followed by on-bead protein digestion, and (v) quantitative tandem-mass-tag (TMT) labeling. We first confirmed that TurboID can label a wide range of cellular proteins in human HEK293 cells and optimized the single-cell-type proteomic pipeline. To analyze specific brain cell types, we generated recombinant AAVs to coexpress TurboID and mCherry proteins, driven by neuron- or astrocyte-specific promoters and validated the expected cell expression by coimmunostaining of mCherry and cellular markers. Subsequent biotin purification and TMT analysis identified ∼10,000 unique proteins from a few micrograms of protein samples with excellent reproducibility. Comparative and statistical analyses indicated that these PL proteomes contain cell-type-specific cellular pathways. Although PL was originally developed for studying protein-protein interactions and subcellular proteomes, we extended it to efficiently tag the entire proteomes of specific cell types in the mouse brain using TurboID biotin ligase. This simple, effective in vivo approach should be broadly applicable to single-cell-type proteomics.

SMAP is a pipeline for sample matching in proteogenomics.

The integration of genomics and proteomics data (proteogenomics) holds the promise of furthering the in-depth understanding of human disease. However, sample mix-up is a pervasive problem in proteogenomics because of the complexity of sample processing. Here, we present a pipeline for Sample Matching in Proteogenomics (SMAP) to verify sample identity and ensure data integrity. SMAP infers sample-dependent protein-coding variants from quantitative mass spectrometry (MS), and aligns the MS-based proteomic samples with genomic samples by two discriminant scores. Theoretical analysis with simulated data indicates that SMAP is capable of uniquely matching proteomic and genomic samples when ≥20% genotypes of individual samples are available. When SMAP was applied to a large-scale dataset generated by the PsychENCODE BrainGVEX project, 54 samples (19%) were corrected. The correction was further confirmed by ribosome profiling and chromatin sequencing (ATAC-seq) data from the same set of samples. Our results demonstrate that SMAP is an effective tool for sample verification in a large-scale MS-based proteogenomics study. SMAP is publicly available at https://github.com/UND-Wanglab/SMAP , and a web-based version can be accessed at https://smap.shinyapps.io/smap/ .

Agromyces agglutinans sp. nov., isolated from saline lake sediment.

A novel actinobacterium, designated strain CFH 90414T, was isolated from sediment sampled at a saline lake in Yuncheng, Shanxi, PR China. The taxonomic position of the strain was investigated by using a polyphasic approach. Cells of strain CFH 90414T were Gram-reaction-positive, aerobic and non-motile. Growth occured at 4-40 °C, pH 5.0-9.0 and in the presence of up to 0-3.0 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CFH 90414T was a member of the genus Agromyces. The 16S rRNA gene sequence similarity analysis indicated that strain CFH 90414T was most closely related to Agromyces italicus JCM 14320T (98.07 %) and Agromyces lapidis JCM 14321T (97.18 %). The whole genome of CFH 90414T was 3.64 Mb, and showed a G+C content of 71.5 mol%. The average nucleotide identity (ANI) values and digital DNA-DNA hybridization (dDDH) values between CFH 90414T and the other species of the genus Agromyces were found to be low (ANI <78.99 % and dDDH <22.9 %). The whole-cell sugars were rhamnose, mannose, ribose, glucose and galactose. The isolate contained l-2,4-diaminobutyric acid, d-alanine, d-glutamic acid and glycine in the cell-wall peptidoglycan. The predominant menaquinone was MK-12. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol and an unidentified glycolipid. On the basis of phenotypic, genotypic and phylogenetic data, strain CFH 90414T is considered to represent a novel species of the genus Agromyces, for which the name Agromyces agglutinans sp. nov. is proposed. The type strain is CFH 90414T (=DSM 105966T=KCTC 49062T).

The standards of obstetrics and gynecology core outcome sets: A scoping review.

BACKGROUND: Core outcome sets (COSs) are the minimum outcomes which should be measured and reported by researchers investigating a specific condition. The definition of standards of COSs vary across different health-related areas. This investigated the characteristics of COSs regarding obstetrics and gynecology (OG) and examined the reports and designs of standards of OG COSs. METHODS: A comprehensive search was conduced on the COMET database on December 20, 2019 to identify systematic reviews on COSs. Two reviewers independently evaluated whether the reported OG COS met the reporting requirements as stipulated in the Core Outcome Set-STAndards for Reporting (COS-STAR) statement checklist and the minimum design recommendations as outlined in the Core Outcome Set-STAndards for Development (COS-STAD) checklist. RESULTS: Forty-four OG COSs related to 26 topics were identified. None of them met all the 25 standards of COS-STAR statement which representing 18 items considered essential for transparent and complete reporting list for all COS studies (range: 6.0-24.0, median: 14.0). The compliance rates to 16 standards of methods and result sections ranged from 27.3%-68.2%. Total COS-STAR compliance items for OG COSs with the prior protocol was significantly higher than without prior protocol (MD = 3.846, 95% CI: 0.835-6.858, P = 0.012). None of the OG COSs met all the 12 criteria in the COS-STAD minimum standards (range: 3.0-11.0, median: 5.0). The compliance rates for all three standards of stakeholders involved and all four standards of the consensus process were lower than 60%. CONCLUSIONS: Methodological and reporting standards of OG COSs should be improved.

Proteomic Profiling of Cerebrospinal Fluid by 16-Plex TMT-Based Mass Spectrometry.

Mass spectrometry (MS) has become a mainstream platform for comprehensive profiling of proteome, especially with the improvement of multiplexed tandem mass tag labeling coupled with two-dimensional liquid chromatography and tandem mass spectrometry (TMT-LC/LC-MS/MS). Recently, we have established a robust method for direct profiling of undepleted cerebrospinal fluid (CSF) proteome with the 16-plex TMTpro method, in which we optimized parameters in experimental steps of sample preparation, TMT labeling, LC/LC fractionation, tandem mass spectrometry, and computational data processing. The extensive LC fractionation not only enhances proteome coverage of the CSF but also alleviates ratio distortion of TMT quantification. The crucial quality control steps and improvements specific for the TMT16 analysis are highlighted. More than 3000 proteins can be quantified in a single experiment from 16 different CSF samples. This multiplexed method offers a powerful tool for profiling a variety of complex biofluids samples such as CSF, serum/plasma, and other clinical specimens.

Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment.

Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (e.g., the GABA receptor subunit of GABRA2), and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.

CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.