Data-driven retrieval of population-level EEG features and their role in neurodegenerative diseases.

Electrophysiologic disturbances due to neurodegenerative disorders such as Alzheimer's disease and Lewy Body disease are detectable by scalp EEG and can serve as a functional measure of disease severity. Traditional quantitative methods of EEG analysis often require an a-priori selection of clinically meaningful EEG features and are susceptible to bias, limiting the clinical utility of routine EEGs in the diagnosis and management of neurodegenerative disorders. We present a data-driven tensor decomposition approach to extract the top 6 spectral and spatial features representing commonly known sources of EEG activity during eyes-closed wakefulness. As part of their neurologic evaluation at Mayo Clinic, 11 001 patients underwent 12 176 routine, standard 10-20 scalp EEG studies. From these raw EEGs, we developed an algorithm based on posterior alpha activity and eye movement to automatically select awake-eyes-closed epochs and estimated average spectral power density (SPD) between 1 and 45 Hz for each channel. We then created a three-dimensional (3D) tensor (record × channel × frequency) and applied a canonical polyadic decomposition to extract the top six factors. We further identified an independent cohort of patients meeting consensus criteria for mild cognitive impairment (30) or dementia (39) due to Alzheimer's disease and dementia with Lewy Bodies (31) and similarly aged cognitively normal controls (36). We evaluated the ability of the six factors in differentiating these subgroups using a Naïve Bayes classification approach and assessed for linear associations between factor loadings and Kokmen short test of mental status scores, fluorodeoxyglucose (FDG) PET uptake ratios and CSF Alzheimer's Disease biomarker measures. Factors represented biologically meaningful brain activities including posterior alpha rhythm, anterior delta/theta rhythms and centroparietal beta, which correlated with patient age and EEG dysrhythmia grade. These factors were also able to distinguish patients from controls with a moderate to high degree of accuracy (Area Under the Curve (AUC) 0.59-0.91) and Alzheimer's disease dementia from dementia with Lewy Bodies (AUC 0.61). Furthermore, relevant EEG features correlated with cognitive test performance, PET metabolism and CSF AB42 measures in the Alzheimer's subgroup. This study demonstrates that data-driven approaches can extract biologically meaningful features from population-level clinical EEGs without artefact rejection or a-priori selection of channels or frequency bands. With continued development, such data-driven methods may improve the clinical utility of EEG in memory care by assisting in early identification of mild cognitive impairment and differentiating between different neurodegenerative causes of cognitive impairment.

Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine.

BACKGROUND: Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing Aconitum species; however, its underlying mechanism remains unclear. OBJECTIVE: The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC. METHODS: The efflux function of P-gp on YAC was explored by using Caco-2 monolayers in combination with the P-gp inhibitor verapamil. The impact of P-gp on regulating the analgesic and anti-inflammatory effects, acute toxicity, tissue distribution, and pharmacokinetics of YAC was determined via male Mdr1a gene knocked-out mice and wild-type FVB mice. RESULTS: The presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco- 2 monolayers (P < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in Mdr1a-/- mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice (P < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD50) of YAC from 2.13 to 0.24 mg/kg (P < 0.05). Moreover, the concentrations of YAC in the tissues of Mdr1a-/- mice were statistically higher than those in wild-type FVB mice (P < 0.05). Particularly, the brain accumulation of YAC in Mdr1a-/- mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice (P < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between Mdr1a-/- and wild-type FVB mice. CONCLUSION: YAC is a sensitive substrate of P-gp. The absence of P-gp enhances the analgesic effect and toxicity of YAC by upregulating its brain accumulation. Co-administration with a P-gp inhibitor may lead to severe YAC poisoning.

Multiplexed CRISPR-Cas system targeting ASFV genes in vivo: solution lies within.

The emergence and spread of the African swine fever virus (ASFV) posed a significant threat to the global swine breeding industry, calling for innovative approaches benefiting viral containment and control. A recent study (Z. Zheng, L. Xu, H. Dou, Y. Zhou, X., et al., Microbiol Spectr 12: e02164-23, 2024, https://doi.org/10.1128/spectrum.02164-23) established a multiplexed CRISPR-Cas system targeting the genome of ASFV and tested the consequent antiviral activity both in vitro and in vivo. Application of this system showed a significant reduction of viral replication in vitro, while the germline-edited pigs expressing this system exhibited normal growth with continuous guide RNA expression. Although no survival advantage was observed upon ASFV challenge compared with nonengineered pigs, this marks the first attempt of germline editing to pursue ASFV resistance and paves the way for future disease-resistant animal breeding approaches utilizing CRISPR-Cas technology.

Vaginal dinoprostone versus Foley catheter for induction of labor at term with an unfavorable cervix: an open-label randomized controlled trial.

BACKGROUND: Induction of labor with mechanical methods or pharmacological agents is used in about 20-30% of all pregnant women. We specialized in comparing the effectiveness and safety of dinoprostone versus transcervical Foley catheter for induction of labor in term pregnant women with an unfavorable cervix with adequate samples. OBJECTIVE: To compare the effectiveness and safety of dinoprostone versus transcervical Foley catheter for induction of labor in term pregnant women with an unfavorable cervix. STUDY DESIGN: This is a parallel, open-label randomized controlled trial in two maternal centers in Shanghai, China between October 2019 and July 2022. Women with a singleton pregnancy in cephalic presentation at term and an unfavorable cervix (Bishop score < 6) scheduled for induction of labor were eligible. 1,860 women were randomly allocated to cervical ripening with either a dinoprostone vaginal insert (10mg) or a 60cc Foley catheter for up to 24 hours. The primary outcomes were vaginal delivery rate and time to vaginal delivery. Secondary outcomes included time to delivery and maternal and neonatal morbidity. Analysis was done from an intention-to-treat perspective. The trial was registered with the China trial registry (CTR2000038435). RESULTS: The vaginal birth rates were 72.8% (677/930) vs. 69.9% (650/930) in vaginal dinoprostone and Foley catheter, respectively (aRR 1.04, 95% CI 0.98 to 1.10, risk difference: 0.03). Time to vaginal delivery was not significantly different between the two groups (sub-distribution hazard ratio 1.11, 95% CI 0.99-1.24). Vaginal dinoprostone was more likely complicated with hyperstimulation with fetal heart rate changes (5.8% vs. 2.8%, aRR 2.09, 95% CI 1.32-3.31) and placenta abruption (0.9% vs. 0.1%, aRR: 8.04, 95% CI 1.01-64.15), while Foley catheter was more likely complicated with suspected intrapartum infection (5.1% vs. 8.2 %, aRR: 0.62, 95% CI 0.44-0.88) and postpartum infection (1.4% vs. 3.7%, aRR: 0.38, 95% CI 0.20-0.72). The composite of poor neonatal outcomes was not significantly different between the two groups (4.5% vs. 3.8%, aRR 1.21, 95% CI 0.78 to 1.88), while more neonatal asphyxia occurred in the dinoprostone group (1.2% vs. 0.2%, aRR 5.39, 95% CI 1.22 to 23.92). In a subgroup analysis, vaginal dinoprostone decreased vaginal birth rate slightly in multiparous women (90.6% vs. 97.0%, aRR 0.93, 95% CI 0.88 to 0.99). CONCLUSIONS: In term pregnant women with an unfavorable cervix, induction of labor with vaginal dinoprostone or Foley catheter has similar effectiveness. Foley catheter leads to better safety for neonates, while it may result in a higher risk of maternal infection. Furthermore, Foley catheter should be preferred in multiparous women.

The Individual Participant Data Integrity Tool for assessing the integrity of randomised trials.

Increasing concerns about the trustworthiness of research have prompted calls to scrutinise studies' Individual Participant Data (IPD), but guidance on how to do this was lacking. To address this, we developed the IPD Integrity Tool to screen randomised controlled trials (RCTs) for integrity issues. Development of the tool involved a literature review, consultation with an expert advisory group, piloting on two IPD meta-analyses (including 73 trials with IPD), preliminary validation on 13 datasets with and without known integrity issues, and evaluation to inform iterative refinements. The IPD Integrity Tool comprises 31 items (13 study-level, 18 IPD-specific). IPD-specific items are automated where possible, and are grouped into eight domains, including unusual data patterns, baseline characteristics, correlations, date violations, patterns of allocation, internal and external inconsistencies, and plausibility of data. Users rate each item as having either no issues, some/minor issue(s), or many/major issue(s) according to decision rules, and justification for each rating is recorded. Overall, the tool guides decision-making by determining whether a trial has no concerns, some concerns requiring further information, or major concerns warranting exclusion from evidence synthesis or publication. In our preliminary validation checks, the tool accurately identified all five studies with known integrity issues. The IPD Integrity Tool enables users to assess the integrity of RCTs via examination of IPD. The tool may be applied by evidence synthesists, editors and others to determine whether an RCT should be considered sufficiently trustworthy to contribute to the evidence base that informs policy and practice.

Assessing the antiviral activity of antimicrobial peptides Caerin1.1 against PRRSV in Vitro and in Vivo.

The Porcine reproductive and respiratory syndrome (PRRS) causes severe financial losses to the global swine industry. Due to continuous virus evolution, the protection against the PRRS provided by current vaccines is limited. In order to find new antiviral strategies, this study investigated the antiviral potential of antimicrobial peptides (AMPs) against PRRSV. Given the diversity of PRRSV strains and the limited effectiveness of existing vaccines in controlling PRRSV, this study evaluated the inhibitory effects of KLAK, Cecropin B, Piscidin1, and Caerin1.1 on 3 strains of PRRSV (lineage 5 classical strain, lineage 8 highly pathogenic strain, and lineage 1 NADC30-like strain). Caerin1.1 exhibited significant dose-dependent antiviral activity, with an effective concentration (EC50) of 7.5 µM. Caerin1.1 effectively inhibited PRRSV replication when added before or in early infection but showed reduced effectiveness when added in late infection, indicating its potential involvement in targeting early transcription mechanisms of viral RNA polymerase and significantly upregulating cytokine gene expression. In the NADC30 strain-based animal infection model, Caerin1.1 treatment significantly reduced lung viral loads and inflammation in the lungs of PRRSV-infected pigs, with a mortality rate of 0 % (0/5) in the treated group compared to 66.67 % (4/6) in the untreated group, indicating a reduction in the mortality rate. Additionally, compared with the untreated group, the Caerin1.1-treated group showed significant improvements, such as lighter fever, more daily weight gain, less clinical symptoms, less viral load in blood, and less virus oral shedding (P < 0.05). These findings reveal the potential of antimicrobial peptides as PRRSV therapeutic agents and suggest that Caerin1.1 is a promising candidate for a novel anti-PRRSV drug.

Non-adiabatic dynamics studies of the C+(2P1/2, 3/2) + H2 reaction: Based on global diabatic potential energy surfaces of CH2.

Global diabatic potential energy surfaces (PESs) of CH2+ are constructed using the neural network method with a specific function based on 18 213 ab initio points. The multi-reference configuration interaction method with the aug-cc-pVQZ basis set is adopted to perform the ab initio calculations. The topographical properties of the diabatic PESs are examined in detail. In general, the diabatic PESs provide an accurate quasi-diabatic representation. To validate the diabatic PESs, the dynamics studies of the C+(2P1/2, 3/2) + H2 (v0 = 0, j0 = 0) → H + CH+(X1Σ+) reaction are performed using the time-dependent wave packet method. The reaction probabilities, integral cross sections, differential cross sections, and rate constants are calculated and compared with the experimental and theoretical results. Non-adiabatic dynamics results are in good agreement with experimental data. In addition, the non-adiabatic effect in the C+(2P1/2, 3/2) + H2 reaction is significant due to the non-adiabatic results being obviously larger than adiabatic values. The reasonable non-adiabatic dynamics results indicate that present diabatic PESs can be recommended for any type of dynamics study.

Diabatic Potential Energy Surfaces of SrH2+ and Dynamics Studies of the Sr+(5s2S) + H2 Reaction.

Based on the ab initio energy points of both ground and excited states, a neural network fitting method combined with a specific function was successfully used to construct the diabatic potential energy surfaces (PESs) of the SrH2+ system. The topographical features of the diabatic PESs were examined in detail. The results indicate that the nonadiabatic transition characteristics between ground and excited states are accurately described by the newly constructed diabatic PESs. To verify the validity and applicability of the diabatic PESs, as well as the nonadiabatic effects during the reaction process, the quantum dynamics studies of the Sr+(5s2S) + H2 reaction were performed based on both adiabatic and diabatic PESs. The dynamics results indicate that adiabatic dynamics results are dozens of times larger than those of nonadiabatic. This illustrates the significant effect of nonadiabaticity, indicating that adiabatic dynamics results often overestimate the actual values. The integral cross sections (ICSs) were calculated and compared with the experimental data. The diabatic ICSs are in good agreement with the experimental results. The reasonable dynamics results indicate that the newly constructed diabatic PESs are suitable for the relevant dynamics studies.

Case Report: Dislocation of lateral menisci secondary to congenital lateral tibiofemoral cartilage thickening in both knees.

A 24-year-old male patient complained of mild knee pain after jogging. The subsequent knee MRI demonstrated bilateral lateral thickened tibiofemoral cartilages, evidenced by deformities of the bilateral subchondral bone beneath the lateral femoral condyle cartilage. The corresponding dislocations of almost all the left lateral meniscus and part of the right lateral meniscus to the center of the joint were detected. After excluding diagnoses of congenital ring-shaped meniscus, bucket handle tear of the C-shaped lateral meniscus, and central tear of the discoid meniscus, the displacement of all or part of the lateral meniscus into the intercondylar notch was considered a consequence of congenital thickening of the lateral superior and inferior cartilage. This case may report a new variant of knee joint pathology.

Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial.

BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

[Progress in research and application of the biotin ligase BirA and its mutants in pathogen-host interaction].

Proteins serve as the primary executors of cellular activities in organisms, and thus investigating the subcellular localization and interactions of proteins is crucial for understanding protein functions and elucidating the molecular mechanisms in organisms. Proximity labeling is a recently developed effective method for detecting protein-protein interactions in live cells. Compared with the conventional methods for studying protein-protein interactions, proximity labeling demonstrates high sensitivity, strong specificity, and low background and is widely employed in the research of protein-protein interactions between pathogens and hosts. This article reviews the recent progress in the development and applications of the biotin ligase BirA and its mutants and elucidates the functioning principles of several classical biotin ligases. This review aims to clarify the role of proximity labeling based on BirA and its mutants in identifying protein-protein interactions between pathogens and hosts.

OIP5-AS1 enhances the malignant characteristics and resistance to chemotherapy of pancreatic cancer cells by targeting miR-30d-5p/MARCH8.

MARCH8, an E3 ubiquitin ligase, plays a crucial role in regulating various cellular processes such as protein degradation and signaling pathways and is implicated in the development and spread of pancreatic cancer. Analysis of pancreatic cancer tissues compared to adjacent normal tissues showed a decrease in miRNA-30d-5p levels and an increase in OIP5-AS1 and MARCH8 levels, as confirmed by qRT-PCR and Western blot analysis. The dual-luciferase reporter assay demonstrated a binding relationship between OIP5-AS1 and miRNA-30d-5p, as well as between miRNA-30d-5p and MARCH8 in PACN-1 cells, derived from a human pancreatic carcinoma specimen. Further investigations utilizing various assays revealed that OIP5-AS1 inhibited apoptosis and promoted cell proliferation, invasion, and migration in PACN-1 cells via the miRNA-30d-5p/MARCH8 axis in vitro. Tumor experiments in nude mice confirmed that OIP5-AS1 enhanced PACN-1 cell growth in vivo through the miRNA-30d-5p/MARCH8 axis. Additionally, OIP5-AS1 was found to activate downstream genes of the JAK-STAT pathway, namely IFNAR2, SOCS3, and JAK1, in PACN-1 cells. Furthermore, OIP5-AS1 increased the IC50 values for doxorubicin, gemcitabine, and cisplatin in PACN-1 cells, as determined by the Cell Counting Kit-8 assay. Overall, OIP5-AS1 was shown to promote aggressive traits and resistance to chemotherapy in PACN-1 cells through the miRNA-30d-5p/MARCH8 axis.

Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial.

BACKGROUND: Patients with Parkinson's disease (PD) undergoing long-term levodopa therapy are prone to develop levodopa-induced dyskinesia (LID). Amantadine is the main drug recommended for the treatment of LID by current guidelines, but it is far from meeting clinical needs. Tianqi Pingchan Granule (TPG), a compound Chinese herbal medicine, has been developed to relieve symptom of LID. OBJECTIVE: This randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a randomized double-blind placebo-controlled trial, conducted from January 2020 to August 2021 at 6 sites in Jiangsu, Zhejiang and Shanghai, China. One hundred PD patients with ≥ 0.5 h of LID were randomly assigned to either the TPG plus amantadine group (TPG group) or the placebo plus amantadine group (placebo group), and treated for a period of 12 weeks. To ensure unbiased results, all study participants, investigators and sponsors were unaware of group allocations. Additionally, the data analysts remained blinded until the analysis was finalized. MAIN OUTCOME MEASURES: The primary outcome was assessed using the Unified Dyskinesia Rating Scale (UDysRS) (Range 0-104). The key secondary end point was improvement of motor and non-motor symptoms. Safety analyses included all enrolled patients. RESULTS: One hundred patients were enrolled and randomized into the two treatment groups. The changes in UDysRS at week 12 were -11.02 for the TPG group and -4.19 for the placebo group (treatment difference -6.83 [-10.53 to -3.12]; P = 0.0004). Adverse events were reported for 2 of 50 patients (4.0%) in each of the groups. CONCLUSION: This study indicated that a 12-week treatment of amantadine plus TPG effectively reduced UDysRS scores and was well tolerated, demonstrating the efficacy and safety of TPG for the treatment of LID in PD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04173832. PLEASE CITE THIS ARTICLE AS: Zhang Y, Zhu XB, Zhao Y, Cui GY, Li WT, Yuan CX, Huang JP, Wan Y, Wu N, Song L, Zhao JH, Liang Y, Xu CY, Liu MJ, Gao C, Chen XX, Liu ZG. Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial. J Integr Med. 2024; Epub ahead of print.

FNIP1: A key regulator of mitochondrial function.

Folliculin interacting protein 1 (FNIP1), a novel folliculin interacting protein 1, is a key regulatory factor for mitochondrial function. FNIP1 mainly responds to energy signal transduction through physical interactions with 5'-AMP activated protein kinase (AMPK). Simultaneously, it affects the transcription of mitochondria-associated genes by regulating the lysosomal localization of mechanistic target of rapamycin kinase (mTORC1). This article takes FNIP1 as the core and first introduces its involvement in the development of B cells and invariant natural killer T (iNKT) cells, muscle fiber type conversion, and the thermogenic remodeling of adipocytes by regulating mitochondrial function. In addition we discuss the detailed impact of upstream regulatory factors of FNIP1 on its function. Finally, the impact of FNIP1 on the prognosis and treatment of clinically related metabolic diseases is summarized, aiming to provide a new theoretical basis and treatment plans for the diagnosis and treatment of such diseases.

FedGMMAT: Federated generalized linear mixed model association tests.

Increasing genetic and phenotypic data size is critical for understanding the genetic determinants of diseases. Evidently, establishing practical means for collaboration and data sharing among institutions is a fundamental methodological barrier for performing high-powered studies. As the sample sizes become more heterogeneous, complex statistical approaches, such as generalized linear mixed effects models, must be used to correct for the confounders that may bias results. On another front, due to the privacy concerns around Protected Health Information (PHI), genetic information is restrictively protected by sharing according to regulations such as Health Insurance Portability and Accountability Act (HIPAA). This limits data sharing among institutions and hampers efforts around executing high-powered collaborative studies. Federated approaches are promising to alleviate the issues around privacy and performance, since sensitive data never leaves the local sites. Motivated by these, we developed FedGMMAT, a federated genetic association testing tool that utilizes a federated statistical testing approach for efficient association tests that can correct for confounding fixed and additive polygenic random effects among different collaborating sites. Genetic data is never shared among collaborating sites, and the intermediate statistics are protected by encryption. Using simulated and real datasets, we demonstrate FedGMMAT can achieve the virtually same results as pooled analysis under a privacy-preserving framework with practical resource requirements.

Body composition characteristics and influencing factors of different parts of sarcopenia in elderly people: A community-based cross-sectional survey.

Objectives: This study aims to describe the differences in body composition among different body parts of the elderly in the community and its relationship with sarcopenia. Methods: Elderly people aged ≥65 underwent bioelectric impedance analysis testing and were categorized into a sarcopenia group, possible sarcopenia group, and control group. The characteristics of body composition indicators in different parts and their relationship with different stages of sarcopenia were analyzed. Results: The sarcopenia group illustrated the lowest values of FFM, FFM%, BFM, BFM%, ICW, and limb PhA, along with higher ECW/TBW in the trunk and left leg compared to the control group. The possible sarcopenia group showed lower FFM% in limbs and trunk, and higher BFM% compared to the control group. Gender differences in elderly body composition were observed, with an increase in BFM% in various body parts posing a risk factor for possible sarcopenia in elderly males, whereas an increase in BFM% except in the left arm was a protective factor for sarcopenia in elderly females. Conclusion: The body composition of the elderly in the community varied significantly in different stages of sarcopenia and genders, which correlated with sarcopenia.

Multi-Omics Analysis by Machine Learning Identified Lysophosphatidic Acid as a Biomarker and Therapeutic Target for Porcine Reproductive and Respiratory Syndrome.

As a significant infectious disease in livestock, porcine reproductive and respiratory syndrome (PRRS) imposes substantial economic losses on the swine industry. Identification of diagnostic markers and therapeutic targets has been a focal challenge in PPRS prevention and control. By integrating metabolomic and lipidomic serum analyses of clinical pig cohorts through a machine learning approach with in vivo and in vitro infection models, lysophosphatidic acid (LPA) is discovered as a serum metabolic biomarker for PRRS virus (PRRSV) clinical diagnosis. PRRSV promoted LPA synthesis by upregulating the autotaxin expression, which causes innate immunosuppression by dampening the retinoic acid-inducible gene I (RIG-I) and type I interferon responses, leading to enhanced virus replication. Targeting LPA demonstrated protection against virus infection and associated disease outcomes in infected pigs, indicating that LPA is a novel antiviral target against PRRSV. This study lays a foundation for clinical prevention and control of PRRSV infections.

Construction of diabatic potential energy surfaces for the SiH2+ system and dynamics studies of the Si+(2P1/2, 3/2) + H2 reaction.

The construction of diabatic potential energy surfaces (PESs) for the SiH2+ system, related to the ground (12A') and excited states (22A'), has been successfully achieved. This was accomplished by utilizing high-level ab initio energy points, employing a neural network fitting method in conjunction with a specifically designed function. The newly constructed diabatic PESs are carefully examined for dynamics calculations of the Si+(2P1/2, 3/2) + H2 reaction. Through time-dependent quantum wave packet calculations, the reaction probabilities, integral cross sections (ICSs), and differential cross sections (DCSs) of the Si+(2P1/2, 3/2) + H2 reaction were reported. The dynamics results indicate that the total ICS is in excellent agreement with experimental data within the collision energy range studied. The results also indicate that the SiH+ ion is hardly formed via the Si+(2P3/2) + H2 reaction. The results from the DCSs suggest that the "complex-forming" reaction mechanism predominates in the low collision energy region. Conversely, the forward abstraction reaction mechanism is dominant in the high collision energy region.

Rescue of expression and function of long QT syndrome-causing mutant hERG channels by enhancing channel stability in the plasma membrane.

The human ether-a-go-go-related gene (hERG) encodes the Kv11.1 (or hERG) channel that conducts the rapidly activating delayed rectifier potassium current (IKr). Naturally occurring mutations in hERG impair the channel function and cause long QT syndrome type 2. Many missense hERG mutations lead to a lack of channel expression on the cell surface, representing a major mechanism for the loss-of-function of mutant channels. While it is generally thought that a trafficking defect underlies the lack of channel expression on the cell surface, in the present study, we demonstrate that the trafficking defective mutant hERG G601S can reach the plasma membrane but is unstable and quickly degrades, which is akin to WT hERG channels under low K+ conditions. We previously showed that serine (S) residue at 624 in the innermost position of the selectivity filter of hERG is involved in hERG membrane stability such that substitution of serine 624 with threonine (S624T) enhances hERG stability and renders hERG insensitive to low K+ culture. Here, we report that the intragenic addition of S624T substitution to trafficking defective hERG mutants G601S, N470D, and P596R led to a complete rescue of the function of these otherwise loss-of-function mutant channels to a level similar to the WT channel, representing the most effective rescue means for the function of mutant hERG channels. These findings not only provide novel insights into hERG mutation-mediated channel dysfunction but also point to the critical role of S624 in hERG stability on the plasma membrane.

SPMLD: A skin pathological image dataset for non-melanoma with detailed lesion area annotation.

Skin tumors are the most common tumors in humans and the clinical characteristics of three common non-melanoma tumors (IDN, SK, BCC) are similar, resulting in a high misdiagnosis rate. The accurate differential diagnosis of these tumors needs to be judged based on pathological images. However, a shortage of experienced dermatological pathologists leads to bias in the diagnostic accuracy of these skin tumors in China. In this paper, we establish a skin pathological image dataset, SPMLD, for three non-melanoma to achieve automatic and accurate intelligent identification for them. Meanwhile, we propose a lesion-area-based enhanced classification network with the KLS module and an attention module. Specifically, we first collect thousands of H&E-stained tissue sections from patients with clinically and pathologically confirmed IDN, SK, and BCC from a single-center hospital. Then, we scan them to construct a pathological image dataset of these three skin tumors. Furthermore, we mark the complete lesion area of the entire pathology image to better learn the pathologist's diagnosis process. In addition, we applied the proposed network for lesion classification prediction on the SPMLD dataset. Finally, we conduct a series of experiments to demonstrate that this annotation and our network can effectively improve the classification results of various networks. The source dataset and code are available at https://github.com/efss24/SPMLD.git.