The Clinical Genome Resource (ClinGen) Von Hippel-Lindau (VHL) Variant Curation Expert Panel (VCEP) has created variant classification specifications tailored to the VHL gene, including phenotype-driven and evidence-based criteria, utilizing somatic and germline mutational hotspots, along with functional and in-silico data. Using the American College of Medical Genetics and Genomics (ACMG) guidance and the ClinGen Sequence Variant Interpretation (SVI) recommendations, the VCEP made substantial modifications to 8 evidence codes (PVS1, PS3, PS4, PM1, BS2, BS3, BS4, BP5), while 14 had minor changes, and 6 were not used (PM3, PP2, BP1, PP4, PP5/BP6). The VHL VCEP applied two literature sets of over >428 papers in Clinical Interpretations of Variants in Cancer (CIViC) and >8700 structured annotations using Hypothesis. From 31 pilot variants, 15 remained pathogenic/likely pathogenic, 9 resolved to benign through the stand-alone benign evidence code while 7 variants with initial uncertain classifications lacking additional evidence, remained uncertain. The versioned VHL VCEP specifications are publicly available in the ClinGen Criteria Specifications Registry and will enhance the transparency and consistency of variant classifications for this highly sequenced hereditary cancer gene.
How host organisms adapt their defense systems to newly invading transposable elements remains poorly understood. Here, we show how Drosophila melanogaster acquired PIWI-interacting RNA (piRNA)-mediated immunity against the endogenous retrovirus Tirant. We uncover two distinct modes of de novo piRNA biogenesis by combining genetics, small RNA profiling, and population genomics. The primary route involves antisense insertions into the flamenco cluster, a master locus for transposon control. Unexpectedly, a second, equally potent mechanism arises from antisense Tirant insertions within host gene 3' UTRs. This process requires host gene transcription but is independent of host gene identity. Our findings challenge prevailing models that tie piRNA precursor specification to genomic origin or nuclear RNA processing context. Instead, they reveal a flexible mechanism that turns a critical vulnerability of transposons into an advantage for the host. When transposition occurs into host gene exons, chimeric antisense transcripts are exported to the cytoplasm, inadvertently initiating piRNA production and enabling rapid, adaptive genome defense against new invaders.
Avian leukosis virus subgroup J (ALV-J) remains a major threat to poultry health and production, particularly in indigenous chicken populations in China. In this study, a highly pathogenic ALV-J field strain, YN2021, was first isolated from indigenous black-bone chickens in Yunnan Province, China, and its biological characteristics and pathogenicity were systematically evaluated in specific-pathogen-free (SPF) chickens. Infected chickens exhibited significant growth retardation, delayed sexual maturation, and increased mortality, accompanied by pathological lesions consistent with ALV-J. To further assess reproductive performance, egg production and egg weight were recorded. YN2021-infected hens showed a reduction in total egg production (70 vs. 92 eggs; ~23.9% decrease) and a significantly lower mean egg weight (35.2 ± 0.2 g vs. 43.7 ± 0.3 g; P < 0.001) compared to controls. To facilitate mechanistic studies and future control strategies, a full-length infectious clone of YN2021 was constructed using a reverse genetics approach, and a synonymous molecular marker was introduced for viral identification. The rescued recombinant virus exhibited replication kinetics, p27 antigen expression, and biological characteristics in DF-1 cells comparable to those of the parental strain, and the molecular marker remained genetically stable during serial passages. Collectively, these results demonstrate that the ALV-J YN2021 strain exhibits high pathogenicity and negatively affects growth and reproductive performance in chickens. The infectious clone established in this study provides a reliable experimental platform for investigating ALV-J pathogenesis and supports the development of effective control strategies to mitigate production losses in poultry.
The Clinical Genome Resource (ClinGen) is creating a central resource of clinically relevant genetic knowledge to improve genomic medicine. Dissemination and use of the ClinGen Resource is essential to ensure broad community uptake. We report on experiences and sustained use of ClinGen tools through engaging international genetics groups based in India, Africa and Singapore in variant classification training workshops using the ClinGen Variant Curation Interface (VCI). We developed pre and post workshop questionnaires and analyzed ClinGen tool use following the workshops. We evaluated organizational aspects and costs of creating a dedicated ClinGen VCI instance for each workshop. The workshops yielded >200 participants, with local scientists as essential participants. While ∼55% of participants were unfamiliar with variant classification, we found ∼79% were likely to use the VCI after the workshop. Further, we identified about ∼10% of workshop participants created permanent accounts. We estimate costs at ∼$3 per VCI instance. Our efforts highlight the yield of international workshops to sustained use of ClinGen's curation tools and identify areas for future consideration such as creating user-groups by experience level, and the importance of local scientist engagement in workshop deployment and organizational aspects.
In this review we comprehensively discuss organic cation transporter novel 1 (OCTN1), encoded by the SLC22A4 gene as a member in the solute carrier 22 (SLC22) family, which facilitates the cellular transport of diverse cationic and zwitterionic substrates. OCTN1 is highly expressed in many vital organs in humans, where it facilitates absorption and distribution of both endogenous compounds and therapeutic drugs. Among its substrates, ergothioneine (EGT) serves as the primary antioxidant and anti-inflammatory molecule, underscoring the essential role of OCTN1 in cellular defense and inflammation control. Genetic polymorphisms in SLC22A4 significantly alter OCTN1 expression, substrate affinity, and drug pharmacokinetics, with strong associations to susceptibility and treatment outcomes in human diseases. Insights from knockout models revealed that OCTN1 deficiency leads to reduced EGT availability, heightened oxidative stress, and aggravated inflammation, particularly in the tissues such as intestine, liver and lung. Moreover, OCTN1 activity is dynamically regulated by epigenetic modifications, cytokines, and hormones, linking it to immune modulation and disease progression. Put together, OCTN1 plays a defined role via high-affinity EGT transport, while its broader transport capacity and pharmacological relevance remain under investigation, with possible - though not yet established - implications for inflammation-associated biomarker development.
Functional validation of candidate genes in congenital anomalies of the kidneys and urinary tract (CAKUT) and other disorders is essential for translating genetic discoveries into clinical applications. Conditional knockout mouse models are indispensable for studying gene function in complex organ systems. The Short Conditional intrON (SCON) system accelerates the generation of such models by inserting the artificial SCON into a coding exon. SCON is designed to be spliced out after transcription, without affecting gene expression. Upon Cre activity, SCON is converted into the ΔSCON allele which cannot be spliced out, introducing premature termination codons (PTCs) to inactivate the gene. Previous validation of the SCON system in mice has focused primarily on phenotypic outcomes. Here, we provide a molecular characterization of the SCON system in Cdh12-a candidate gene implicated in kidney damage in CAKUT. We found that both Cdh12SCON and Cdh12ΔSCON alleles caused unintended skipping of the exon downstream of the insertion site, culminating in a frameshift and PTC. Consequently, the Cdh12SCON allele led to a ~ 25% reduction in mRNA expression, indicating that it was not transcriptionally inert as designed. Despite unintended exon skipping, the Cdh12ΔSCON allele still effectively suppressed mRNA expression. These findings highlight the importance of transcript-level characterization of engineered alleles prior to functional studies, as artefactual splicing events may occur across multiple gene-targeting strategies, including artificial intron-based conditional alleles as shown here.
Neurofibrillary tangles in Alzheimer's disease (AD) stereotypically spread from the medial temporal lobe to association areas and then to idiotypic areas (i.e., primary motor, somatosensory, auditory, and visual). Previous studies have reported variable and clinically relevant tangle densities across the hippocampus and association cortices, but the idiotypic tangle burden is understudied. In this study, we measured tangle density using immunohistochemistry in three idiotypic cortices (primary motor, somatosensory, and visual), three association cortices (middle frontal, superior temporal, and inferior parietal), and two hippocampal sectors (CA1 and subiculum) in 144 cases with a high level of AD neuropathologic change. Clinical diagnoses included late-onset AD (LOAD, n = 50), early-onset AD (EOAD, n = 21), behavioral variant frontotemporal dementia (bvFTD, n = 19), corticobasal syndrome (CBS, n = 18), logopenic primary progressive aphasia (lvPPA, n = 21), and posterior cortical atrophy (PCA, n = 15). We algorithmically assigned cases outside the interquartile ranges of mean tangle ratios of association:hippocampal, idiotypic:association, and idiotypic:hippocampal to mutually exclusive subtypes: idiotypic-susceptible, associative-predominant, limbic-predominant, or typical Braak (for all remaining cases). Regional tangle burdens differentiated subtypes, while female sex, younger ages, and longer disease durations also influenced tangle severity. Compared to typical Braak cases, idiotypic-susceptible and associative-predominant cases exhibited shorter disease duration and younger age at death while limbic-predominant cases were older. The MAPT H1H1 haplotype also differed by subtype, being most prevalent in limbic-predominant and least common in idiotypic-susceptible and associative-predominant subtypes. Clinically, the idiotypic-susceptible subtype associated with CBS (56%), the associative-predominant subtype with bvFTD (53%), and the limbic-predominant subtype with LOAD (14%). The typical Braak subtype characterized 74-76% of amnestic AD cases and 32-53% of non-amnestic AD cases. Moreover, k-means clustering corroborated four clusters including the idiotypic-susceptible and associative-predominant patterns. Our results confirm previously described tau subtypes and describe an idiotypic-predominant subtype with clinical relevance and distinct demographic and genetic characteristics in AD.
Urological cancers exhibit significant sex differences in incidence, treatment response, and prognosis, with males generally showing higher morbidity and mortality. This review systematically summarizes the underlying molecular and clinical mechanisms of these disparities, focusing on sex hormones, chromosome biology, tumor immune microenvironment, and microbiota. Sex hormones modulate key tumor processes including proliferation, apoptosis, non-apoptotic cell death, and DNA repair. Genetic factors such as X chromosome inactivation escape genes and Y chromosome loss also contribute to sex-biased cancer susceptibility. Furthermore, sex-specific differences in the urinary system and gut microbiota influence local immunity and inflammation, thereby affecting tumor progression and therapeutic response. Lifestyle and environmental factors, including smoking, alcohol consumption, and occupational exposures, further exacerbate these disparities. Clinically, sex differences impact the efficacy of immunotherapy and targeted therapies, underscoring the need for sex-informed treatment strategies. Integrating sex as a biological variable in research, clinical practice, and public health policies is essential for advancing precision oncology in urologic cancers.
With coral reefs increasingly threatened by rapid environmental changes, understanding genetic diversity at microgeographic scale is critical for assessing their capacity to respond to local stress regimes. Theory for continuous populations predicts that brooding corals with restricted dispersal should exhibit fine-scale genetic structure and isolation-by-distance, yet such patterns remain poorly resolved in marginal and environmentally extreme reef ecosystems. Here, we investigated the genetic structure of the catch bowl coral, Isopora cf. palifera, across 11 sites within ~ 14 km in Kenting National Park (KNP), southern Taiwan, a reefscape characterized by strong small-scale environmental heterogeneity, including chronic thermal influence from a nuclear power plant and tidally driven upwelling. We genotyped 466 colonies (six microsatellite loci yielding 302 unique multilocus genotypes) and sequenced nuclear PaxC 46/47-intron from 322 colonies of I. cf. palifera. Microsatellite data revealed strong genetic structure (K = 2, K = 5): principal coordinate analyses identified four geographic groupings, and Bayesian clustering (STRUCTURE) supported two major clusters separating Nanwan (plus Tantzei Bay) from the remaining coastal sites, with one site (Shiaowan) showing admixture. The PaxC marker resolved ten haplotypes, with H1 widespread, H2 concentrated along Nanwan, and H3 dominant at thermally influenced sites near the nuclear power plant outfall. Overall, populations showed high site differentiation, significant isolation-by-distance, and high self-recruitment (68-92%), indicating limited effective dispersal. A temporal comparison (2000-2015) at Tantzei Bay indicated stable genetic structure through time despite repeated regional disturbances. Generalized estimating equation (GEE) models showed that site-level seawater temperature was positively associated with both host haplotype composition (GEE; coefficient = 0.0479, p < 0.001) and Symbiodiniaceae genera (GEE; coefficient = 0.0462, p < 0.001, symbiont data from a previous work in KNP), suggesting non-random host-symbiont-environment associations at microgeographic scale. Together, these results indicate that I. cf. palifera in KNP exhibits pronounced fine-scale genetic structure consistent with restricted dispersal and possible microgeographic adaptation of the holobiont to local thermal regimes. While such structuring may enhance local resilience by maintaining diverse, site-specific host-symbiont combinations, it also implies limited scope for rescue via gene flow if future warming pushes populations beyond their adapted tolerances. Our findings underscore the importance of accounting for microgeographic genetic structure and local adaptation when designing management and conservation strategies for reefscape such as those in KNP.
The study aims to explore the role of miR-371a-3p in cognitive dysfunction and its underlying mechanisms. This research comprised 143 elderly orthopedic patients undergoing anesthesia. They were further categorized into POCD and NPOCD groups based on postoperative MoCA scores. The relative expression and predictive value of miR-371a-3p in POCD were analyzed. The effects of miR-371a-3p on cognitive dysfunction in rats were assessed by the MWM test. The impact of miR-371a-3p overexpression on cell viability, apoptosis, apoptosis-related genes, inflammatory response, oxidative stress, and ferroptosis-related factors was examined in sev-induced HT22 cells. The target relationship between miR-371a-3p and FKBP5 was validated via database and dual luciferase assays. miR-371a-3p was markedly downregulated in POCD patients. miR-371a-3p demonstrated good predictive efficacy for POCD. Agomir-371a-3p effectively shortened the escape latency period, prolonged the dwell time in the target quadrant, and increased the platform crossing frequency in sev-induced rats. Concurrently, low miR-371a-3p expression was discovered in rat hippocampal tissue and HT22 cells exposed to sev. miR-371a-3p overexpression mitigates the decrease in cell vitality and increased apoptosis in sev-induced HT22 cells, and improves the inflammatory response, oxidative stress, and ferroptosis. Mechanistically, miR-371a-3p targets and regulates FKBP5. FKBP5 overexpression reverses the effects of miR-371a-3p on sev-induced neuronal cell damage. miR-371a-3p is a promising predictive biomarker for POCD. Agomir-371a-3p ameliorates sev-induced cognitive dysfunction in rats. Overexpression of miR-371a-3p alleviates sev-induced cognitive dysfunction by targeting FKBP5, offering a novel therapeutic approach for POCD.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
Methylene Blue (MB), a widely used cationic dye, is of particular concern due to its persistence and adverse effects on ecosystems and human health. This study used batch and fixed-bed column adsorption studies to evaluate dried water hyacinth roots as an environmentally benign, affordable, and sustainable adsorbent for MB removal. The effects of operating parameters on MB adsorption were systematically investigated in batch experiments. Under optimized conditions (pH 6, 0.2 g dose, 90 min contact time), a maximum extraction efficiency of 96.5% was achieved. The pseudo-second-order model best describes the adsorption process. At the same time, isotherm analysis confirmed multilayer adsorption with a maximum capacity of 154.54 mgg-1 as predicted by the Freundlich model. Column experiments were conducted to evaluate continuous adsorption performance. Kinetic models, including Thomas, Yoon-Nelson, and Bohart-Adams, were utilized, with the Thomas model (R2 = 0.96) showing the strongest agreement with experimental data. A Genetic Algorithm (GA) was employed to accurately predict adsorption performance. Phytotoxicity tests of the treated effluent confirmed reduced toxicity, underscoring the environmental safety of the process. Overall, the findings establish water hyacinth root as a promising green adsorbent for the remediation of industrial dyes, with clear potential for scale-up.
BACKGROUND Kennedy disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare and incurable X-linked neuromuscular disorder mainly affecting men aged 30 to 60 years. Polymyositis can present similarly, but can be excluded by measuring muscle enzymes, performing muscle imaging, and electromyography. This report describes the case of a 52-year-old man with a 10-year history of progressive limb weakness due to Kennedy disease, established by genetic testing. CASE REPORT A 52-year-old man presented with a 10-year history of gradually progressive proximal limb weakness and persistently elevated creatine kinase levels ranging from 808-2300 U/L (normal 39-308 U/L). One year prior to this admission, the limb weakness had worsened, but initial electromyography, neuroimaging, and muscle biopsy showed no specific abnormalities. Despite a trial of immunosuppressive therapy due to suspected polymyositis, there was no clinical improvement. Neurological examination later revealed gynecomastia, proximal muscle atrophy, and bilateral tongue atrophy with tremor. Electromyography showed chronic neurogenic changes and reduced sensory nerve action potentials. Repeat expansion analysis identified a hemizygous pathogenic CAG repeat expansion in exon 1 of the androgen receptor gene using a short-read next-generation sequencing-based repeat detection algorithm (ExpansionHunter), with an estimated repeat number of 51 (range 50-53). At 6-month follow-up, the patient demonstrated mild progression of motor symptoms but remained functionally stable. CONCLUSIONS This report presents a rare case of Kennedy disease, initially diagnosed as polymyositis, and highlights the importance of follow-up with genetic testing when neurological and electromyography investigations are not typical for polymyositis. Early identification of Kennedy disease helps avoid unnecessary immunosuppressive treatments.
Therapeutic resistance to chemotherapy or radiotherapy is a significant issue in several cancers, including head and neck squamous cell carcinoma (HNSCC). One pathway associated with therapeutic resistance is the NFκB pathway, which promotes survival in response to the cytokine TNFα, a key mediator of chemotherapy and radiotherapy-induced cytotoxicity. However, direct targeting of the NFκB pathway is associated with significant toxicity and thus targeting the regulation of this pathway is a promising therapeutic target. We recently demonstrated that the USP14/UCHL5 inhibitor b-AP15 inhibits NFκB activity, inhibiting proliferation and inducing apoptosis in HNSCC cells. Furthermore, b-AP15 treatment sensitised HNSCC cells to the cytotoxic effects of TNFα, as well as TNF-inducing radiation treatment. Here, we investigated if b-AP15 sensitised HNSCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cancer selective member of the TNF family. b-AP15 treatment sensitised HNSCC cells to TRAIL treatment. Mechanistically, we show that b-AP15 induced expression of the TRAIL receptor Death Receptor 5 (DR5)/TRAIL Receptor 2 (TRAILR2), which was required for b-AP15-mediated TRAIL sensitisation. b-AP15 induced reactive oxygen species (ROS) and activated the JNK signalling pathway and both ROS and JNK signalling were required for the induction of DR5 expression and TRAIL sensitisation. We further show that b-AP15-mediated reduction of the NFκB-dependent gene XIAP induced DR5 expression and TRAIL sensitisation and that combination between b-AP15 and IAP antagonists was synergistic in HNSCC cells in vitro. Our data further define the mechanism of b-AP15-mediated cytotoxicity and highlight potential combination treatments that warrant further exploration in pre-clinical studies in HNSCC.
Starch serves as a vital energy reserve in plants. During its biosynthesis, malto-oligosaccharides (MOS) are essential primers. One of the key pathways for MOS production involves plastidial α-glucan phosphorylase (PHS1/Pho1) and disproportionating enzyme (DPE1). However, the functional relationship between these enzymes is unclear. Here, we demonstrate that rice PHS1 and DPE1 assemble into a multimeric complex. Cryo-EM structures of the PHS1-DPE1 complex reveal an assembly mechanism and suggest a potential substrate tunnel. Biochemical assays show the complex dramatically enhances catalytic efficiency over individual enzymes. Single-molecule fluorescence resonance energy transfer (smFRET) visualizes conformational dynamics, enabling rapid substrate transfer between the enzymes. We further identify the unique L80 loop in PHS1 as a potential regulator. Its deletion reduces catalytic efficiency and prolongs conformational state lifetimes during substrate transfer, thereby reducing the production of longer MOSs. Our findings establish that the PHS1-DPE1 complex facilitates efficient MOS primer synthesis through efficient substrate transfer or diffusion between the two enzymes, providing mechanistic insight into a critical step of starch biosynthesis with agronomic implications.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by progressive motor neuron degeneration, with diverse clinical manifestations and complex genetic and environmental triggers. The variability in disease progression underscores the necessity for tailored diagnostic and therapeutic approaches. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising biomarkers and therapeutic targets in ALS. Dysregulation of specific miRNAs has been linked to mechanisms of ALS, including neuromuscular dysfunction, neuroinflammation, and neuronal survival/apoptosis. The potential of miRNA-based therapies, such as mimics and inhibitors, offers a more integrated approach by modulating entire disease networks, rather than targeting isolated pathways. However, challenges persist, particularly in delivering these therapies efficiently across the blood-brain barrier and minimizing off-target effects. Current delivery strategies involving nanoparticles, viral vectors, and exosome-based approaches require optimization for clinical use. This review synthesizes the latest research on miRNA-mediated mechanisms in ALS, evaluating their diagnostic, prognostic, and therapeutic potential, while highlighting the current limitations in clinical validation. It underscores the importance of standardized methodologies, multi-omics integration, and rigorous validation to facilitate the clinical translation of miRNA-based strategies. Standardized protocols and multicenter validation in large cohorts are essential to confirm the diagnostic accuracy of miRNAs, paving the way for their clinical application in ALS precision medicine.
Soybean stay-green associated virus (SoSGV) is an emerging begomovirus associated with severe disease in soybean crops in East Asia. This study investigated its evolutionary relationships, population structure, recombination history, adaptive signal, and candidate host-interaction features using integrated phylogenetic, population genetic, natural selection, and structural modeling analyses of 54 complete genome sequences. Maximum-likelihood and Bayesian phylogenetic analyses recovered SoSGV as a distinct monophyletic lineage, with strong support in the maximum-likelihood analysis (96% bootstrap support). Population genetic analysis revealed high haplotype diversity (Hd = 0.962), moderate nucleotide diversity (π = 0.022), and a negative Tajima's D value (D = - 1.49, p < 0.05), a pattern consistent with recent demographic expansion but not, by itself, proof of emergence timing. Recombination screening identified two robust coat protein-associated events (best p = 1.95 × 10⁻⁷ and 1.91 × 10⁻¹⁴), and sliding-window similarity analysis independently supported the resulting mosaic structure. Natural selection analyses detected adaptive signal in the V2 gene; MEME identified episodic selection at residues 35 and 36 (p < 0.1), while complementary methods supported additional method-dependent signals. ColabFold predicted a moderate-confidence V2 structure (mean pLDDT = 73.36). Protein docking identified a plausible V2-SKP1-related interface comprising 39 contacting residues, while a short 10 ns molecular dynamics simulation indicated preliminary structural compatibility rather than biological validation. These findings support the hypothesis that recombination contributed to SoSGV diversification and that V2 may interact with SKP1-related host proteins.
Propofol is a widely employed intravenous general anesthetic that can induce neurotoxic effects on neurons. Previous research has indicated dysregulation of miR-140-3p in the hippocampal tissues of propofol-treated mice. This research was designed to investigate the function and underlying mechanism of miR-140-3p in propofol-induced neurotoxicity. To simulate propofol-induced neurotoxicity, human SH-SY5Y cells and mice were treated with propofol. Commercial kits were used to measure LDH, MDA, SOD, GSH-Px, and BDNF levels. Cells were transfected with miR-140-3p mimics, inhibitor, or BACE1 overexpression plasmids. Gene expression was assessed by RT-qPCR, cell viability by CCK-8, and apoptosis by flow cytometry. Dual-luciferase and RIP assays confirmed that miR-140-3p targets BACE1. The results confirmed that as the concentration of propofol increased, miR-140-3p levels were progressively downregulated, while BACE1 was correspondingly upregulated. Upregulation of miR-140-3p rescued propofol-treated SH-SY5Y cells from cytotoxicity, as evidenced by enhanced viability, suppressed apoptosis, and ameliorated oxidative stress. Consistently, miR-140-3p overexpression also attenuated propofol-induced neurotoxicity in vivo. Furthermore, BACE1 was confirmed to be a direct target of miR-140-3p through experimental validation, and this post-transcriptional repression was shown to mediate the observed neuroprotection. miR-140-3p attenuates propofol-induced neurotoxicity via BACE1 in vitro and in vivo, providing new insights and a potential biomarker for managing propofol-associated neurotoxicity.
Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case, a 9 year-old female with severe mesomelic lower limb shortening and characteristic radiographic findings, highly resembling those identified in previous MDST patients. No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3. As hypothesized for deletions detected in this disorder we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression. Thus, this case broadens the genetic spectrum in MDST and provides further support to the role of ID4 dysregulation as the main underlying molecular mechanism of this ultra-rare skeletal disorder.
The genetic architecture of cardiovascular traits is poorly characterised in non-European populations, limiting our understanding of disease aetiology and contributing to health disparities. Here, we analyse the genetic architecture of four cardiovascular traits (systolic and diastolic blood pressure, pulse rate, and maximum heart rate) using multi-trait analysis of genome-wide association studies and local genetic correlation analysis in 459,327 European (EUR) and 6654 African (AFR) ancestry individuals from the UK Biobank. Our analysis identifies 957 and 45 novel variants in the EUR and AFR cohorts, respectively, but reveals a profound divergence in the pleiotropic architecture of blood pressure. We identify 181 genomic loci with significant local genetic correlation between systolic and diastolic blood pressure (SBP-DBP) in the European sample, whereas such signals are completely absent in the African ancestry cohort. This marked disparity in local genetic correlation structure highlights that pleiotropic mechanisms can be highly ancestry-specific, underscoring the limitations of transferring genetic risk models across populations and the critical need for inclusive genomic research.