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Chiari-like malformation (CM) and syringomyelia (SM) are prevalent in Cavalier King Charles Spaniels (CKCS). We hypothesized that CKCS with clinical signs compatible with CM+/-SM exhibit sleep disturbances. Thirty-seven CKCS with and without clinical signs compatible with CM+/-SM were included. No magnetic resonance imaging was required for inclusion. A questionnaire-based study was conducted using two validated instruments: CHASE to assess CM+/-SM severity and SNoRE 3.0 to evaluate sleep disturbances. Dogs with CHASE scores ≥7 were classified as having clinical signs. Nineteen dogs with clinical signs (median: 5 years, range: 3-10 years) and 18 without clinical signs (mean: 4.1 years, SD: 2.6) were included, with median CHASE scores of 13 (range: 7-18) and 1 (range: 0-6), respectively. Dogs with clinical signs had higher median SNoRE scores (median: 10, range: 6-30) than dogs without clinical signs (median: 7, range: 6-15). Sleep quality (padj = 0.008) and sleep interruptions due to dreaming (padj = 0.003) were significantly different between groups, with clinically affected dogs showing higher scores and greater variability. CKCS with clinical signs compatible with CM+/-SM show evidence of sleep disturbances, warranting confirmation with polysomnography and consideration in therapeutic management.

Liver fibrosis represents a common advanced pathological stage of various chronic liver diseases. Macrophages serve as key regulators of innate immunity and play important roles in the development of liver fibrosis. Cellular senescence is an irreversible cell cycle arrest state. However, the mechanisms underlying the role of senescent macrophages in liver fibrosis remain incompletely understood. Liver fibrosis was induced in young (8-week) and middle-aged (12-month) mice by intraperitoneal injection of 25% carbon tetrachloride (CCl4). Hepatic function and the immune microenvironment were evaluated using histopathology, serum biochemistry, Western blotting, RT-qPCR, immunohistochemistry, and immunofluorescence. A senescent macrophage model was established in RAW264.7 cells by exposure to H2O2. Conditioned medium from senescent macrophages was transferred to LX-2 cells to assess hepatic stellate cell (HSC) activation. Transcriptome sequencing of senescent RAW264.7 cells was performed to identify underlying mechanisms. FASN protein stability was examined using cycloheximide (CHX) chase assays, and degradation pathways were preliminarily explored by combined treatment with MG132 and chloroquine (CQ). In vivo, middle-aged mice treated with CCl4 exhibited more severe hepatic collagen deposition, fibrosis, and senescence than young mice. In vitro, senescent macrophages showed upregulated expression of SASP components, including pro-inflammatory cytokines and chemokines, and DNA damage markers, and their conditioned medium promoted LX-2 cell activation. Transcriptome sequencing of senescent RAW264.7 cells revealed a bidirectional fatty acid metabolic reprogramming characterized by downregulation of genes involved in fatty acid β-oxidation and upregulation of genes involved in fatty acid synthesis. Furthermore, FASN protein was found to undergo dual degradation via both the ubiquitin-proteasome and autophagy pathways. Moreover, pharmacological inhibition of FASN attenuated the DNA damage response in senescent macrophages. Macrophages in middle-aged fibrotic livers exhibit cellular senescence. FASN-mediated enhancement of fatty acid synthesis leads to lipid metabolic disorder and accumulation in senescent macrophages. These senescent macrophages promote HSC activation and drive the progression of liver fibrosis.

Preterm brain injury (PBI) can lead to severe neurodevelopmental impairment. F-box and WD repeat domain-containing 7 (FBXW7) is a key regulator of neural development. This study evaluated the effect of FBXW7 on nerve regeneration after PBI. A mouse model of PBI and an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) in neural stem cells (NSCs) were established. Cognitive and motor functions were assessed using Morris water maze, wire hanging, and cylinder tests. Histopathological changes and apoptosis were evaluated by hematoxylin and eosin and TdT-mediated dUTP Nick-End Labeling, and immunohistochemical staining for myelin basic protein and microtubule-associated protein 2 (MAP2). Neuroregeneration was analyzed via immunofluorescence (IF) staining for bromodeoxyuridine, doublecortin, and MAP2. FBXW7 and Notch receptor 1 (Notch1) expressions were detected by real-time quantitative PCR and Western blot. The viability, apoptosis and differentiation of NSCs were measured by cell counting kit-8, flow cytometry, and IF/Western blot. Protein interaction, stability, and ubiquitination were examined by co-immunoprecipitation and cycloheximide chase assays. FBXW7 expression was decreased in PBI mice and OGD/R-treated NSCs. Overexpression of FBXW7 significantly alleviated the pathological damage and behavioral impairments after PBI, and also enhanced the nerve regeneration process. Moreover, FBXW7 not only enhanced NSCs survival and suppressed apoptosis following OGD/R, but also actively drove their differentiation toward a neuronal lineage. Mechanistically, FBXW7 promoted the ubiquitination and degradation of Notch1. FBXW7 induced NSCs differentiation following OGD/R and mediated neuroprotection to protect PBI by inhibiting Notch1 signaling. By enhancing neuroregeneration via degradation of Notch1, FBXW7 appears to play a protective role in PBI, which suggests therapeutic targets for PBI treatment that merit further exploration.

Among mammals, spatial organization (home range size and overlap) may be influenced by kinship, and tolerance among kin is believed to play a role in the evolution of sociality. In solitary species, adults-including close kin-are presumed to have home ranges that are distinct and non-overlapping. We characterized spatial organization and behavioral interactions, including the role of kinship in a free-living population of golden-mantled ground squirrels (Callospermophilus lateralis), a presumably asocial and solitary species. We also capitalized on changes in population size over 25 years (1995 to 2019) to quantify the influence of density on that spatial organization. We found extensive overlap between female home ranges (30%) and between male and female home ranges (28%) after the breeding season. However, the core areas of adult female home ranges overlapped minimally (7%), suggesting that squirrels were territorial, but only for the inner part of their home range. Contrary to expectation for solitary ground squirrels, kinship played a role in the spatial organization: related females shared space more than unrelated females. We did not find an effect of overall population density on home range or core area size, but increased local density was associated with an increase in home range size. While we did not find an effect of density alone on spatial overlap, there was a density-mediated increase in space-sharing among kin; space-sharing by female kin was expressed primarily at high densities, suggesting that familiarity and inclusive fitness benefits may offset costs of competition and promote philopatry under certain conditions. We also found behavioral evidence to support this interaction: greater spatial overlap of home range core areas reliably increased the number of chases between squirrels, unless those squirrels were highly related. Overall, we provide evidence of a facultative transition in golden-mantled ground squirrels from asociality to the formation of single-family kin clusters at high densities, the first step toward developing sociality. Our study highlights the importance of considering behavioral interactions in asocial species, as well as the interactive effects of environmental conditions and kinship when assessing the spatial and social organization of mammals.

Ophiopogonis Radix (Mai-Dong) has been widely used in traditional Chinese medicine for the treatment of cardiovascular diseases, particularly those associated with ischemia and impaired cardiac function. Methylophiopogonanone A (MOA), a bioactive homoisoflavonoid isolated from Ophiopogonis Radix, has demonstrated antioxidant and anti-inflammatory activities; however, its role and molecular mechanisms in myocardial ischemia-reperfusion injury (MIRI) remain unclear. This study aimed to investigate the cardioprotective effects of MOA in MIRI and to determine whether VEGFR2-associated PI3K/Akt signaling, inhibitory phosphorylation of GSK-3β, and preservation of mitochondrial function contribute to these effects. MOA-VEGFR2 target engagement and stabilization were assessed using computational prediction and biochemical target-stability assays. The cardioprotective effects of MOA were evaluated in a rat myocardial ischemia-reperfusion model and in primary cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), with emphasis on cardiac function, infarct size, mitochondrial injury, mitochondrial permeability transition pore (mPTP) opening, and VEGFR2/PI3K/Akt/GSK-3β signaling. The involvement of VEGFR2 and PI3K signaling was further examined using VEGFR2 siRNA, SU5416, and LY294002. Integrative target screening prioritized VEGFR2/KDR as a functionally relevant candidate target of MOA in MIRI. Molecular docking and molecular dynamics simulations provided structural predictions; DARTS, CETSA, and ITDRF-CETSA supported VEGFR2 target engagement by MOA, whereas CHX-chase analysis showed a prolonged VEGFR2 protein half-life. In vivo, MOA reduced infarct size, improved cardiac function, lowered serum CK-MB, LDH, and cTnI levels, increased myocardial ATP content and SOD activity, enhanced phosphorylation of VEGFR2, PI3K, Akt, and GSK-3β, suppressed mPTP opening, and preserved mitochondrial ultrastructure. In vitro, MOA improved the viability of OGD/R-treated cardiomyocytes, decreased apoptosis and ROS accumulation, restored ΔΨm and ATP production, and inhibited mPTP opening. These protective effects were partially attenuated by VEGFR2 silencing, SU5416, or LY294002, supporting roles for VEGFR2-associated PI3K/Akt signaling and inhibitory phosphorylation of GSK-3β in MOA-mediated cardioprotection. MOA attenuates acute MIRI and preserves mitochondrial function. The findings support a model in which MOA-associated VEGFR2 target engagement and increased VEGFR2 protein stability are accompanied by enhanced PI3K/Akt signaling and inhibitory phosphorylation of GSK-3β. However, direct physical binding to VEGFR2 and classical VEGFR2 agonism were not established.

Deceptive actions such as head fakes are a hallmark of interactive sports, yet it is not well understood how decisions and whole-body responses to head fakes unfold over time. In the present study, participants viewed video sequences of a basketball player passing to the left or right, either with or without a head fake. In the buzzer task, participants moved laterally to press a response button as if to intercept the pass. In the vocal task, they verbally indicated pass direction. Reaction times (RTs), movement times (MTs), and medio-lateral center-of-pressure (CoP) displacements were recorded to investigate whether motor output is rapid and stimulus-driven or rather requires continuous integration of fake and pass cues. Further, we investigated whether the mere observation of a basketball player leads to overt micromovements even if no response movement is intended. The data analysis shows that head fakes increased RTs in both the buzzer and vocal tasks. In the buzzer task, head fakes induced an initial, small erroneous CoP shift, which was then rapidly corrected. When CoP trajectories were aligned by head orientation, fake and non-fake trajectories diverged shortly after movement onset. In the present dynamic sport-related context, this pattern is more compatible with the early integration of head and pass information than with a strictly sequential prime-target account, although the paradigm differs from classic Rapid Chase Theory designs with discrete primes and target events. In the vocal task, participants were not instructed to move, yet CoP traces showed tiny but systematically lateralized micromovements with a temporal structure resembling that in the buzzer task, albeit without an initial erroneous shift for head fakes. These postural fluctuations are consistent with action-observation-related motor activation, although they do not uniquely identify motor resonance and may also reflect attentional or generalized embodied response tendencies. A clear deceptive response conflict at the postural level emerged only when a lateralized action was prepared.

In non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement, bypass signaling activation commonly leads to resistance against alectinib. Identifying key molecular targets that integrate signals from resistance-driving kinases is crucial for overcoming this resistance. However, these targets have not yet been identified. We generated alectinib-resistant (AR) subclones from H3122 and H2228 cells. Subsequently, we analyzed bypass signaling pathways using western blotting, evaluated drug sensitivity with Cell Counting Kit-8 (CCK-8) assays. To assess the function of Grb2-associated binder 1 (Gab1), we employed siRNA-mediated knockdown and lentiviral shRNA both in vitro and in xenograft models. Additionally, we determined the stability of Gab1 through cycloheximide chase assays. AR cells demonstrated concurrent activation of the mesenchymal epithelial transition receptor tyrosine kinase (MET) and Rous sarcoma oncogene cellular homolog non-receptor tyrosine kinase (Src), accompanied by upregulation of Gab1. The combined inhibition of MET and Src, as opposed to single-agent blockade, effectively suppressed Gab1/protein kinase B (AKT) signaling and restored sensitivity to alectinib. Gab1 knockdown mirrored the effects of dual kinase inhibition, by disrupting MET/Src/AKT signaling and resensitizing cells to alectinib. Mechanistically, the elevation of Gab1 resulted from post - translational stabilization, with a significantly extended half - life in resistant cells. In vivo, silencing Gab1 inhibited the growth of H3122-AR2 xenografts without causing systemic toxicity, which correlated with decreased phosphorylation of MET, Src and AKT in tumor tissues. In ALK-positive NSCLC with acquired resistance to alectinib, Gab1 emerged as a crucial downstream signaling convergence target of MET and Src co-activation. Targeting this adaptor protein presented a promising therapeutic strategy to overcome bypass-mediated resistance.

Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) is crucial for the canonical wingless signaling pathway and the clearance of LDL from the bloodstream. Genetic variants in the LRP6 gene have been conclusively associated with cardiovascular diseases (CVDs) and metabolic syndrome. However, the structural, cellular, and functional implications of these variations have not been fully elucidated. In this study, we examined the subcellular localization, stability, and degradation of 10 LRP6 missense variants (K82N, R360H, Y418H, N433S, R473Q, S488Y, R611C, P1066T, P1206H, and I1264V) previously reported to be associated with various CVD conditions. We assessed the effect of these missense variants on LRP6 subcellular localization by overexpressing them in HeLa and human embryonic kidney (HEK293T) mammalian cell lines. Molecular dynamic (MD) simulation was performed on two variants to evaluate their stability. In addition, the stability of all the variants was evaluated experimentally by measuring their half-lives and comparing them to the wild-type (WT) protein, using cycloheximide chase assays and inhibitor treatments. Our findings suggest that approximately 45% of the wild-type LRP6 protein achieves its mature form within 24-48 h of overexpression, indicating its modest trafficking through the endoplasmic reticulum (ER), maturation, and transport to the plasma membrane. On the other hand, CVD-associated LRP6 variants Y418H, N433S, R473Q, and P1206H exhibited significantly lower maturation levels and, in some cases, were semi-quantitatively present in the immature form, suggesting retention within the ER and failure to pass the highly stringent ER quality control systems. The in silico stability assessment revealed that all 10 LRP6 missense variants are predicted to have a negative impact on protein stability. Interestingly, MD simulation elaborated that one fully ER-retained variant, P1066T, has altered structural interactions of the protein, affecting its folding. ER retention of some CVD-associated LRP6 variants could contribute to diseases via the reduction in LRP6 plasma membrane localization and consequently loss or reduction of LRP6 function, potentially leading to dysregulated signaling efficiency. This study contributes to improving our understanding of the cellular behavior of several LRP6 missense variants causing CVD conditions and has potential applications in diagnosis and the development of new therapies for their associated conditions.

PAX2 encodes a transcription factor critical for kidney development. Pathogenic PAX2 variants are associated with heterogeneous kidney and extrarenal manifestations. However, the clinical heterogeneity of PAX2-associated kidney disease and the functional consequences of newly identified variants remain incompletely characterized in pediatric cohorts. We retrospectively analyzed probands from a single-center pediatric genetic kidney disease program (2018-2024). Clinical data, imaging, kidney pathology, follow-up kidney function and genetic results were reviewed. Selected variants were functionally assessed in HEK293 cells using protein expression, cycloheximide-chase, and dual-luciferase reporter assays. We identified 14 distinct PAX2 variants in 15 probands, including seven previously unreported variants: p.D2Y, p.T210A, p.S242N, p.V206D, p.A160T, p.F256Ffs*40, and p.L44_A45insV. The cohort showed substantial phenotypic heterogeneity, including variability in age at diagnosis, kidney manifestations, disease severity, extrarenal involvement, and intrafamilial expressivity. Kidney biopsy findings, available in seven patients, were heterogeneous and nonspecific. Functional analyses showed that several variants reduced PAX2 protein expression, impaired protein stability, and/or decreased transcriptional activity. This study expands the clinical and molecular spectrum of PAX2-related kidney disease in Chinese children and highlights its substantial phenotypic and pathological heterogeneity. Early genetic testing, retrospective reanalysis, and longitudinal follow-up are valuable for children with unexplained kidney disease.

Lifespan is increasing throughout the world leading to a rise in non-communicable diseases in the global population that impacts over 800 million individuals with metabolic disorders, such as diabetes mellitus. Metabolic disease presents a significant challenge for clinical care since multi-organ disease progression ensues despite a broad array of treatment protocols. The pursuit of innovative strategies with mammalian forkhead transcription factors of the "O" class (FoxOs) and intimately related pathways of aging, cellular senescence, telomere integrity, oxidative stress, programmed cell death with apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis, Wnt/β-catenin signaling, Wnt1 inducible signaling pathway protein 1, and the gut microbiome becomes vital to address the clinical hurdles of metabolic disorders. Platforms incorporating novel diagnostics with artificial intelligence and machine learning can further address the underlying mechanisms tied to FoxOs that include the mechanistic target of rapamycin, AMP activated protein kinase, silent mating type information regulation 2 homolog 1 (S. cerevisiae), and glucagon-like peptide-1 receptor agonists that can markedly influence biological outcomes. Given the premise that it is essential to comprehend the intimate relationship that FoxO signaling pathways hold, FoxOs offer an exciting and promising approach to address the clinical aspects of disease onset, progression, and treatment with metabolic disorders.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a leading contributor to developing familial and idiopathic Parkinson's disease (PD). Most PD-causing LRRK2 mutations increase the kinase activity, leading to increased phosphorylation of Rab GTPases, disrupting vesicular trafficking, cytoskeletal dynamics, and autophagy. Under homeostatic conditions, the bulk of WT and PD-mutant LRRK2 is found in the cellular cytosol. However, exogenously expressed LRRK2 can form microtubule-associated filaments that have been shown to affect molecular transport along microtubules in vitro. While the physiological relevance of microtubule binding has not been established yet, inhibitors being designed and tested as therapeutics have been shown to either promote or prevent filament formation of LRRK2. In this study, we examine the localization and resulting molecular organization of hyperactive LRRK2-I2020T, a common PD mutant, in HEK 293FT cells treated with type I (MLi-2) or type II (GZD-824) kinase inhibitors. Treatment with a type I kinase inhibitor results in extensive LRRK2-I2020T decoration around microtubules and microtubule bundling. Stabilization of LRRK2-I2020T filaments by type I inhibitor treatment allowed us to build a full-length closed-kinase model of LRRK2-I2020T in its cellular environment. Conversely, treatment with a type II inhibitor resulted in minimal microtubule decoration by LRRK2-I2020T compared to type I inhibitor-treated cells. This study provides a structural framework for understanding how type I and type II kinase inhibitors differentially modulate LRRK2 filament formation, demonstrating that type I inhibitor treatment promotes a distinct filament architecture, whereas such assemblies are not observed with type II inhibitors.

MYCN amplification is a strong predictor of poor prognosis in neuroblastoma, an embryonal malignancy that accounts for 15% of pediatric cancer deaths. Here, we found that MYCN-amplified neuroblastoma tumors had increased 5-hydroxymethylcytosine (5-hmC) deposition on Polycomb repressive complex 2 (PRC2) target genes. 5-hmC and H3K27me3, a catalytic product of PRC2, directly co-localized at the nucleosomal level in MYCN-amplified neuroblastoma. Genes with the co-localization of 5-hmC/H3K27me3 were involved in development-related pathways, transcriptionally repressed in MYCN-amplified neuroblastoma, and more likely to be transcriptionally activated upon PRC2 inhibition. Inhibition of 5-hmC deposition resulted in a loss of H3K27me3 on protein-coding genes, accumulation of 5-methylcytosine to maintain transcriptional repression, and sensitized neuroblastoma to DNA demethylating agents. Low expression of genes marked by 5-hmC/H3K27me3 was associated with poor clinical outcome. Our results suggest that 5-hmC/H3K27me3 co-operate to repress mediators of development, highlighting a link between DNA and chromatin modifications with potential therapeutic implications in MYCN-amplified neuroblastoma.

The large effector arsenal of the bacterial pathogen Legionella pneumophila has been a rich source of biochemistry, highlighting the immense diversity of strategies deployed in host-pathogen conflict. Here, we redefine the purported translation inhibitor SidL as an adenylyltransferase that targets a glycolytic metabolite, discovering that it modifies 3-phosphoglycerate with adenosine monophosphate (AMP) to produce the previously unknown molecule 2-AMP-3-phosphoglycerate. When expressed alone in mammalian cells, SidL adenylates 3-phosphoglycerate, disrupts glycolysis, and blocks the nutrient-responsive translation regulator mTORC1, which we propose indirectly causes translation inhibition. Moreover, we observe SidL-dependent production of 2-AMP-3-phosphoglycerate in macrophages during L. pneumophila infection, the timing of which is consistent with a role for SidL in the early stages of the infection cycle. Thus, our study uncovers a mechanism by which an intracellular pathogen uses the chemical modification of a glycolytic intermediate to target central carbon metabolism in the host.

Newsweek has published annual "America's Best Plastic Surgeons" rankings based on a peer-nomination survey for five years, now encompassing six aesthetic surgery categories that each identify the top 30 surgeons. To evaluate gender representation, geographic distribution, and recurrence patterns among surgeons included in these national rankings. All available ranked surgeons were reviewed (n=720). Surgeon gender and location were recorded. Duplicate entries were removed to identify unique surgeons. Recurrence across categories was evaluated. Of the 720 rankings published, 149 unique surgeons were identified. 134 (89.9%) were male and 15 (10.1%) were female. Compared with their estimated 20% representation in the national workforce, female plastic surgeons were significantly underrepresented in the rankings (10.1% vs 20%; p=0.002). Each year, female representation was significantly lower than expected (2021, p=0.004; 2022-2025, all p<0.001). Compared with their respective inaugural years, the proportion of female surgeons decreased in four categories. 35.6% of surgeons (n=53) appeared in more than one category, averaging 2.3 additional category listings. In 2025, surgeons previously ranked within the same category had appeared on average 2.8 times before. Geographically, surgeons were located in the South (n=54), Northeast (n=52), West (n=29), and Midwest (n=14). Significant gender disparities characterize the "America's Best Plastic Surgeons" lists, and redundancy patterns may indicate concentration among a limited subset of surgeons. Reevaluating survey methodology and the ranking process may improve representation and patient access to a more diverse selection of surgeons.

Whole-genome sequencing of Mycobacterium tuberculosis (Mtb) populations from clinical samples has increasingly identified genes undergoing selection within and between hosts that drive differential infection and treatment outcomes. However, the intrahost Mtb mutational landscape-especially in the context of human immunodeficiency virus (HIV) coinfection and antiretroviral therapy (ART)-remains less clear, as do the potential impacts of such mutations on Mtb infection dynamics. Here, we performed whole-genome sequencing of Mtb populations isolated from 477 infected tissues across 20 non-human primates (NHP), including animals co-infected with simian immunodeficiency virus (SIV) with or without virological suppression by ART. We identified 116 mutations that emerged during infection, including those that are overrepresented within individual tissues and a subset that are shared across tissues during Mtb dissemination. We further find differential mutation trajectories across treatment groups, with higher mutation frequency and bacterial outgrowth in SIV-infected hosts and increased prevalence of oxidative damage-associated mutations in coinfected animals on ART. Finally, we demonstrate a common pattern of mutation in Mtb lipid metabolism and polyketide synthase genes and identify a subset of NHP-derived mutations that have also independently arisen in human clinical isolates. Together, our population-based sequencing uncovers Mtb diversification during early infection, captures discrete bacterial dissemination events, and infers differential immune pressures faced by Mtb in the setting of SIV-Mtb coinfection and ART suppression. Tuberculosis (TB) remains a leading cause of death worldwide, especially in people living with HIV (PLHIV). How HIV infection and antiretroviral therapy impact Mycobacterium tuberculosis (Mtb) intrahost evolution remains unclear. Using whole-genome sequencing from hundreds of infected tissues from non-human primates, we find that simian immunodeficiency virus coinfected hosts and those receiving antiretroviral therapy exert different immune pressures on Mtb, leading to differences in mutation rates and types of DNA damage that are incurred. Mtb mutations were enriched in genes involved in lipid metabolism, and some of these are also seen in human TB strains. This work highlights the role of immune pressure in altering bacterial pathways that may enable Mtb adaptation to the host.

Primary intestinal lymphangiectasia (PIL; Waldmann's disease, ORPHA 90362) is a rare protein-losing enteropathy in which dilated intestinal lacteals leak chyle into the gut lumen. Cross-sectional imaging and lymphoscintigraphy have historically dominated assessment, while transabdominal B-mode intestinal ultrasound (IUS)-a cornerstone modality for inflammatory bowel disease-has remained almost unmapped in PIL. We conducted a PRISMA-ScR scoping review (Open Science Framework preregistration gfbc9) of all primary studies reporting transabdominal B-mode IUS in PIL, searching three bibliographic platforms (PubMed/MEDLINE, Ovid Multifile, Scopus) supplemented by forward and backward citation chasing. Studies using only extra-intestinal ultrasound, endoscopic ultrasound, those describing secondary lymphangiectasia or focal lymphangioma, and those using ultrasound only as procedural guidance for lymphangiography were excluded at full-text stage. Fifteen primary studies, published 1986-2026 across thirteen countries, met eligibility (nine paediatric, six adult). All fifteen reported per-patient B-mode IUS findings extractable for synthesis. A consistent sonographic signature emerged: diffuse, regular, slightly hypoechoic small-bowel-wall thickening with preserved five-layer stratification and prominent valvulae conniventes; dilated fluid-filled loops with reduced peristalsis; oedematous mesentery, variable ascites; and characteristically absent mesenteric lymphadenopathy (with two notable exceptions framed only as a research hypothesis). Diagnostic accuracy as a screening tool has been evaluated only in one study (n&#x2009;=&#x2009;20: accuracy 80%, 95% CI 56.3-94.3%). We illustrate this signature in a 42-year-old woman with Hennekam syndrome and report quantitative B-mode IUS values as anecdotal single-observation-single sonographer, single device, single fasted time-point, mid-jejunal segment to motivate, prospective standardisation.

Melanomas display distinct transcriptomic states, but it remains unclear how they associate with clinical outcomes. We performed digital spatial RNA profiling (DSP-RNA) of metastatic tumors from patients to investigate how transcriptomic states correlate with melanoma specific survival (MSS) and acral melanoma (AM). We performed DSP-RNA across a tissue microarray constructed from 111 patients with in-transit metastatic melanoma (ITM) diagnosed from 1990 to 2020. Data quality control, noise correction, and normalization yielded high-quality profiles from 105 patients, including 30 (36%) who received immune checkpoint inhibitors and 20 (24%) with AM. We performed principal component (PC) analysis and correlated the results with published gene signatures: The PC1 axis differentiated transitory from undifferentiated melanoma, PC2 reflected immune cell infiltration, PC3 corresponded to stromal cells and neural crest-like melanoma, and PC4 associated with melanocytic melanoma. Across a cohort of treatment-na&#xef;ve ITM, high expression of the melanocytic state conferred a median MSS difference of 7.72 years (melanocytic "high"&#xa0;=&#xa0;5.16 years versus "low"&#xa0;=&#xa0;12.88 years, log-rank P&#xa0;=&#xa0;0.0061) and independently associated with poor survival in multivariate analysis. AMs showed higher melanocytic state gene expression compared to nonacral. Findings were validated in external datasets, supporting that the melanocytic state predicts poor prognosis. The melanocytic state is associated with poor prognosis and may be enriched in AM, implying that identifying patients with melanocytic melanoma may be important for therapeutic decisions. Unlike other gene expression predictors proposed for prognostic stratification, the melanocytic state characterizes a biological subtype, suggesting that it may have specific therapeutic vulnerabilities.

Within a One Health framework, pollution is no longer a passive backdrop to host-virus interactions but actively reshapes disease dynamics across humans, animals, and ecosystems. The aim of this review was to synthesize evidence across free-ranging wildlife and wild-derived models to define environmental virotoxicology, which is the study of how environmental contaminants alter susceptibility, replication, shedding, transmission, pathogenesis, persistence, and viral evolution in hosts. A systematic search of PubMed, Scopus, and Web of Science (26 Oct 2025), augmented by citation-chasing, yielded 162 eligible studies spanning more than 100 taxa (marine mammals, birds, amphibians, reptiles, fish, invertebrates) and major DNA/RNA virus families. Across 9 contaminant classes (>180 chemicals), including legacy persistent organic pollutants, petroleum hydrocarbons/polycyclic aromatic hydrocarbons (PAHs), metals, agrochemicals, pharmaceuticals, per- and polyfluoroalkyl substances (PFAS), and micro/nanoplastics, recurrent patterns emerge: (1) suppression or dysregulation of antiviral immunity, (2) reactivation of latent infections, and (3) increases in viral load, severity, and epizootic magnitude. Effects are context-dependent, with documented null or mixed outcomes shaped by dose, timing, life stage, immune compartment, and host ecology. Two broad implications follow: 1) contaminants might amplify wildlife epizootics and reshape reservoir competence, and in at least one well-supported case (2) low, environmentally realistic exposure to antiviral residues in wild waterfowl may impose selective pressure on viral populations and select for antiviral resistance. It is recommended to integrate contaminant surveillance with viral infectious disease monitoring and prioritizing multifactor, mechanistic designs that couple exposure history, immune phenotype, and virological endpoints.

Publicly available RNA sequencing (RNA-seq) data provide a cost-effective springboard for biomarker discovery. However, heterogeneity across studies often complicates analysis. This study presents a modular analytics pipeline that combines publicly available datasets with established open-source tools; standardizes quality control, differential expression analysis, and pathway analysis; and leverages competitive machine learning to unify disparate RNA-seq datasets for robust biomarker identification. The workflow is demonstrated across three disease contexts, ranging from small pilot datasets to larger, integrated analyses: (1) identifying differentially expressed gene signatures associated with COVID-19 severity, (2) combining differential expression and machine learning techniques to analyze multi-cohort sepsis datasets, resulting in concise biomarker panels, and (3) utilizing both bulk and single-cell data to examine tissue and cell-type specificity of N-acyl-phosphatidylethanolamine phospholipase D in atherosclerosis. These applications demonstrate how an adaptable, modular pipeline using open-source tools can repurpose public data to reduce noise, generate new hypotheses, and reveal meaningful biological insights, thereby establishing a foundation for future research and underscoring the importance of public data in exploratory biomarker discovery.