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The De Ritis ratio mediates the association between creatinine-to-body weight ratio and normoglycemic conversion in Chinese health examinees
Reply to Chen et al.: Coarse simulations overestimate the distance to recover NO–NO <sub>2</sub> –O <sub>3</sub> photochemical steady state in fresh NO <sub>x</sub> plumes
Genes of the Fatty Acid Oxidation Pathway are Upregulated in Female as Compared to Male Cardiomyocytes
Characteristics and distribution of tectonic fracture networks in low permeability conglomerate reservoirs
Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy
BACKGROUND: Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias. METHODS: A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes ( TTN and LMNA ), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios. RESULTS: A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28–0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26–0.36]; M:F 2.22:1; P =0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24–0.37]; M:F 2.29:1; P =0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for TTN (0.28 [95% CI, 0.22–0.36]; M:F 2.51:1; P =0.82) or LMNA (0.35 [95% CI, 0.27–0.44]; M:F 1.84:1; P =0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28–0.40]; M:F 1.98:1; P =0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively. CONCLUSIONS: This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance. REGISTRATION: URL: https://www.crd.york.ac.uk/prospero ; Unique identifier: CRD42023451944.
Discovery of rhynchophylline and mitraphylline in two Thai Mitragyna species and the investigation of their biological activity via opioid gene expression analysis
Abstract Mitragyna speciosa (Ms), M. diversifolia (Md), M. hirsuta (Mh) and M. rotundifolia (Mr) were investigated for phytochemicals by GC-MS and GC-FID, cytotoxicity and genotoxicity testing by MTT and comet assay, and biological activity examination through gene expression of human µ, δ, κ, and nociceptin opioid receptors by qRT-PCR. The opioid substances mitragynine, 7-hydroxymitragynine, and mitraphylline were found in all studied species, and, for first time, rhynchophylline was found in Mr, and mitraphylline in Md, Mh and Mr. The MTT and comet assays of the ethanol and hexane leaf extracts on PBMCs revealed no cytotoxicity and no significant genotoxicity compared to the negative control, except for the hexane leaf extract of Mh, which caused significant DNA damage. The biological activity of the ethanolic extract of the four species showed a binding affinity to the µ (MOR) receptor revealing a relative gene expression of 89.54 and 50.41 by Ms and Md at 1.92 and 1.133 mg/ml, 32.42 and 19.97 mg/ml by Md and Ms at 3.77 and 1.76 mg/ml. Mr contained the three opioids mentioned plus rhynchophylline and showed low relative µ (MOR) gene expression of 16.89 at 0.189 mg/ml, while as an additional species, Ipomoea aquatica (Ia) showed higher relative µ (MOR) gene expression of 37.75 and 59.76 at 2.878, and 5.813 mg/ml. A combination of Mr and Ia at 1.227, 2.907 and 0.0123, 0.0291 mg/ml extract showed high relative µ (MOR) gene expression at 71.01 and 21.71. These Mitragyna species and the combination (formula details are patent registered), substances and their biological activities can be used for the innovative production of new medicines and further clinical investigation.
Reenacting a mouse genetic evolutionary arms race in yeast reveals that SLXL1/SLX compete with SLY1/2 for binding to Spindlins
The house mouse X and Y chromosomes have recently acquired multicopy, rapidly evolving gene families representing an evolutionary arms race. This arms race between proteins encoded by X-linked Slxl1 / Slx and Y-linked Sly gene families can distort offspring sex ratio, but how these proteins compete remains unknown. Here, we report how Slxl1 / Slx and Sly encoded proteins compete in a protein family–specific and dose-dependent manner using yeast. Specifically, SLXL1 competes with SLY1 and SLY2 for binding to the Spindlin SPIN1. Similarly, SLX competes with SLY2 for binding the Spindlin SSTY2. These competitions are driven by the N termini of SLXL1, SLX, SLY1, and SLY2 binding to the third Tudor domains of SPIN1 and SSTY2. SLY1 and SLY2 form homo- and heterodimers, suggesting that the competition is between complex multimers. Residues under positive selection mapping to the interaction domains and rapid exon gain/loss are consistent with competition between the X- and Y-linked gene families. Our findings support a model in which dose-dependent competition of these X- and Y-linked encoded proteins to bind Spindlins occurs in haploid X- and Y-spermatids to influence X- versus Y-sperm fitness and thus sex ratio.
Missing (Black) Women
Assessment of potato varieties of Lithuanian breeding resistance potato wart causative agents and late blight
Inhibition of GABARAP or GABARAPL1 prevents aminoglycoside- induced hearing loss
Aminoglycosides (AGs) are highly potent, broad-spectrum antibiotics frequently used as first-line treatments for multiple life-threatening infections. Despite their severe ototoxicity, causing irreversible hearing loss in millions of people annually, no preventive therapy has been approved. We previously reported that GABARAP and several other central autophagy proteins are essential for AG-induced hearing loss. This finding opens avenues for the rational design and development of inhibitors that selectively target proteins in this pathway, thereby mitigating AG ototoxicity. In this study, we generated a mouse model with a targeted deletion of GABARAPL1, a homolog of GABARAP, and another model deficient in both GABARAP and GABARAPL1. We found that normal hearing is unaffected by the depletion of these proteins. Remarkably, both proteins are essential for AG-induced hearing loss, with GABARAP playing a more significant role. To further explore the therapeutic potential, we designed and validated short hairpin RNAs targeting the mouse and human GABARAP gene. By inhibiting GABARAP expression in inner ear hair cells using adeno-associated virus-mediated RNA interference, we successfully prevented AG-induced hair cell death and subsequent hearing loss. Our findings underscore the critical role of GABARAP in AG ototoxicity and highlight its potential as a therapeutic target for preventing AG-induced hearing loss.
Framework for Cultivating Leadership and Driving Growth
Phase-free traffic signal control for balanced flow in sensor-limited environments
Giant RNA genomes: Roles of host, translation elongation, genome architecture, and proteome in nidoviruses
Positive-strand RNA viruses of the order Nidovirales have the largest known RNA genomes of vertebrate and invertebrate viruses with 36.7 and 41.1 kb, respectively. The acquisition of a proofreading exoribonuclease (ExoN) by an ancestral nidovirus enabled crossing of the 20 kb barrier. Other factors constraining genome size variations in nidoviruses remain poorly defined. We assemble 76 genome sequences of invertebrate nidoviruses from >500.000 published transcriptome experiments and triple the number of known nidoviruses with >36 kb genomes, including a 64 kb RNA genome. Many of the identified viral lineages acquired putative enzymatic and other protein domains linked to genome size, host phyla, or virus families. The inserted domains may regulate viral replication and virion formation, or modulate infection otherwise. We classify ExoN-encoding nidoviruses into seven groups and four subgroups, according to canonical and noncanonical modes of viral replicase expression by ribosomes and genomic organization (reModes). The most-represented group employing the canonical reMode comprises invertebrate and vertebrate nidoviruses, including coronaviruses. Six groups with noncanonical reModes include invertebrate nidoviruses with 31-to-64 kb genomes. Among them are viruses with segmented genomes and viruses utilizing dual ribosomal frameshifting that we validate experimentally. Moreover, largest polyprotein length and genome size in nidoviruses show reMode- and host phylum-dependent relationships. We hypothesize that the polyprotein length increase in nidoviruses may be limited by the host-inherent translation fidelity, ultimately setting a nidovirus genome size limit. Thus, expansion of ExoN-encoding RNA virus genomes, the vertebrate/invertebrate host division, the control of viral replicase expression, and translation fidelity are interconnected.
Risk of Incident Atrial Fibrillation in Women With a History of Hypertensive Disorders of Pregnancy: A Population-Based Retrospective Cohort Study
BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity and mortality and are associated with acute cardiac events in the peripartum period, as well as cardiovascular disease later in life. Despite the robust association between hypertension and atrial fibrillation (AFib), comparatively little is known about HDP and its subtypes as sex-specific risk factors for AFib. METHODS: A population-based retrospective cohort study was conducted, including 771 521 nulliparous women discharged for obstetrical delivery of their first live or stillborn singleton infant between 2002 and 2017 in Ontario, Canada. Data were obtained from record-level, coded, and linked population-based administrative databases housed at ICES. Using competing risks Cox proportional hazards regression, we estimated crude and multivariable-adjusted cause-specific hazard ratios and 95% CIs for associations between history of any HDP (and its 6 subtypes), and AFib before death, as well as all-cause mortality without a previous AFib diagnosis. RESULTS: Approximately 8% of women were diagnosed with HDP during the 16-year exposure accrual period. The total person-time of follow-up was 7 380 304 person-years, during which there were 2483 (0.3%) incident AFib diagnoses and 2951 (0.4%) deaths. History of any HDP was associated with an increased cause-specific hazard ratios of incident AFib and death without a previous AFib diagnosis (adjusted cause-specific hazard ratios, 1.45 [95% CI, 1.28–1.64] and 1.31 [95% CI, 1.16–1.47], respectively). These associations were observed in relatively young women (median time to event, 7 years postpartum). Associations suggestive of a dose-response relationship were observed, with more severe HDP subtypes and prepregnancy chronic hypertension associated with a 1.5 to 2.2 times higher cause-specific rate of AFib, and a 1.4 to 2.1 times higher cause-specific rate of death compared with no hypertension in pregnancy. CONCLUSIONS: Women exposed to HDP in their first delivery have a significantly increased cause-specific hazard ratios of incident AFib compared to their unexposed counterparts, with higher rates observed in subjects exposed to more severe de novo HDP diagnoses as well as chronic hypertension in pregnancy. These findings underscore the need to consider HDP history in risk calculation/stratification for arrhythmic and nonarrhythmic cardiovascular diseases, improve surveillance of traditional and female-specific cardiovascular disease risk factors, and develop targeted prevention strategies to reduce the occurrence and burden of HDP.
Substance use during pregnancy and childhood dental caries: a Brazilian cohort study
Double assurance in the induction of axial development by egg dorsal determinants in <i>Xenopus</i> embryos
We recently reported that microinjection of Xenopus nodal-related ( xnr ) mRNAs into β-catenin-depleted Xenopus embryos rescued a complete dorsal axis. Xnrs mediate the signal of the Nieuwkoop center that induces the Spemann–Mangold organizer in the overlying mesoderm, a process inhibited by the Nodal antagonist Cerberus-short (CerS). However, β-catenin also induces a second signaling center in the dorsal prospective ectoderm, designated the Blastula Chordin and Noggin Expression (BCNE) center, in which the homeobox gene siamois ( sia ) plays a major role. In this study, we asked whether the Xnrs and Sia depend on each other or function on parallel pathways. Expression of both genes induced β-catenin-depleted embryos to form complete axes with heads and eyes via the activation of similar sets of downstream organizer-specific genes. Xnrs did not activate siamois , and, conversely, Sia did not activate xnrs , although both were induced by β-catenin stabilization. Depletion with morpholinos revealed a robust role for the downstream target Chordin. Remarkably, Chordin depletion prevented all ectopic effects resulting from microinjection of the mRNA encoding the maternal cytoplasmic determinant Huluwa , including the radial expansion of brain tissue and the ectopic expression of the ventral gene sizzled . The main conclusion was that the BCNE and Nieuwkoop centers provide a double assurance mechanism for axial formation by independently activating similar downstream transcriptional target gene repertoires. We suggest that Siamois likely evolved from an ancestral Mix-type homeodomain protein called Sebox as a Xenopus -specific adaptation for the rapid differentiation of the anterior neural plate in the ectoderm.
Population-Level Screening for Diabetes and Dyslipidemia After Pregnancies Complicated by Hypertension or Diabetes
HDL-ACO hybrid deep learning and ant colony optimization for ocular optical coherence tomography image classification
Abstract Optical Coherence Tomography (OCT) plays a crucial role in diagnosing ocular diseases, yet conventional CNN-based models face limitations such as high computational overhead, noise sensitivity, and data imbalance. This paper introduces HDL-ACO, a novel Hybrid Deep Learning (HDL) framework that integrates Convolutional Neural Networks with Ant Colony Optimization (ACO) to enhance classification accuracy and computational efficiency. The proposed methodology involves pre-processing the OCT dataset using discrete wavelet transform and ACO-optimized augmentation, followed by multiscale patch embedding to generate image patches of varying sizes. The hybrid deep learning model leverages ACO-based hyperparameter optimization to enhance feature selection and training efficiency. Furthermore, a Transformer-based feature extraction module integrates content-aware embeddings, multi-head self-attention, and feedforward neural networks to improve classification performance. Experimental results demonstrate that HDL-ACO outperforms state-of-the-art models, including ResNet-50, VGG-16, and XGBoost, achieving 95% training accuracy and 93% validation accuracy. The proposed framework offers a scalable, resource-efficient solution for real-time clinical OCT image classification.