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Abstract Introduction Epidural analgesia (EA) is the most widely used intervention for the reduction of labor pain; however, it is contra-indicated for patients with spinal deformity or allergy to anesthetics and may be refused by parturients. As a noninvasive and nonnarcotic analgesic intervention, transcutaneous electrical acupoint stimulation (TEAS) has gained increasing attention in recent years. Therefore, we performed a network meta-analysis to compare the efficacy and safety of TEAS and EA as measured by visual analog scale score, the failure rate of natural delivery, adverse events, and Apgar scores. Methods Relevant randomized controlled trials (RCTs) from four electronic databases (PubMed, EMBASE, Web of Science, and Cochrane CENTRAL) and clinical trials.gov were searched from inception until September 4, 2022. A random effects model was used during analysis, and outcomes were evaluated as standard mean difference (SMD), odds ratio (OR), and 95% confidence intervals (CrI) using STATA (version SE15.0), R (version 3.6.1), and ADDIS (version 1.16.8) software. Results Ten RCTs comprising 1214 parturients were identified by screening. Six RCTs compared TEAS and controls, three compared EA and controls, and one compared TEAS and EA. No heterogeneity was found within the four outcomes. There was no significant difference in any outcomes between interventions or control treatments in terms of SMD, OR, and CrI. Combined with the highest surface under the cumulative ranking curve score, TEAS demonstrated possible better effects in the aspects of analgesic efficacy and safety under certain circumstances. Conclusions TEAS may be a potential alternative for parturients as a simple, noninvasive, and non-pharmacological intervention compared with EA in terms of analgesic efficacy and safety for mothers and neonates.

Abstract Purpose Bifidobacterium is an important probiotic used in food and medicine production. The probiotic properties of bifidobacteria are strain specific, so it is necessary to evaluate the probiotic properties of bifidobacteria isolated from specific populations, especially when developing products suitable for specific populations. The objective of this study was to evaluate the probiotic potential and safety of bifidobacteria isolated from healthy Uyghur infants from northwestern China. Methods In this study, antimicrobial activity, antibiotic sensitivity, hemolytic, acid and bile tolerance, hydrophobicity, co-aggregation, auto-aggregation, and antioxidant activity were evaluated. Results Based on antagonistic activity spectrum against seven intestinal pathogenic bacteria, 14 excellent strains were initially selected. Among 14 strains, four bifidobacteria strains (BF17-4, BF52-1, BF87-3, and BF88-5) were superior to strain Lactobacillus rhamnosus GG in cell surface hydrophobicity and auto-aggregation percentages and close to strain GG in co-aggregation with Escherichia coli EPEC O127: K63 (CICC 10411). The antioxidant activities of each of the 14 bifidobacteria strains varied with the cell components. Most of the strains were sensitive to all the antimicrobials tested, except kanamycin and amikacin. Conclusion BF17-4 and BF52-1 are good candidates for further in vivo studies and further used in functional foods.

Background: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) therapy may experience further damage to the vascular endothelium, leading to increased inflammatory response and in-stent thrombosis. In many clinical studies, sodium tanshinone IIA sulfonate injection (STS) has been found to reduce inflammatory factors and enhance vascular endothelial function in patients with ACS while improving the prognosis of PCI. However, to date, there has been no systematic review assessing the effectiveness and safety of STS on inflammatory factors and vascular endothelial function.Purpose: The aim of this study is to systematically review the effects of STS on inflammatory factors and endothelial function in patients with ACS treated with PCI.Methods: Until October 2022, eight literature databases and two clinical trial registries were searched for randomized controlled trials (RCTs) investigating STS treatment for ACS patients undergoing PCI. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool 2.0. Meta-analysis was performed using RevMan 5.4 software.Results: Seventeen trials met the eligibility criteria, including 1,802 ACS patients undergoing PCI. The meta-analysis showed that STS significantly reduced high-sensitivity C-reactive protein (hs-CRP) levels (mean difference [MD = −2.35, 95% CI (−3.84, −0.86), p = 0.002], tumor necrosis factor-alpha (TNF-α) levels (standard mean difference [SMD = −3.29, 95%CI (−5.15, −1.42), p = 0,006], matrix metalloproteinase-9 (MMP-9) levels [MD = −16.24, 95%CI (−17.24, −15.24), p < 0.00001], and lipid peroxidation (LPO) levels [MD = −2.32, 95%CI (−2.70, −1.93), p < 0.00001], and increased superoxide dismutase (SOD) levels [SMD = 1.46, 95%CI (0.43, 2.49), p = 0,006] in patients with ACS. In addition, STS significantly decreased the incidence of major adverse cardiovascular events (relative risk = 0.54, 95%CI [0.44, 0.66], p < 0.00001). The quality of evidence for the outcomes was assessed to be very low to medium.Conclusion: STS can safely and effectively reduce the levels of hs-CRP, TNF-α, MMP-9, and LPO and increase the level of SOD in patients with ACS treated with PCI. It can also reduce the incidence of adverse cardiovascular events. However, these findings require careful consideration due to the small number of included studies, high risk of bias, and low to moderate evidence. In the future, more large-scale and high-quality RCTs will be needed as evidence in clinical practice.

Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases (CHD) worldwide; however, its pathogenesis remains unclear. Recent studies have shown that circular RNAs (circRNAs) act as “sponges” for microRNAs (miRNAs) to compete for endogenous RNA (ceRNA) and play important roles in regulating gene transcription and biological processes. However, the mechanism of ceRNA in TOF remains unclear. To explore the crucial regulatory connections and pathways of TOF, we obtained the human TOF gene, miRNA, and circRNA expression profiling datasets from the Gene Expression Omnibus (GEO) database. After data pretreatment, differentially expressed mRNAs (DEmRNAs), microRNAs (DEmiRNAs), and circRNAs (DEcircRNAs) were identified between the TOF and healthy groups, and a global triple ceRNA regulatory network, including circRNAs, miRNAs, and mRNAs based on the integrated data, was constructed. A functional enrichment analysis was performed on the Metascape website to explore the biological functions of the selected genes. Then, we constructed a protein-protein interaction (PPI) network and identified seven hub genes using the cytoHubba and MCODE plug-ins in the Cytoscape software, including BCL2L11, PIK3R1, SOCS3, OSMR, STAT3, RUNX3, and IL6R. Additionally, a circRNA–miRNA–hub gene subnetwork was established, and its enrichment analysis results indicated that the extrinsic apoptotic signaling pathway, JAK-STAT signaling pathway and PI3K-Akt signaling pathway may be involved in the pathogenesis of TOF. We further identified the hsa_circ_000601/hsa-miR-148a/BCL2L11 axis as a crucial signaling pathway axis from the subnetwork. This study provides a novel regulatory network for the pathogenesis of TOF, revealing the possible molecular mechanisms and crucial regulatory pathways that may provide new strategies for candidate diagnostic biomarkers or potential therapeutic targets for TOF.

Abstract Background Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosomal membrane associated protein 2a (LAMP2a) is the lysosomal membrane receptor of CMA and influences CMA activity. Although it has been suggested that higher expression of LAMP2a is associated with more advanced tumor node metastasis (TNM) stages and shorter survival time in patients with esophageal squamous cell carcinoma (ESCC), the underlying mechanism has not been known yet. Methods In this study, we modulated the activity of CMA through LAMP2a or small molecular compounds in human ESCC cells to investigate its role in ESCC. Results We found that down‐regulating the activity of CMA could inhibit the proliferation and colony formation of ESCC cells as well as increase their sensitivity to cisplatin. Conclusions Our results promote better understanding of how CMA affects human ESCC and provide a new therapeutic target against ESCC through down‐regulating LAMP2a.

Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world, and there remains an urgent need to develop long-lasting therapies to treat CRC and prevent recurrence in patients. Oncolytic virus therapy (OVT) has demonstrated remarkable efficacy in a number of different cancer models. Here, we report a novel vaccinia virus (VV)-based OVT for treatment of CRC. The novel VV, based on the recently reported novel VVLΔTKΔN1L virus, was armed with the pleiotropic cytokine interleukin-21 (IL-21) to enhance anti-tumor immune responses stimulated after viral infection of tumor cells. Compared with an unarmed virus, VVLΔTKΔN1L-mIL-21 had a superior anti-tumor efficacy in murine CMT93 subcutaneous CRC models in vivo, mediated mainly by CD8+ T cells. Treatment resulted in development of long-term immunity against CMT93 tumor cells, as evidenced by prevention of disease recurrence. These results demonstrate that VVLΔTKΔN1L-mIL-21 is a promising therapeutic agent for treatment of CRC.

The maternal gut is thought to be the principal source of potential probiotic bacteria in the infant gut during the lactation stage. It is not clear whether facultative symbiont lactobacilli strictly follow vertical transmission from mother to infant and display the ethnic specificity in terms of species and strain composition in mother–infant cohorts. In the present study, a total of 16 former Lactobacillus species (365 strains) and 11 species (280 strains) were retrieved from 31 healthy mother–infant pairs of two ethnic groups, which have never intermarried, respectively. The result showed that the composition and number of Lactobacillus species between the two ethnic groups varied. Among 106 Lacticaseibacillus paracasei strains isolated, 64 representative strains were classified into 27 sequence types (ST) by means of multilocus sequence typing (MLST), of which 20 STs derived from 33 Uighur strains and 7 STs from 31 Li strains, and no homologous recombination event of genes was detected between strains of different ethnic groups. A go-EBURST analysis revealed that except for a few mother–infant pairs in which more than one STs were detected, L. paracasei isolates from the same mother–infant pair were found to be monophyletic in most cases, confirming vertical transfer of Lactobacillus at the strain level. More notably, L. paracasei isolates from the same ethnic group were more likely than strains from another to be incorporated into a specific phylogenetic clade or clonal complex (CC) with similar metabolic profile of glycan, supporting the hypothesis of ethnic specificity to a large degree. Our study provides evidence for the development of personalized probiotic tailored to very homogenous localized populations from the perspective of maternal and child health.

Managers of nonprofit organizations are challenged to manage revenue growth and risk (i.e., volatility) in order to sustain current and future financial operations. Although the negative repercussions of revenue risk are generally perceived as undesirable, not all risk is bad. If higher levels of revenue risk are compensated with a greater amount of revenue growth, then organizations may rationally pursue volatile revenues that produce growth. This article examines the extent to which a reliance on major revenue sources by nonprofit organizations affects the magnitude of total revenue volatility as well as the pace of total revenue growth. A monitoring application is introduced that can be used to compare the effectiveness of revenue management among similar nonprofit organizations. It can also be used to guide nonprofit managers striving to achieve sustainable financial growth for their organizations.

Breast milk acts as an intermediary for the transfer of functionally important commensal bacteria from mother to infant, especially for Bifidobacterium that can colonize the infant gut. However, the vast majority of rRNA amplicon-based studies reported the conspicuous intercohort and interindividual variation for the prevalence of Bifidobacterium in breast milk. In order to elucidate whether Bifidobacterium phylotypes persistently co-occured at the species or strain level in mother–breast milk–infant triads, we analyzed collectively the next-generation sequencing (NGS) datasets of bacterial 16S rRNA gene and the Bifidobacterium-specific groEL gene from maternal feces, breast milk, and infant feces in a small yet very homogeneous cohort of 25 healthy Uyghur mother–infant pairs (lactation for 7–720 days) in Kashgar, Xinjiang, China. Overall, 16S rRNA gene analysis showed that microbiome in the newborn gut was closer to that of breast milk in the first 4 months of lactation, and subsequently showed an obvious trend of adulthood at 6–12 months. Based on the BLAST accurate taxonomic result of the representative sequences of all ASVs (amplicon sequencing variants), only three sets of ASVs could be clearly assigned into Bifidobacterium species, whereas the remaining eight sets of ASVs corresponded to four indefinite Bifidobacterium species group. By contrast, the groEL gene dataset was partitioned into 376 ASVs, at least belonging to 13 well-known Bifidobacterium species or subspecies, of which 15 ASVs, annotated to seven well-known Bifidobacterium species or subspecies, showed triadic synchronism in most 23 mother–infant pairs tested. However, several other rare bifidobacterial phylotypes, which were frequently encountered in animals, were found to display no correspondence of the presence between the three ecosystems of mother–infant pairs. Our test results were obviously to support the hypothesis that breast milk acts as an intermediary for the transfer of probiotic commensal bacteria from mother to infant, especially for endosymbiotic Bifidobacterium that can colonize the infant gut. Some oxygen-insensitive exogenous Bifidobacterium phylotypes with a cosmopolitan lifestyle may be indirectly transferred to breast milk and the infant’s intestinal tract through environmental contamination. Thus, the groEL gene proved to be a very effective target for the depth resolution of Bifidobacterium community by high-throughput sequencing technologies.

Acrylamide, a II A carcinogen, widely exists in fried and baked foods. L-asparaginase can inhibit acrylamide formation in foods, and enzymatic stability is the key to its application. In this study, the Escherichia coli L-asparaginase (ECA) stable variant, D60W/L211R/L310R, was obtained with molecular dynamics (MD) simulation, saturation mutation, and combinatorial mutation, the half-life of which increased to 110 min from 60 min at 50 °C. Furthermore, the working temperature (maintaining the activity above 80%) of mutation expanded from 31 °C–43 °C to 35 °C–55 °C, and the relative activity of mutation increased to 82% from 65% at a pH range of 6–10. On treating 60 U/mL and 100 U/g flour L-asparaginase stable mutant (D60W/L211R/L310R) under uncontrolled temperature and pH, the acrylamide content of potato chips and bread was reduced by 66.9% and 51.7%, which was 27% and 49.9% higher than that of the wild type, respectively. These results demonstrated that the mutation could be of great potential to reduce food acrylamide formation in practical applications.

The maternal gut is the principal source of commensal bacteria in the infant gut during the lactation stage, where breast milk acts as an intermediary for the transfer of potential probiotic bacteria consortia, including Lactobacillus. This study aimed to characterize the bacterial communities in human milk, maternal, and infant feces in a small yet very homogeneous cohort of 25 healthy mother–infant pairs in northwestern China (n = 25, infant age from 7 days to 2 years), with special emphasis on the cooccurrence and vertical transfer of Lactobacillus phylotypes at the species or strain level in mother-breast milk-infant triads. Accurate sequencing analysis revealed that among 73 Lactobacillus zero-radius operational classification units (ZOTUs) identified, 58 belonging to 18 recognized species or species groups were distributed in all three types of samples. Lactobacillus ruminis, L. mucosae and L. gasseri-johnsonii as true residents were the most represented in all three ecosystems, whereas the content of Lactobacillus phylotypes commonly developed as probiotics was not dominant. While the numbers of Lactobacillus species in breast milk and infant feces were greater than that in maternal feces, principal coordinates analysis (PCoA) based on beta diversity, coupled with the frequency of isolates determined by culture methods, showed that the Lactobacillus community in the infant gut was more similar to that in the maternal gut than to that in breast milk, suggesting that the gut is niche selective for Lactobacillus populations. In addition, identical strains of L. ruminis, L. paracasei, L. mucosae and L. salivarius were isolated from multiple mother–infant pairs, supporting the hypothesis that vertical transfer of bacteria via breastfeeding contributes to the initial establishment of the microbiota in the developing infant intestine.

Lung cancer is one of the most commonly diagnosed cancer and despite therapeutic advances, mortality remains high. The long period of clinical latency associated with lung cancer provides an ideal window of opportunity to administer vaccines to at-risk individuals that can prevent tumor progression and initiate long-term anti-tumor immune surveillance. Here we describe a personalized vaccination regime that could be applied for both therapeutic and prophylactic prevention of lung cancer, based on the derivation of lung cancer cells from induced pluripotent stem cells. Stem cells from healthy mice were modified to express Cre-dependent KRASG12D and Trp53R172H prior to differentiation to lung progenitor cells. Subsequent viral delivery of Cre caused activation of exogenous driver mutations, resulting in transformation and development of lung cancer cells. iPSC-derived lung cancer cells were highly antigenically related to lung cancer cells induced in LSL-KRASG12D/+; Trp53R172H/+ transgenic mice and were antigenically unrelated to original pluripotent stem cells or pancreatic cancer cells derived using the same technological platform. For vaccination, induced lung cancer cells were infected with oncolytic Adenovirus or Vaccinia virus, to act as vaccine adjuvants, prior to delivery of vaccines sequentially to a murine inducible transgenic model of lung cancer. Application of this Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime primed tumor-specific T cell responses that significantly prolonged survival in both subcutaneous post-vaccine challenge models and induced transgenic models of lung cancer, demonstrating that stem cell-derived prophylactic vaccines may be a feasible intervention for treatment or prevention of lung cancer development in at-risk individuals.

Multi-terminal voltage sourced converter (VSC)-based high voltage direct current (HVDC) system composes of a number of VSCs connected to an HVDC grid (or dc grid). The dc grid is often configured by cable interconnections between converter stations, thus imposing resonance issues affecting harmonic interaction in the system. Based on the harmonic transfer characteristics of VSC and HVDC systems, the appearance and the interaction of inter-harmonics in the multi-terminal VSC-based HVDC system are analyzed. Simulation models are built and implemented using SimPowerSystems in MATLAB. The simulation results show that, a series of inter-harmonics are produced and tend to be dominant in low-frequency range. Especially in the dc grid, the inter-harmonic transfer can be magnified due to inter-harmonic resonances. The complex resonance issues in the dc grid are investigated in combination with interaction through the VSC, it is beneficial to harmonic filter designs as well as other harmonic mitigation methods.

It is a common practice for storage batteries to be connected to DC microgrid buses through DC-DC converters for voltage support on islanded operation mode. A feed-forward control based dual-loop constant voltage PI control for three-branch interleaved DC-DC converters (TIDC) is proposed for storage batteries in DC microgrids. The working principle of TIDC is analyzed, and the factors influencing the response rate based on the dual-loop constant voltage control for TIDC are discussed, and then the method of feed-forward control for TIDC is studied to improve the response rate for load changing. A prototype of the TIDC is developed and an experimental platform is built. The experiment results show that DC bus voltage sags or swells caused by load changing can be reduced and the time for voltage recovery can be decreased significantly with the proposed feed-forward control.

Abstract Doxorubicin’s antitumor effectiveness may be constrained with ineffective tumor penetration, systemic adverse effects, as well as drug resistance. The co-loading of immune checkpoint inhibitors and doxorubicin into liposomes can produce synergistic benefits and address problems, including quick drug clearance, toxicity, and low drug penetration efficiency. In our previous study, we modified a nanobody targeting CTLA-4 onto liposomes (LPS-Nb36) to be an extremely potent CTLA-4 signal blocker which improve the CD8+ T-cell activity against tumors under physiological conditions. In this study, we designed a drug delivery system (LPS-RGD-Nb36-DOX) based on LPS-Nb36 that realized the doxorubicin and anti-CTLA-4 Nb co-loaded and RGD modification, and was applied to antitumor therapy. We tested whether LPS-RGD-Nb36-DOX could targets the tumor by in vivo animal photography, and more importantly, promote cytotoxic T cells proliferation, pro-inflammatory cytokine production, and cytotoxicity. Our findings demonstrated that the combination of activated CD8+ T cells with doxorubicin/anti-CTLA-4 Nb co-loaded liposomes can effectively eradicate tumor cells both in vivo and in vitro. This combination therapy is anticipated to have synergistic antitumor effects. More importantly, it has the potential to reduce the dose of chemotherapeutic drugs and improve safety.

Abstract Background Neurovascular cells have wide-ranging implications on skeletal muscle biology regulating myogenesis, maturation, and regeneration. Although several in vitro studies have investigated how motor neurons and endothelial cells interact with skeletal myocytes independently, there is limited knowledge about the combined effect of neural and vascular cells on muscle maturation and development. Methods Here, we report a triculture system comprising human-induced pluripotent stem cell (iPSC)-derived skeletal myocytes, human iPSC-derived motor neurons, and primary human endothelial cells maintained under controlled media conditions. Briefly, iPSCs were differentiated to generate skeletal muscle progenitor cells (SMPCs). These SMPCs were seeded at a density of 5 × 104 cells/well in 12-well plates and allowed to differentiate for 7 days before adding iPSC-derived motor neurons at a concentration of 0.5 × 104 cells/well. The neuromuscular coculture was maintained for another 7 days in coculture media before addition of primary human umbilical vein endothelial cells (HUVEC) also at 0.5 × 104 cells/well. The triculture was maintained for another 7 days in triculture media comprising equal portions of muscle differentiation media, coculture media, and vascular media. Extensive morphological, genetic, and molecular characterization was performed to understand the combined and individual effects of neural and vascular cells on skeletal muscle maturation. Results We observed that motor neurons independently promoted myofiber fusion, upregulated neuromuscular junction genes, and maintained a molecular niche supportive of muscle maturation. Endothelial cells independently did not support myofiber fusion and downregulated expression of LRP4 but did promote expression of type II specific myosin isoforms. However, neurovascular cells in combination exhibited additive increases in myofiber fusion and length, enhanced production of Agrin, along with upregulation of several key genes like MUSK, RAPSYN, DOK-7, and SLC2A4. Interestingly, more divergent effects were observed in expression of genes like MYH8, MYH1, MYH2, MYH4, and LRP4 and secretion of key molecular factors like amphiregulin and IGFBP-4. Conclusions Neurovascular cells when cultured in combination with skeletal myocytes promoted myocyte fusion with concomitant increase in expression of various neuromuscular genes. This triculture system may be used to gain a deeper understanding of the effects of the neurovascular niche on skeletal muscle biology and pathophysiology.

Abstract In recent years, artificial intelligence (AI) technology has been used in most if not all domains and has greatly benefited our lives. While AI can accurately extract critical features and valuable information from large amounts of data to help people complete tasks faster, there are growing concerns about the non-transparency of AI in the decision-making process. The emergence of explainable AI (XAI) has allowed humans to better understand and control AI systems, which is motivated to provide transparent explanations for the decisions made by AI. This article aims to present a comprehensive overview of recent research on XAI approaches from three well-defined taxonomies. We offer an in-depth analysis and summary of the status and prospects of XAI applications in several key areas where reliable explanations are urgently needed to avoid mistakes in decision-making. We conclude by discussing XAI’s limitations and future research directions.

Abstract 3-Hydroxybutanone (Acetoin, AC) and 2,3-butanediol (BD) are two essential four-carbon platform compounds with numerous pharmaceutical and chemical synthesis applications. AC and BD have two and three stereoisomers, respectively, while the application of the single isomer product in chemical synthesis is superior. AC and BD are glucose overflow metabolites produced by biological fermentation from a variety of microorganisms. However, the AC or BD produced by microorganisms using glucose is typically a mixture of various stereoisomers. This was discovered to be due to the simultaneous presence of multiple butanediol dehydrogenases (BDHs) in microorganisms, and AC and BD can be interconverted under BDH catalysis. In this paper, beginning with the synthesis pathways of microbial AC and BD, we review in detail the studies on the formation mechanisms of different stereoisomers of AC and BD, summarize the properties of different types of BDH that have been tabulated, and analyze the structural characteristics and affinities of different types of BDH by comparing them using literature and biological database data. Using microorganisms, recent research on the production of optically pure AC or BD was also reviewed. Limiting factors and possible solutions for chiral AC and BD production are discussed.

Abstract Despite the great success of CTLA-4 blocking in cancer treatment, the use of anti-CTLA-4 monoclonal antibodies still faces many limitations. Now, immune checkpoint blocking coupled with adoptive cell therapy is gaining much attention. In this paper, we reported a strategy on the basis of anti-CTLA-4 nanobody (Nb)-modified liposomes to improve these obstacles. An Nb36/liposome complex was constructed and utilized as a blocker of the CTLA-4/B7 signal pathway in a combination with dendritic cell (DC)/tumor fusion vaccine to enhance the CD8+ T cell cytokine secretion, activation, proliferation, as well as specific cytotoxicity. Moreover, the CD8+ T cells induced by LPS-Nb36 and DC/tumor fusion vaccine led to higher CD8+ T cell effector function in vivo, which significantly retarded tumor growth and lengthened survival of tumor-bearing mice (HepG2, A549, and MGC-803). Our data demonstrate that the anti-CTLA-4 Nb-modified liposomes in connection with DC/tumor fusion vaccines enhance the CD8+ T cell antitumor activity in vitro and in vivo, and is expected to be an alternative therapy for patients with malignancies that have T cell dysfunction or have poor treatment against anti-CTLA-4 mAb.

Summary: Background: Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS. While GWAS can identify genetic loci conferring risk, it does not determine which cell types drive the genetic aetiology of the trait, which variants are “causal” at a given signal, and which effector genes correspond to these non-coding variants. These obstacles limit interpretation of potential disease mechanisms. Methods: We analysed CTS GWAS findings in the context of chromatin conformation between gene promoters and accessible chromatin regions across cellular models of bone, skeletal muscle, adipocytes and neurons. We identified proxy variants in high LD with the lead CTS sentinel SNPs residing in promoter connected open chromatin in the skeletal muscle and bone contexts. Findings: We detected significant enrichment for heritability in skeletal muscle myotubes, as well as a weaker correlation in human mesenchymal stem cell-derived osteoblasts. In myotubes, our approach implicated 117 genes contacting 60 proxy variants corresponding to 20 of the 53 GWAS signals. In the osteoblast context we implicated 30 genes contacting 24 proxy variants coinciding with 12 signals, of which 19 genes shared. We subsequently prioritized BZW2 as a candidate effector gene in CTS and implicated it as novel gene that perturbs myocyte differentiation in vitro. Interpretation: Taken together our results suggest that the CTS genetic component influences the size, integrity, and organization of multiple tissues surrounding the carpal tunnel, in particular muscle and bone, to predispose the nerve to being compressed in this disease setting. Funding: This work was supported by NIH Grant UM1 DK126194 (SFAG and WY), R01AG072705 (SFAG & KDH) and the Center for Spatial and Functional Genomics at CHOP (SFAG & ADW). SFAG is supported by the Daniel B. Burke Endowed Chair for Diabetes Research. WY is supported by the Perelman School of Medicine of the University of Pennsylvania.

ABSTRACTIn China, 45% of adolescents with obesity develop fatty liver disease, a condition that increases the long-term risk of developing cirrhosis and liver cancer. Although the factors triggering nonalcoholic fatty liver disease (NAFLD) vary in children, the composition of intestinal microflora has been found to play an increasingly important role. However, evidence is limited on the prevalence of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) in Chinese children. Therefore, this study aimed to evaluate the fecal microbiome of Chinese children with NAFLD and further analyze the potential of flora in regulating NAFLD-related symptoms and metabolic functions. Specifically, the study applied a 16S rRNA and metagenomic sequencing to the fecal samples of pediatric patients with NAFLD, NASH, and NAFL, as well as healthy controls, to explore the correlation among NAFLD-related indexes, metabolic pathways, and gut flora. The findings showed that some fecal microbiota had a negative correlation with body mass index, and various NAFLD-related bacteria, including Lachnoclostridium, Escherichia-Shigella, and Faecalibacterium prausnitzii, were detected. Consequently, the study concluded that the variation in gut microbiota might be more important in improving NAFLD/NASH compared with single species, providing a microbiota diagnostic profile of NAFLD/NASH.IMPORTANCEThis study aims to characterize the gut microbiota in Chinese children with nonalcoholic fatty liver disease (NAFLD) through 16S rRNA and metagenomic sequencing. The results highlight the association between fecal microbiota and NAFLD in Chinese children, demonstrating distinct characteristics compared to adults and children from other countries. Based on the sequencing data from our cohort’s fecal samples, we propose a microbiota model with a high area under the curve for distinguishing between NAFLD and healthy individuals. Furthermore, our follow-up study reveals that changes in the relative abundance of microbial biomarkers in this model are consistent with variations in patients’ body mass index. These findings suggest the potential utility of the microbiota model and microbial biomarkers for diagnosing and treating NAFLD in children.