Search Results (8,039)

N-glycosylation is a fundamental post-translational modification that contributes to protein folding, stability, and secretion in eukaryotes. The catalytic subunit STT3 of the oligosaccharyltransferase complex mediates the transfer of preassembled oligosaccharides to nascent polypeptides in the endoplasmic reticulum. Here, we identified and functionally characterized PsSTT3B, one of the STT3 paralogs in Phytophthora sojae (P. sojae). PsSTT3B plays an important role in the growth, development, and pathogenicity of P. sojae. CRISPR/Cas9-mediated deletion of PsSTT3B resulted in reduced vegetative growth, sporangia production, and zoospore production in P. sojae. PsSTT3B deletion mutants demonstrated significantly reduced virulence on soybean leaves and etiolated seedlings. Importantly, PsSTT3B deletion mutants also exhibited reduced zoospore germination and diminished chemotaxis toward soybean isoflavones. Moreover, deletion of PsSTT3B increased sensitivity to tunicamycin and dithiothreitol and influenced the ConA-binding glycoprotein profile. Our findings show that PsSTT3B is associated with asexual development, virulence, and sensitivity to ER stress-related conditions of P. sojae. Our study suggests that PsSTT3B represents a potential candidate gene for the prevention and control of P. sojae. Full article

Several southern Italian dialects show a systematic alternation in the forms of the third person object clitic between proclisis and enclisis; moreover, in proclisis, the object clitic and the definite article have different forms that alternate between prevocalic and preconsonantal contexts. On the whole, the distribution of forms constitutes a varied and complex picture, which has often been treated in terms of allomorphy. In particular, this article examines the arrangement of proclitic forms in the Neapolitan variety in which the forms are distributed according to three different patterns. The article explores the possibility of analysing the alternations in purely phonological terms, using the representational tools of “floating melody”, “stress space” and “virtual geminate”. The results obtained are encouraging: while some alternations have proven to be allomorphic in nature, a unified phonological explanation has been developed for challenging issues, including the so-called “l-deletion” and the corresponding vowel lengthening. Full article

Higher rates of food insecurity have been observed among Hispanic immigrants, yet these individuals have traditionally been excluded from food insecurity survey development. The most common Spanish translated food insecurity scale—the Spanish Translation of the U.S. Household Food Security Survey Module (S-FSSM)—may not be capturing how Spanish-speaking immigrant parents conceptualize food insecurity. The purpose of this study was to gain insight into how Spanish-speaking immigrant parents with low English literacy conceptualize household food insecurity within the 18-item S-FSSM and to use this information to revise the S-FSSM instrument. Researchers conducted two rounds of cognitive interviews with Spanish-speaking adults at a community center in Houston, TX, USA (N = 19; Round 1: n = 9, October 2023; Round 2: n = 10, July 2024). Researchers used participants’ feedback to refine the S-FSSM. All participants were female (Rounds 1 and 2 = 100%) and most born in Mexico (Round 1 = 66.7%; Round 2 = 50%). In Round 1, eight items were combined to enhance cultural relevance and to add definitions. Follow-up questions were added to improve clarity. Two items were revised for relevancy, two items had no change, six items were deleted. In Round 2, modifications to wording occurred and one item was added. The revised scale, named Food Access Measure for Immigrant Latinos In America (FAMILIA), resulted in 17 survey items. Study findings suggested that the S-FSSM needed refinement to enhance relevancy for Spanish-speaking immigrant parents with low English literacy. Full article

Regulated cardiomyocyte death is a central contributor to myocardial infarction (MI)-associated injury. Mixed lineage kinase domain-like protein (MLKL), a key effector of necroptosis, has been implicated in cardiovascular disease; however, its role in MI remains incompletely defined. MLKL expression was evaluated in hypoxia-treated cardiomyocytes, infarcted murine hearts, and human cardiac tissue. MLKL function was investigated using siRNA-mediated knockdown in neonatal mouse cardiomyocytes and genetic deletion in mice subjected to left anterior descending (LAD) coronary artery ligation. Apoptosis- and pyroptosis-related signaling were assessed by immunoblotting and immunostaining. RIP3 expression and regulation were examined at both protein and mRNA levels, and the RIP3 inhibitor GSK’872 was used to assess pathway dependence. MLKL expression was increased in hypoxic cardiomyocytes, infarcted mouse hearts, and human failing cardiac tissue. Unexpectedly, MLKL deficiency was associated with aggravated myocardial injury, impaired cardiac function, and increased fibrosis following MI. Mechanistically, MLKL deficiency was associated with increased RIP3 protein abundance without a corresponding increase in RIP3 mRNA, consistent with post-transcriptional regulation. Further analyses indicated that MLKL deficiency reduced RIP3 ubiquitination and impaired proteasome-mediated degradation, resulting in RIP3 stabilization. Elevated RIP3 levels were accompanied by increased expression of apoptosis- and pyroptosis-related proteins, particularly at early time points after MI. Pharmacological inhibition of RIP3 with GSK’872 was associated with reduced apoptosis- and pyroptosis-related signaling and improved cardiac function. MLKL deficiency is associated with stabilization of RIP3 and enhanced activation of apoptosis- and pyroptosis-related signaling following MI, contributing to aggravated myocardial injury. These findings support a regulatory role for the MLKL–RIP3 axis in cardiomyocyte death and suggest that targeting RIP3 may represent a potential therapeutic strategy in myocardial infarction. Full article

The anticancer ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole) ruthenate (III)—also known as KP1019—inhibits cancer cell proliferation in vitro, causes tumor regression in animal models, and showed no dose-limiting toxicity in a phase I clinical trial. Previous studies found that KP1019 damages DNA in both cancer cells and the budding yeast Saccharomyces cerevisiae. To identify other potential targets of KP1019 along with pathways that modulate the drug’s cellular effects, we screened the yeast gene deletion strain library by quantitative high-throughput cell array phenotyping (Q-HTCP). Fitness differences, as judged by growth curve analysis, identified genes for which loss of function (gene deletion) interacts with (enhances or suppresses) KP1019 effects. Drug-enhancing deletions were enriched for DNA repair functions, consistent with DNA damage being a primary target of KP1019 in yeast. pH homeostasis also modified the effects of KP1019. Drug-suppressing deletions prominently involved ribosomal proteins. A mechanistic link between ribosomal protein function and KP1019 toxicity was supported by dose-dependent accumulation of Rpl7a-GFP in the nucleolus, which is a hallmark of ribosomal biogenesis stress. Furthermore, KP1019 acted synergistically with the TOR pathway inhibitor everolimus to inhibit cell proliferation. The resulting model, wherein KP1019 perturbs ribosome assembly, can inform the design of future combination therapies. Full article

Background/Objectives: We aimed to report three novel MAGED2 variants associated with transient antenatal Bartter syndrome (TABS) and to summarize the prenatal and postnatal features of MAGED2-related TABS through case analysis and literature review. Methods: Three unrelated Chinese families with polyhydramnios-affected pregnancies underwent genetic testing. Clinical data, including prenatal imaging, delivery details, and postnatal outcomes were reviewed. A literature review of reported MAGED2 variants and associated phenotypes was conducted. Results: Three previously unreported MAGED2 variants were identified: two frameshift variants (c.1511del [p.Gly504Alafs*72] and c.338del [p.Pro113ArgfsTer4]) and one deletion (chrX:54,820,664–54,839,053 [GRCh37]). All fetuses presented with polyhydramnios; two were large for gestational age (LGA). Additional findings included ventriculomegaly and scrotal enlargement. Two male infants were delivered at 33 weeks following repeated amnioreduction, with transient postnatal electrolyte abnormalities and normal neurodevelopment at 3 and 4 years. One fetus with a frameshift variant died in utero at 26 + 1 weeks. A literature review of 53 cases revealed 38 distinct MAGED2 variants, predominantly null variants (65.8%). Polyhydramnios was the most consistent antenatal sign. No intellectual disability was reported in surviving individuals. Conclusions: These findings expand the MAGED2 mutational spectrum. Polyhydramnios and LGA represents the most frequent features in TABS. In fetuses presenting with early-onset severe polyhydramnios (around 19–20 weeks of gestation), particular attention should be paid to possible exon-level or partial deletions involving MAGED2 during genetic evaluation. Full article

Background: Comprehensive genomic profiling (CGP) is increasingly used in precision oncology to identify actionable genomic alterations and guide targeted therapies in solid tumors. However, the clinical implementation of CGP assays requires rigorous analytical validation to ensure accurate and reproducible detection of diverse genomic alterations across heterogeneous tumor samples. Despite rapid advancements in next-generation sequencing technologies, there remains a need for validated CGP platforms that demonstrate reliable performance and readiness for routine clinical use. Methods: This study evaluated the analytical and clinical performance of a CGP assay capable of detecting multiple genomic alteration types, including single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), gene fusions, and tumor mutational burden (TMB). Validation was conducted using patient-derived 117 FFPE tumor samples, external proficiency testing materials, and reference standards. Assay performance was assessed through comparison with orthogonal methods and through evaluation of reproducibility, limit of detection, and TMB concordance. Results: The assay demonstrated excellent analytical performance, achieving 100% sensitivity, specificity, and accuracy for variant detection across evaluated samples. Strong concordance was observed for TMB estimation (R² = 0.9925), with consistent classification of TMB-high cases. The assay showed robust inter- and intra-run reproducibility and reliable detection of low-frequency variants. Limit-of-detection (LOD) analysis confirmed accurate SNV detection at approximately 1% variant allele frequency and reliable RNA fusion detection at low input levels. Conclusions: The validated CGP assay provides accurate, reproducible, and comprehensive detection of clinically relevant genomic alterations in solid tumors. These results support its suitability for routine clinical deployment, enabling reliable genomic profiling to inform precision oncology treatment decisions. Full article

As a leading method for Novel View Synthesis (NVS), 3D Gaussian Splatting (3DGS) faces limitations. Fixed thresholds governing Gaussian scale and opacity lead to over-reconstruction or under-reconstruction, while the linear penalty used for handling outliers during optimization tends to introduce artifacts. Therefore, we propose Adaptive 3DGS featuring a dynamic deletion mechanism. Specifically, our method calculates coverage for each Gaussian based on its scale during removal. Gaussians with high coverage face stricter scale thresholds to reduce over-reconstruction, while those with lower coverage receive lenient thresholds to preserve details. Simultaneously, transparency-based contribution assessment is applied. Gaussians with low contribution meet stricter transparency thresholds to combat over-reconstruction, while high-contribution ones get lenient thresholds to mitigate under-reconstruction. During optimization, introducing Huber loss promotes quadratic growth for small errors, reducing smoothing to alleviate artifacts and better preserve details. Evaluation on standard datasets shows our method improves peak signal-to-noise ratio (PSNR) by 0.3 dB over 3DGS and 0.5 dB over MS-3DGS at 4× resolution, and it achieves a 0.1 dB gain over Mip-Splatting, confirming its effectiveness and robustness. Full article

Hypertension continues to be a major global public health challenge. Dopamine generated in the kidney is a vital coordinator of sodium homeostasis and blood pressure control. Dopamine exerts its effects by activating its receptors, which are divided into the D₁-like receptor family (D₁R and D₅R) and the D₂-like receptor family (D₂R, D₃R, and D₄R). All five dopamine receptor subtypes are differentially expressed along the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium transporters/exchangers/channels, decrease renal oxidative stress, and interact with other receptors, including angiotensin II receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure. The germline deletion or renal-selective silencing of any of the five dopamine receptor subtypes may impair sodium excretion and increase blood pressure. In addition, renal dopamine receptor expression and/or function are regulated by some factors such as G protein-coupled receptor kinases, oxidative stress, and sorting nexins. In this article, we summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension and discuss the potential regulatory mechanisms of their expression and function. These may lead to the development of novel therapeutic approaches to the prevention and treatment of hypertension. Full article

Gut dysbiosis, defined as a disruption in the structure or function of the intestinal microbiota, is increasingly recognized as a key contributor to inflammatory, metabolic, and neuropsychiatric diseases. Conventional interventions such as broad-spectrum antibiotics, generic probiotics, and fecal microbiota transplantation (FMT) often show limited and inconsistent efficacy because they lack specificity, durability, and robust safety controls. In contrast, recent advances in DNA-based technologies are reshaping the therapeutic landscape by enabling targeted, programmable, and mechanistically informed modulation of the gut ecosystem. This review presents an integrated overview of three major domains driving this shift: CRISPR-based systems that selectively delete, silence, or reprogram microbial genes; synthetic biology-driven live therapeutics engineered to sense disease-associated cues and execute controlled responses; and metagenomics-informed strategies that tailor interventions to patient-specific microbial gene profiles and functional deficits. Additionally, we examine the continued evolution of FMT toward DNA-optimized workflows and defined microbial consortia that offer safer, more standardized alternatives to crude donor material. Across these domains, we discuss delivery platforms (including bacteriophages, conjugative plasmids, extracellular vesicles, and synthetic nanoparticles), and compare their efficiency, specificity, and scalability. We further highlight how DNA-guided interventions interface with host immunity—shaping Treg/Th17 balance, mucosal barrier function, and inflammatory signaling—while also analyzing ecological and evolutionary risks, biocontainment strategies, and regulatory classification gaps that will govern clinical translation. Together, these developments signal a transition from empirical microbiome manipulation to rational ecosystem engineering. DNA-guided therapies hold strong promise for precise and personalized management of gut-related diseases, but their success will depend on rigorous ecological risk assessment, long-term monitoring, and adaptive regulatory frameworks alongside continued technological innovation. Full article

Mobile apps are essential for communication, transactions and leisure and frequently rely on access to personal data. This study examines Google Play’s Data Safety section and declared permissions five years after the GDPR came into force, focusing on how developers disclose data collection, sharing, security practices and deletion controls. We use metadata from 49,578 Android apps and analyze self-reported disclosures in relation to permission categories, app categories, installs and user ratings. The results show that free apps request broader permission access than paid ones and that declared permission use has gradually increased over time. In addition, 25.44% of the sampled apps had not completed any part of the Data Safety section and non-completion was associated with app age, installation band and pricing model. Among apps with completed relevant Data Safety section disclosures, 11% of developers explicitly declared that data are not encrypted in transit and 34% explicitly declared that no user-initiated data deletion mechanism is available. Category-level differences in declared data collection and sharing were modest, while the relationship between permission breadth and user ratings was small. Overall, the findings indicate that structured disclosure mechanisms can improve visibility of privacy-related information, but do not necessarily ensure its completeness or consistency. Full article

Background: Kölliker’s organ (KO) support cells undergo orderly, time-dependent degeneration that is essential for auditory development and is accompanied by precisely regulated autophagic activity; however, the molecular hierarchy linking autophagy to this remodeling remains obscure. This study aimed to elucidate the regulatory mechanisms connecting autophagic flux to lysosomal biogenesis and auditory function during cochlear development. Method: We established an Atg5^flox/flox; Sox2Cre+ mouse model with deletion of the autophagy gene Atg5 in cochlear-supporting cells. Auditory function was assessed via Auditory Brainstem Response (ABR) testing. Transcriptomic profiling of the neonatal basilar membrane was performed to screen for downstream targets. Mechanistic validation included spatiotemporal immunofluorescence mapping (E18–P30) and in vitro functional assays using siRNA-mediated knockdown and lysosomal tracking. Results: At 2 months of age, Atg5^flox/flox; Sox2Cre+ mice exhibited moderate-to-severe sensorineural hearing loss accompanied by significant outer hair cell loss. Bulk RNA-seq of the basilar membrane identified fork-head box A3 (Foxa3) as a significantly downregulated transcription factor within the lysosomal–autophagy network. Spatiotemporal immunolabelling from embryonic day 18 to postnatal day 30 revealed that FOXA3 expression becomes progressively restricted to KO cells during postnatal development, with ATG5 loss reducing FOXA3 protein levels by 62.4%. In vitro, deficiency of either Atg5 or Foxa3 in primary KO cells resulted in comparable reductions in LAMP1-positive puncta. Conclusions: These findings support a model wherein the ATG5-FOXA3 axis contributes to lysosomal biogenesis in developing KO cells, with implications for understanding mechanisms of congenital sensorineural hearing loss. Full article

Bacterial adaptation to hostile environments depends on the coordinated expression of stress response genes. When adverse conditions persist and nutrients become limiting, sporulating species may initiate sporulation as a last-resort survival strategy. However, sporulation under such conditions may alter the resistance and germination properties of the resulting spores. In this study, we investigated whether stress response regulators that facilitate vegetative cell adaptation to temperature and/or salinity changes during growth can influence the properties of Bacillus subtilis 168 spores. To this end, we examined the resistance and germination of mutant spores lacking key regulators of stress response pathways (SigB, SigW, SigX, Fur, HrcA, CtsR, and CssRS regulon), all produced under optimal sporulation conditions. The constitutive activation of the SigB-mediated general stress response, achieved through the deletion of its negative regulator RsbX, reduced spore heat resistance by 2.2-fold compared to the parental strain, while no effect was observed in vegetative cells. Additionally, ΔrsbX spores displayed both impaired nutrient-induced and CaDPA-induced germination. Collectively, these findings suggest that stress response regulators can influence spore behavior, although their effects may differ from those observed in vegetative cells. Full article

Background: Short stature is a frequent clinical problem with a broad differential diagnosis. Emerging evidence indicates that pathogenic variants in the ACAN gene represent an underrecognized cause of growth failure and are often misclassified as idiopathic short stature. Case presentation: We report two pediatric patients harboring pathogenic ACAN gene variants, both presenting with short stature and distinctive facial dysmorphism. The first patient, a 15-year-old boy, exhibited short stature, advanced bone age, and a characteristic facial gestalt, including ptosis, hypertelorism, down-slanting palpebral fissures, and fleshy auricles, features not previously described in association with aggrecanopathy. Genetic analysis revealed a novel heterozygous frameshift variant, c.5677_5684del (p.Glu1893TrpfsTer8), in exon 12 of the ACAN gene. The second patient, a 5.5-year-old girl, presented with short stature, mild facial dysmorphism (down-slanting palpebral fissures and retracted mandible), and feeding difficulties. Copy number variation analysis identified a heterozygous deletion encompassing exons 15–19 of the ACAN gene. In both patients, the endocrine evaluation was unremarkable, and no chronic systemic disease was identified. The genetic findings were concordant with the clinical phenotype, confirming aggrecanopathy as the underlying cause of growth failure. Conclusions: These cases further delineate the phenotypic spectrum of ACAN-related short stature and underscore the diagnostic value of genetic testing in children with unexplained or idiopathic growth failure. Importantly, we expand the dysmorphological phenotype of aggrecanopathy by describing previously unreported facial features, which may facilitate earlier clinical recognition and diagnosis. The timely identification of pathogenic variants in the ACAN gene may have significant implications for patient management and long-term outcomes. Full article

The rapid evolution of 6G networks and large-scale Internet of Things (IoT) deployments intensifies security and privacy challenges in embedded SIM (eSIM) Remote SIM Provisioning (RSP), particularly during the bootstrap and profile delivery phases. Traditional perimeter-based and VPN-centric approaches expose static attack surfaces, making provisioning workflows vulnerable to denial-of-service (DoS) attacks, reconnaissance, and profile lock-in risks. This paper presents MTD-SDP-eSIM, a hardware-anchored Zero Trust Architecture that secures eSIM provisioning by integrating the embedded Universal Integrated Circuit Card (eUICC) as a root of trust with Software-Defined Perimeter (SDP), Software-Defined Networking (SDN), and Moving Target Defense (MTD). The framework introduces Hardware-Anchored Single Packet Authorization (ES-SPA), which cryptographically binds initial access to tamper-resistant eUICC credentials and enforces an authenticate-before-connect model. A unified Zero Trust controller dynamically orchestrates SDP access control, SDN-based micro-segmentation, and MTD-driven Network Address Shuffling during high-risk provisioning phases. This framework is validated on a high-fidelity 6G testbed built using ns-3, Open5GS, and P4-programmable switches. Experimental results demonstrate a 90% DoS survival rate during provisioning, a 35% scalability improvement over VPN-based baselines, and a 75% reduction in profile lock-in failures through runtime deletion verification. These findings confirm that anchoring dynamic network defenses in hardware-rooted identity significantly enhances the resilience, scalability, and privacy of eSIM provisioning for massive 6G IoT deployments. Full article