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Global climate change disproportionately threatens island endemics because their restricted ranges and limited dispersal opportunities constrain their ability to shift their distributions. Therefore, when developing conservation strategies for species, it is crucial to incorporate population genomics data with ecological information to evaluate resilience and forecast vulnerability. However, genomic case studies that explicitly link these factors in island endemics remain scarce. Here, we examine population genetic differentiation of the Formosan Duke (Euthalia formosana), an endemic butterfly in Taiwan, to evaluate its potential vulnerabilities under future climate conditions. Our results reveal that the combined effects of topographic barriers, historical connectivity, and climatic heterogeneity can drive rapid diversification, even in species with strong flight ability. The Central Mountain Range has shaped pronounced genetic structure, separating eastern and western lineages, with diversification stronger in the western lineage. This within-island diversification appears to be shaped by environmental gradients, enhancing persistence in local habitats while reducing a lineage's niche breadth and resulting in different lineage-specific climate vulnerability. Thus, we suggest that genomic approaches should be included to assess environmental constraints and to guide conservation planning on the persistence of lowland endemics such as the Formosan Duke. This framework also integrates the concepts of habitat restoration with lineage-specific connectivity to enhance the species' genetic resilience while preserving its capacity for local adaptation. Moreover, this study provides an evidence-based framework for insular biodiversity conservation under accelerating climate change.

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Regulatory CD4+ T cells (Tregs), as defined by expression of the transcription factor Foxp3, strongly depend on the cytokine interleukin 2 (IL-2) for their survival and function and are often identified by the combination of high IL-2Rα (CD25) and low IL-7Rα (CD127) expression. Nevertheless, subsets expressing higher levels of IL-7Rα have been described, and IL-7 signaling does play a role in Treg function in some specific biologic contexts and tissues. The precise role of IL-7Rα-expressing Tregs in autoimmunity remains poorly defined though, potentially hampering current efforts to develop IL-7Rα blockade for the treatment of various autoimmune diseases. To ask whether cell-intrinsic IL-7Rα expression in Tregs was required for their function during type 1 diabetes (T1D) development, we generated non-obese diabetic (NOD) mice in which IL-7Rα is exclusively deleted in Foxp3-expressing Tregs. In young NOD mice, IL-7Rα deficiency did not alter Treg numbers and phenotype. However, 100% of NOD mice with IL-7Rα-deficient Tregs became diabetic, while the T1D incidence is typically around 50-60% in our colony. This increased susceptibility for T1D indicates that IL-7Rα expression in Tregs is required to protect a subset of NOD mice against islet autoimmunity. At the time of T1D onset, CD4+ and CD8+ T cells from NOD mice with IL-7Rα-deficient Tregs showed increased IFN-γ and IL-2 cytokine production. Our data demonstrate that cell-intrinsic IL-7R signaling in Foxp3+ Tregs is required to suppress effector T cell responses and to prevent full penetrance of T1D in NOD mice.

Liquid biopsy now provides minimally invasive access to tumor-derived genomic and epigenetic information across the lung cancer continuum, and its clinical role continues to expand. This review examines that role across cancer detection (screening and diagnosis), treatment monitoring (advanced-disease genotyping, minimal residual disease (MRD) assessment, and resistance profiling at progression), and clinical outcome prediction. Plasma-based genotyping is now well established in advanced non-small cell lung cancer (NSCLC), while circulating tumor DNA (ctDNA)-based MRD detection in the curative-intent setting has accumulated a substantial evidence base over the past 5 years. Cell-free DNA (cfDNA) methylation, fragmentomics, and circulating tumor RNA (ctRNA) are emerging as complementary modalities, particularly when tumor shedding is low. We also consider concordance between liquid and tissue biopsies, the use of cerebrospinal fluid (CSF) ctDNA in central nervous system (CNS)-involved disease, and the practical issues of cost, reimbursement, and access that shape clinical adoption. The current state of the field can be framed across three tiers of evidence, with established applications, applications under prospective evaluation, and applications not yet ready for routine clinical use. No multi-cancer early detection (MCED) test has shown a mortality benefit to date, and ctDNA-guided treatment changes in metastatic disease still lack randomized overall-survival data.

Phosphatase and tensin homolog (PTEN) is a key tumor suppressor gene that negatively regulates the PI3K/AKT pathway. PTEN deficiency is the most frequent molecular alteration in triple-negative breast cancer (TNBC); however, the relationship between PTEN protein loss and underlying genomic alterations remains incompletely understood. Fifty TNBC cases were evaluated for PTEN protein expression by immunohistochemistry on tissue microarrays. PTEN hotspot mutations (Exons 1, 5, 7, and 9) were analyzed using Sanger sequencing, whereas copy number alterations were assessed by multiplex ligation-dependent probe amplification (MLPA) assay. PTEN alterations were correlated with clinicopathological characteristics. External validation of PTEN mRNA and protein expression and prognostic significance was performed using publicly available TCGA/CPTAC datasets and Kaplan-Meier plotter. PTEN protein loss was observed in 41/50 TNBC cases (82%), indicating that PTEN deficiency is a frequent event in this subtype. PTEN mutations were detected in six cases (12%) and were confined exclusively to Exon 5, comprising one missense mutation (c.277C>A) and two truncating mutations (c.430del and c.433del). MLPA identified PTEN copy number alterations in four cases (8%), including heterozygous deletions and duplications. No significant association was observed between PTEN protein expression and genomic alterations, highlighting a substantial genotype-phenotype discordance. Analysis of independent public datasets confirmed significantly reduced PTEN mRNA and protein expression in TNBC compared with luminal and HER2-positive breast cancers. Patients with low PTEN expression showed a trend toward shorter overall survival (23.5 vs. 38.9 months), though the difference did not reach statistical significance. PTEN protein loss is highly prevalent in TNBC but is only partially explained by mutations and copy number alterations, suggesting that additional regulatory mechanisms, such as epigenetic or posttranscriptional events, contribute to PTEN inactivation. These findings underscore the biological importance of PTEN deficiency in TNBC and support further investigation of PTEN as a potential prognostic biomarker and therapeutic target.

High-molecular-weight glutenin subunits (HMW-GSs) form the structural backbone of the wheat gluten network, and their compositional and structural polymorphisms strongly shape dough rheological properties. As wheat processing becomes increasingly standardized and specialized, the requirements for dough properties, especially strength and extensibility, are becoming more stringent and diverse. This makes it essential to clarify the structure-function and dose-effect relationships between HMW-GS and dough rheological properties. On the basis of current evidence, this review focuses on three main aspects: (1) the contributions of HMW-GS allelic variation to dough strength and extensibility; (2) the molecular mechanisms by which multidimensional structural features of HMW-GSs determine these rheological traits; and (3) the relationships between multidimensional structural polymorphism and dough strength and extensibility. Subunits, such as Ax1, Ax2*, Bx14 + By15, and Bx17 + By18, can synergistically enhance both strength and extensibility, whereas Bx7OE + By8 and Dx5+Dy10 generally enhance strength at the expense of extensibility. We propose a multidimensional structure-function framework in which "loop-train" motifs and helical conformations confer elasticity; disulfide bonds cross-link elastic units into a gluten network; and non-covalent interactions (e.g., hydrogen bonding, hydrophobic, and ionic interactions) cooperate to build and stabilize the network. Single amino-acid substitutions at key residues can shift dough properties by altering local conformations and intermolecular interactions, including cysteine substitutions (e.g., Cys10Ser-N, Cys40Ser-N, Ser8Cys-central repetitive domain [CRD], Tyr612Cys-CRD, and Cys25Ser-N) and non-cysteine substitutions (e.g., Gly244Glu-CRD for Ax1). However, reported sequence polymorphisms-rheological traits remain difficult to reconcile with large-scale sequence datasets, and systematic analyses of higher order structural polymorphisms remain limited. Future work should resolve these gaps to enable more precise quality control and rational design of wheat-based products.

Kidney renal clear cell carcinoma (KIRC) is the most common and aggressive subtype of renal cell carcinoma and is characterized by poor prognosis and high molecular heterogeneity. Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cancer, yet the functional role of SNHG11 in KIRC remains unclear. In this study, we perform integrated multiomics analysis using data from the TCGA and ICGC cohorts and reveal that SNHG11, a methylation-associated lncRNA, is significantly correlated with poor clinical outcomes. In vitro and in vivo assays demonstrate that SNHG11 promotes tumor proliferation and progression. Mechanistically, SNHG11 enhances oxidative phosphorylation, as evidenced by increased ATP production, disrupted mitochondrial membrane potential, and altered NAD +/NADH ratios. Furthermore, SNHG11 expression is associated with somatic mutation patterns, particularly those involving BAP1 and PBRM1, indicating potential crosstalk between epigenetic regulation and genetic alterations. These findings reveal that SNHG11 is a novel biomarker in KIRC and a potential therapeutic target.

The nosology of primary cutaneous apocrine carcinoma remains controversial, as the term has often been used as a heterogeneous diagnostic category. The aim of this study was to clarify the clinicopathological and molecular features of strictly defined apocrine carcinoma using modified diagnostic criteria. Thirty cases were collected from three institutions. Male predominance (28/30, 93%), predominance in elderly patients (median age, 72 years; range, 33-89 years) and the favourite site of the axilla (29/30, 97%) were observed. Lymph node and distant metastases occurred in 64% (16/25) and 28% (7/25) of cases, respectively. Two patients died of the disease (2/25, 8%), with a median follow-up period of 2 years and 1 month. Histopathologically, all tumours harboured cytoplasmic zymogen-like granules; however, some (8/30, 27%) lacked apocrine secretion features. Nucleoli were either moderately prominent (n = 17) or prominent (n = 13). Apocrine gland hyperplasia was identified in 5 (17%) of the 30 cases. Immunoexpression of androgen receptor, BerEP4, cytokeratin 7, GATA3 and GCDFP15 was observed in all tested cases. In contrast, BCL2, CEA, oestrogen receptor and progesterone receptors were negative in all tested cases. Only 13 cases underwent molecular studies. PIK3CA hotspot mutations were detected in 8 of the 13 cases. Panel sequencing revealed KMT2D (MLL2/4) mutations in three cases, all of which have no PIK3CA mutations. Primary cutaneous apocrine carcinoma is a distinct entity characterized by remarkably consistent clinical, cytopathological, immunohistochemical and molecular features.

HLA-DPB1*1822:01N has a single C>T substitution in exon 3 position 463, causing a premature stop codon.

To evaluate the feasibility and performance of spent culture medium (SCM)-based non-invasive pre-implantation genetic testing for aneuploidy (niPGT-A) after 8 h of post-warming in vitrified-warmed human blastocysts, and to determine whether post-amplification library concentration improves SCM-based result interpretation. This study included 26 discarded vitrified-warmed blastocysts from 17 patients. After 8 h of post-warming culture, SCM was collected and analyzed by next-generation sequencing together with trophectoderm (TE) biopsy samples and whole blastocysts (WB). Concordance at the chromosome and category levels was evaluated between SCM and WB and between TE biopsy and WB, and the association of library concentration with performance and euploid probability was assessed. SCM analysis was informative in 92.3% (24/26) of embryos. Chromosome-level concordance with WB was lower for SCM than for TE (30.8% vs. 57.7%), whereas category-level concordance was 69.2% for SCM and 76.9% for TE. Combining SCM category with library concentration improved prediction of euploid embryos (AUC 0.9527 vs. 0.8077, p = 0.0158). The leave-one-out cross-validated AUC of the combined model was 0.896. SCM-based niPGT-A after 8 h of post-warming culture is feasible in vitrified-warmed human blastocysts. Library concentration improves interpretation of SCM-based results and may help identify embryos likely to be euploid.

Genotyping cost is one of the major limiting factors for wide adoption of genomic selection in wheat. The present study compared two genotyping platforms, a low-density 4K single nucleotide polymorphism (SNP) chip and a Wheat iSelect 90K SNP, in genomic prediction of grain yield (YLD) and yield related traits in a training population composed of 224 spring wheat lines, and a new population composed of 141 spring wheat lines, with and without consideration of a fixed effect for major plant adaptation genes-derived competitive allele specific PCR (KASP) markers. Five models were evaluated and compared, which included 4K SNP-only, 4K SNP + KASP, 90K SNP-only, 90K SNP + KASP, and KASP-only. Within the training population, the 90K array showed slightly higher predictive ability for YLD, whereas the 4K panel performed better for thousand kernel weight (TKW). Incorporating KASP fixed effects, the 4K SNP + KASP and 90K SNP + KASP models significantly improved prediction for YLD, heading date (HD), and plant height (PHT) compared to the corresponding SNP-only models. KASP-only outperformed both SNP-only models for HD, but for PHT it only outperformed the 4K SNP-only model. In cross-population prediction, KASP-only models outperformed 4K SNP-only for HD and PHT. These results suggest that breeding programs can deploy genomic selection with a mid-density marker platform, especially, the 4K SNP + KASP model offers a cost-effective strategy for genomic prediction, while KASP-only genotyping provides a practical ultra-low-cost option for screening heading date and plant height.

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ATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk. Using data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE ε2 and ε4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest. Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding. Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.

Mitochondrial dysfunction is linked to urolithiasis, but causal genetic drivers remain unclear. We integrated multi-omics data using Mendelian randomization to identify mitochondrial-related genes causally associated with urolithiasis. We obtained mitochondrial methylation (mQTL), gene expression (eQTL), and protein abundance (pQTL) from respective quantitative trait locus (QTL) studies along with GWAS summary data for nephrolithiasis, ureterolithiasis and bladder calculus from the Million Veteran Program (discovery), with replication in FinnGen and UK Biobank. Summary-data-based Mendelian randomization (SMR) and colocalization were applied to infer causality. Integrated analysis identified FXN as the leading candidate for nephrolithiasis. Genetically elevated circulating FXN protein was inversely associated with nephrolithiasis risk (OR 0.69, 95% CI 0.56-0.84). This protective effect was supported at the epigenetic level: FXN methylation at cg14656297 and cg13974534 correlated with lower nephrolithiasis risk. For ureterolithiasis, higher GRHPR protein levels were protective (OR 0.81, 95% CI 0.71-0.91). In a mouse kidney stone model, Fxn expression and frataxin protein levels were decreased, providing correlative in vivo support consistent with human genetic findings. This multi-omics MR study links mitochondrial genes, particularly FXN, to urolithiasis risk. Although colocalization evidence was weak (PP.H4 = 0.0239) and replication in independent cohorts was not statistically significant, the multi-omics consistency across methylation, expression, and protein levels prioritizes FXN as a hypothesis-generating candidate for further investigation. Because all QTL data are blood- or plasma-derived, this study provides blood/plasma QTL-based genetic prioritization rather than kidney-specific causal inference.

The persistent shortage of human organs for transplantation has intensified efforts to develop alternative sources, specifically xenotransplantation and exogenesis. Xenotransplantation uses genetically engineered pigs to provide organs, tissues, and cells for clinical use. Significant progress has occurred in developing multigene-modified pigs that lack glycan xenoantigens while expressing human complement and coagulation regulators. These modifications have successfully mitigated hyperacute, antibody-mediated, and cellular rejection in preclinical nonhuman primate models. Recent compassionate-use cases in humans have demonstrated the feasibility of heart, kidney, and liver xenotransplantation, although achieving long-term survival remains a challenge. Complementing this approach, exogenesis aims to generate human-compatible organs within animal hosts through interspecies chimerism. Although advances in establishing organ niches and overcoming xeno-barriers have yielded preliminary success in heart, pancreas, and muscle development, formidable immune and developmental hurdles remain. Together, these approaches offer promising strategies to expand the donor organ pool and address the growing global demand for transplantation. Further advances in genetic engineering, immune modulation, and developmental biology, supported by rigorous preclinical and clinical evaluation, will be critical for widespread translation. This review outlines the current progress, major challenges, and future directions in xenogeneic and exogenic organ generation.

Autoimmune-inflammatory myopathy-related interstitial lung diseases (AIM-ILDs) are often progressive and fibrotic. Given their rarity, little is known about the safety and tolerability of antifibrotic nintedanib in combination with immunosuppression in AIM-ILD. Is the addition of nintedanib to immunosuppression safe and tolerable in patients with AIM-ILD, and does nintedanib administration induce peripheral blood cell gene expression changes? This was a single-arm, open-label trial to assess safety and tolerability of nintedanib with immunosuppression. Patients with progressive, fibrotic AIM-ILD on background immunosuppression were given nintedanib for 24 weeks. The primary end point was the percentage of patients who took ≥ 90% study drug doses. The secondary end points included safety (adverse events) and efficacy (lung function) outcomes. Bulk RNA sequencing of peripheral blood was performed at baseline and each subsequent visit to examine gene expression. A total of 11 participants were enrolled; of these, 9 completed the study visits as per protocol. The trial was discontinued due to slow recruitment. Three participants (27%) took ≥ 90% doses of nintedanib. Drug compliance ranged from 27% to 95%. The most common adverse events were diarrhea, nausea/vomiting, and abdominal pain. There were no overall significant changes in lung function, or difference in gene expression in peripheral blood over time identified. Tolerability of combined nintedanib and immunosuppression in AIM-ILD appears challenging. Nintedanib treatment did not induce measurable gene expression changes in peripheral blood. However, the study's small sample size, compounded by recruitment difficulties leading to early discontinuation, restricts the robustness and generalizability of the findings. ClinicalTrials.gov; No.: NCT05335278; URL: www.clinicaltrials.gov.

Apis dorsata and Vespa sp. venoms represent underexplored Hymenopteran bioresources with potential chemical and peptide diversity relevant to antimicrobial, cytoregulatory, and enzyme-target discovery. This exploratory venomics study generated a molecular profile comprising 510 metabolite features and 118 peptides/proteins, including 29 curated metabolite annotations and seven venom-associated peptide/protein classes supported by spectral evidence, database matching, and literature-supported curation. Major metabolite classes included lipids, hydrocarbons, heterocyclic compounds, fatty acids, phenols, terpenoids, esters, and amino acid/peptide-related metabolites. Proteomic profiling identified melittin, apamin, phospholipase A2, hyaluronidase, lysozyme, chymotrypsin inhibitor, and Kazal-like proteins in A. dorsata, while comparative Vespa sp. proteomics revealed homology-supported PLA1/PLA2-like proteins, DPP4-like proteins, serpins, PNGase, and QPCT. Exploratory co-abundance mapping suggested possible relationships among antioxidant triterpenoids, immune-regulating enzymes, neuropeptides, and lipid-associated venom components. Docking indicated preliminary interactions of vorinostat with Histone Deacetylase (HDAC) and adipostatin derivatives with Fatty Acid Synthase (FASN). Overall, this study prioritizes putative bioactive metabolites, venom-associated proteins, and predicted peptide candidates for future biochemical and functional validation.