The genomic era revolution has significantly enhanced our understanding of hereditary cancer predisposition syndromes (HCPSs). However, despite the identification of pathogenic variants in cancer predisposition genes such as RB1, TP53, BRCA1, and BRCA2 and mismatch repair genes as the molecular explanations for familial clustering of specific cancer types, the biological basis behind the striking tissue preference for cancer development in these conditions remains unclear. Although the cancer spectra for each HCPS are widely recognized and routinely used to inform clinical strategies, most cancer predisposition genes are ubiquitously expressed and have DNA damage repair functions that would be expected to impact any tissue involved by loss (or gain, for oncogenes) of function. This narrative review aims to provide a comprehensive overview of the literature on the tissue specificity of HCPSs, integrating insights from molecular biology and epigenetics and discussing the evolving landscape of multi-omics. A structured literature search was conducted in PubMed (March 2023-September 2025) using predefined keywords related to tissue specificity and hereditary cancer, with additional screening of reference lists to identify relevant studies. While isolated mechanisms, including higher proliferation rates and organ-specific sequential patterns of mutation acquisition during carcinogenesis, have been proposed, the marked heterogeneity in tumor spectra across syndromes, together with their intrinsic complexity, suggest that no single mechanism is likely to fully explain tissue specificity. In support of this view, recent literature proposes that germline defects interact with the distinct epigenetic landscape of each cell type, which is inherently multifactorial. The epigenetic "hardwiring" prior to malignant transformation would include differential expression of genes that interact with the causal gene, and the presence of redundant compensatory pathways in unaffected organs. In parallel, the combined effects of inherited DNA repair defects and tissue-specific endogenous or exogenous genotoxic exposures, including hormone-mediated oxidative stress or ultraviolet radiation, further shape organ vulnerability. Experimental models reinforce the complexity, demonstrating that loss of tumor suppressor function is tolerated in certain cellular contexts but triggers cell death in others, suggesting that differential thresholds for genomic instability-induced apoptosis versus malignant transformation can delineate target tissues. Additionally, emerging evidence implicates microRNAs and regulatory variants in modifying cancer risk and organ tropism within hereditary syndromes. Collectively, the tissue specificity in HCPSs likely reflects the convergence of the germline defect with tissue-specific epigenetic architecture, regulatory networks, and environmental exposures, rather than a single causative mechanism. A better understanding of these factors could provide insights into tailored surveillance strategies and guide future research directions.

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases.

The significant temperature variations across northern and southern China have driven the adaptive evolution of Chinese native cattle breeds, allowing them to thrive in diverse and extreme bioclimate environments. Understanding how these breeds have adapted to varying temperatures is essential for identifying genetic factors that contribute to their survival in such conditions. In this study, using whole-genome sequence data of 336 individuals (with an average sequencing depth of 30.12 ×) from 21 cattle breeds, including 8 breeds from cold regions, 3 from warm regions, and 10 from hot regions, clear genetic differentiation among the three groups of breeds was revealed. Using whole-genome SNP, InDel, and SV data, a series of selective genomic regions, genes, and variants/SVs associated with cold or hot temperature adaptability were identified. Key genes, including KLB, HSPA4, ECSCR, DNAJC18 and SLC9A1 are speculated to be responsible for cold/hot adaptability based on the extreme difference in allele frequency of the selective variants/SVs harbored by these genes, their known biological functions, protein-protein interaction network, findings from previous studies on their relation to environmental adaptation, and their tissue specificities. By integrating SNP, InDel, and SV data, this study provides a comprehensive genetic framework for understanding selective environmental adaptation. These findings enhance our understanding of the mechanisms underlying temperature adaptation in cattle and offer a molecular foundation for the development of new breeds.

Push pin induced artifact: A mimic of iron pill injury in gastrointestinal pathology.

Standard treatment for locally advanced rectal cancer involves neoadjuvant chemoradiation therapy (nCRT) followed by total mesorectal excision, but this approach carries significant morbidity and often results in incomplete resections owing to poor intraoperative tumor visualization. For patients with complete response to nCRT, a watch-and-wait (W&W) strategy can spare surgery, but current imaging techniques inadequately identify complete responders, leading to regrowth in ~30% of cases. To improve nCRT response assessment and guide resections, we developed PH10, a topically applied, pH-activatable near-infrared (NIR) fluorescent probe for rapid, tumor-specific imaging. PH10, a small-molecule cyanine analog, was tested in murine models and on human tumor specimens (n = 11). Fluorescence activation, tumor specificity, and tumor-to-background ratio (TBR) were evaluated in vivo and ex vivo within clinically relevant timeframes. PH10 enabled rapid and specific tumor visualization, achieving a median TBR of 3.2 within 1 min in vivo in murine models and 2.2 within 10 min ex vivo on human samples. The probe demonstrated high specificity for tumor tissue within the acidic tumor microenvironment without requiring systemic administration or prolonged incubation. PH10 is a promising, fast-acting topical NIR agent for real-time tumor detection during colorectal cancer endoscopy and surgery. Its simplicity and rapid kinetics support potential clinical translation. Moreover, its pH-activatable mechanism may extend its utility to other solid cancers with acidic microenvironments.

Copper is an essential micronutrient required for mitochondrial respiration, antioxidant defense, and metabolic homeostasis. Accumulating evidence demonstrates that dysregulated copper handling, including deficiency, redistribution, or overload, is a reproducible feature of multiple cardiometabolic disorders, including heart failure, diabetes mellitus, obesity, and NAFLD/MASLD. Human, animal, and cellular studies consistently implicate altered copper trafficking and compartmentalization in mitochondrial dysfunction, oxidative stress, and tissue remodeling across these conditions. The recent identification of cuproptosis, a copper-dependent form of regulated cell death characterized by mitochondrial copper binding to lipoylated tricarboxylic acid cycle enzymes, has expanded mechanistic understanding of copper toxicity in cancer. However, the defining molecular hallmarks of canonical cuproptosis, including lipoylated protein aggregation, iron-sulfur cluster loss, and respiration-dependent cell death, have not yet been demonstrated in vivo in cardiometabolic tissues. Accordingly, cuproptosis is discussed here as a testable mechanistic hypothesis rather than an established driver of cardiometabolic pathology. In this review, we synthesize current evidence for copper dysregulation in cardiometabolic disease and carefully distinguish established copper-dependent pathology from speculative cuproptotic mechanisms. We explicitly address the apparent paradox that the cardiac tissue context in cardiometabolic disease is dominated by a copper-deficient phenotype, which is the opposite of the mitochondrial copper-loading state required for canonical cuproptosis, and reconcile this through the concept of intracellular copper redistribution and tissue-selective susceptibility. We evaluate clinical and preclinical studies of copper-modulating therapies with attention to tissue specificity and safety, and we outline a framework for rigorously testing cuproptosis in vivo using convergent molecular, functional, and clinical criteria. Together, this review clarifies what is known about copper biology in metabolic disease and defines the experimental standards required to determine whether cuproptosis contributes to these conditions.

Establishment of a high-efficiency transient expression system for subcellular localization studies in plants based on vacuum-assisted Agrobacterium infiltration.

Development and validation of an LC-MS method for quantification of sex steroid hormones in skeletal muscle.

Amino acid substitutions may substantially alter protein stability and function1,2. However, the contribution of substitutions that arise from alternate translation (deviations from the genetic code) is unknown. Here to address this issue, we analysed deep proteomic, transcriptomic and genomic data from more than 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,803 fragmentation spectra corresponding to 8,746 unique substitutions in proteins derived from 1,767 genes, including 1,955 confidently localized sites. Some substitutions were shared across samples, whereas others exhibited strong tissue-type and cancer specificity. Notably, products of alternate translation were more abundant than their canonical counterparts for hundreds of proteins, which suggests that there is sense-codon recoding. Recoded proteins included transcription factors, proteases, signalling proteins and proteins associated with neurodegeneration. Mechanisms that contribute to substitution abundance included protein stability, codon frequency, codon-anticodon mismatches and RNA modifications. We also characterized how alternatively translated proteoform ratios vary across protein domains, tissue types and cancers. These ratios were positively associated with intrinsically disordered regions and genetic polymorphisms in the gnomAD database, although the polymorphisms could not account for the substitutions. The sequence, relative abundance and the tissue specificity of alternatively translated proteins were conserved between humans and mice. These results demonstrate the contribution of alternate translation to the diversification of mammalian proteomes and its association with protein stability, tissue-specific proteomes and disease.

Vascular plants (tracheophytes) rely on specialized tissues, xylem and phloem, for structural support, nutrient transport, and physiological adaptation. Understanding the structural and functional properties of these vascular tissues is essential for elucidating plant development and stress responses. Traditional staining methods, which utilize both fluorescent and non-fluorescent dyes, have been employed to visualize xylem and phloem; however, their limited specificity and sensitivity restrict detailed analysis. To overcome these limitations, we synthesized novel cationic pyridinium derivatives with enhanced sensitivity-enabled by intramolecular charge transfer-and high specificity for xylem tissues across diverse plant species. Comparative staining with traditional dyes such as propidium iodide, berberine, basic fuchsin, and rhodamine confirmed the superior sensitivity of these derivatives, while tissue-specific assays demonstrated strong xylem selectivity with minimal background noise across diverse plant species. Furthermore, staining of the Arabidopsis eskimo1 mutant with a collapsed xylem vessel phenotype indicated the utility of these derivatives in developmental biology studies. Our study presents a faster, specific, and highly sensitive staining method using pyridinium derivatives, offering a powerful tool for advancing research on xylem biology.

High-latitude populations represent valuable case studies to investigate the genetic bases of human biological adaptations to cold climates. Nevertheless, by relying on traditional natural selection models, a limited fraction of them was identified. To overcome this issue, we integrate diverse inferential methods in the attempt to pinpoint combinations of genes presenting both selection signatures and functional relationships supporting their synergic role in regulating a biological trait, as expected under polygenic adaptation. We analyze Yakut genomes from Northeastern Siberia and Russian ones, pointing to adaptive evolution at genes contributing to functions modulated during cold exposure, such as thyroid hormone/insulin signalling (THRB, RCAN2, INSR, NFKB1), brown adipose tissue differentiation (ERBB4) and glycerolipid metabolism (GPAT3). Concerted changes at these loci may support enhanced heat production and responsiveness to insulin, having been partly influenced also by Neanderthal introgression, and provide suggestive insights into the complex adaptations that enabled Eurasians' ancestors to colonize cold environments.

Oral cancer is a significant global health challenge, ranking as the sixth most prevalent cancer worldwide, with approximately 377,000 new cases diagnosed annually. The high morbidity and mortality rates are largely attributed to tobacco and alcohol use. While conventional treatments such as surgery, radiation, and chemotherapy have improved survival rates, they often lead to unfavourable aesthetic and functional outcomes. Tissue engineering offers a promising alternative, providing regenerative solutions aimed at restoring both oral function and appearance. By integrating biomaterials, biological systems, and engineering principles, tissue engineering enables the creation of functional tissue replacements. The current review examines different t pathways the potential applications of autologous tissue, oral cancer cell lines, CRISPR, gene-editing technologies, and epigenetic modifications for tissue regeneration. Advanced scaffold technologies that mimic the natural extracellular matrix, along with stem cell-based therapies and bioactive molecules, are employed to support tissue growth and differentiation. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) show significant potential in regenerating hard and soft oral tissues, while also targeting cancer stem cells (CSCs) to prevent recurrence. Furthermore, innovative technologies like 3D bio printing, combined with vascularization strategies, hold promise for developing patient-specific tissue constructs for reconstructive procedures. In conclusion, tissue engineering offers transformative potential for oral cancer treatment, presenting regenerative therapies that can significantly enhance patient outcomes and quality of life.

Genetic and epigenetic predictors of antidepressant response.

Targeted protein degradation (TPD) has emerged as a transformative paradigm in the biomedical research. Central to this field are Proteolysis-targeting chimeras (PROTACs), bifunctional molecules exhibiting immense therapeutic potential, particularly in oncology and autoimmune diseases. By recruiting target proteins to E3 ubiquitin ligases, PROTACs harness the ubiquitin-proteasome system (UPS) to induce protein degradation. This event-driven mechanism overcomes the "target occupancy-driven" limitations of conventional small-molecule inhibitors, offering novel avenues for tackling undruggable targets. Despite this promise, conventional PROTACs face significant translational challenges, including poor tissue specificity, off-target toxicity, and insufficient accumulation within the tumor microenvironment. Therefore, the development of on-demand activatable PROTAC prodrugs, capable of spatiotemporally precise protein degradation, has become a central research focus in this field. This review systematically summarizes the design principles and research progress of three major categories of activatable PROTACs: endogenously activatable PROTACs, exogenously photo-activatable PROTACs, and bioorthogonally activatable PROTACs. We also compare the merits and limitations of these strategies to foster a deeper understanding of the field and accelerate the clinical advancement of PROTAC-based therapeutics.

AGAMOUS (AG) is a C-class Mcm1, Agamous, Deficiens, and Serum response factor (MADS)-box transcription factor classically defined by its roles in specifying stamen and carpel identity and enforcing floral meristem determinacy. Accumulating evidence now indicates that AG also coordinates a series of late developmental programs whose outputs are rewired over time based on tissue context, chromatin state, and phytohormone-mediated inter-organ communication. In the gynoecium, AG promotes regional patterning and tissue differentiation by regulating downstream target genes, thereby supporting ovule- and fruit-related development while safeguarding epidermal fate by repressing ectopic leaf-like traits and inappropriate stomatal differentiation. In stamens, AG integrates epigenetic timing with plant hormonal signaling, where delayed activation of AG targets is associated with the gradual dilution of H3K27me3 marks, and AG-dependent induction of jasmonic acid biosynthesis supports filament elongation and anther progression. Notably, AG activity also extends beyond its expression domain by shaping perianth fate in a non-cell-autonomous manner: jasmonic acid produced in reproductive organs activates transcriptional and autophagy-related programs at the bases of petals, promoting senescence and abscission after anthesis. Together, these findings support a unified view of AG as a regulator of spatiotemporal systems that links the specification of organ identity to late morphogenesis, reproductive maturation, and coordinated organ disposal. This review summarizes recent advances in AG-mediated regulatory networks and highlights how dynamic, multilayered control enables AG to orchestrate late flower development across multiple organs.

Circulating extracellular vesicles as systemic mediators of cardiac aging: Mechanisms, biomarkers, and therapeutic perspectives.

Unraveling the role of miRNAs in placental function: insights into trophoblast biology and pregnancy pathology.

Drought and nitrogen (N) deposition significantly impact plant growth in northern regions. The balance between carbon (C) and N metabolism is crucial for plant adaptation to global environmental change. Salix gordejevii is widely distributed across the northern temperate zone and is characterized by rapid growth and high adaptability. However, the molecular mechanisms underlying its adaptation to drought and N deposition remain largely unclear. Sucrose non-fermenting 1-related protein kinases (SnRKs) represent a class of serine/threonine protein kinases that are extensively involved in plant C and N metabolism, as well as in responses to abiotic stress. We hypothesised that the SnRK gene family was essential for willow adaptation to drought and N deposition, with its evolutionary and structural features being closely linked to its stress-responsive expression patterns. A total of 43 SpSnRK genes were identified and classified into three subfamilies: SpSnRK1 (2 members), SpSnRK2 (11 members), and SpSnRK3 (30 members). These genes exhibited an uneven distribution across the genome. Among them, 37 genes contained both coding and non-coding regions, while 6 consisted solely of coding regions. Most SpSnRK proteins were predicted to localize in the cytoplasm. The promoters of SpSnRK genes were found to be enriched with numerous stress- and hormone-responsive cis-acting elements. Furthermore, the SnRK genes expression profiles in leaves and roots were analyzed under four treatments (control, drought, N deposition, and a combination of drought and N deposition). The expression profile analysis revealed that, under drought stress or N deposition, a greater number of responsive SgSnRK genes were detected in the roots. However, under the combined conditions of drought and N deposition, the number of responsive SgSnRK genes increased significantly in the leaves. The SnRK gene family in willow consisted of three subfamilies that exhibit structural differences and were unevenly distributed across the chromosomes. These genes played critical roles in multiple stress signaling pathways. Furthermore, their expression in response to drought and N deposition showed tissue specificity and varies according to the mode of stress combination.These findings provide a basis for further exploration of the molecular mechanisms underlying SnRK-associated abiotic stress responses.

Epithelial-to-mesenchymal transitions (EMT) require extensive cytoskeletal remodeling to enable changes in cell polarity, adhesion, and migration. Although transcriptional programs controlling EMT are well characterized, how microtubule composition is developmentally regulated during cell state transitions remains poorly understood. Here we establish a spatially resolved resource delineating the expression of α- and β-tubulin isotypes during neural crest (NC) EMT and tissue differentiation in the chick embryo. Integration of publicly available single-cell RNA sequencing datasets reveals diverse patterns of tubulin gene expression, ranging from broadly expressed isotypes (TUBA1A, TUBA1B) to more cell-type-restricted transcripts (TUBAL3, TUBB4B). Several tubulin genes, including TUBB3, TUBA3E, and TUBG1, are enriched within NC and NC-associated cell types. Using fluorescent in situ hybridization chain reaction (HCR) to spatiotemporally characterize transcripts encoding selected tubulin isotypes, we validate these patterns and map their expression across developmental stages. These transcript patterns provide a map of tubulin gene expression, but further studies are needed to determine how they relate to microtubule composition. We further identify expression of the microtubule motor genes KIF11 and DYNC1LI1, revealing overlapping expression patterns between tubulin and motor-associated genes during EMT. Together, these data define a cell state-resolved atlas of tubulin gene expression during vertebrate EMT.

Transcriptional regulatory elements (TREs) orchestrate gene expression programs fundamental to cellular identity and transitions across physiological and pathological states. Here, we present a high-resolution atlas of RNA Polymerase II-engaged TREs (enhancers and promoters) across all major human organ systems and a broad spectrum of developmental and disease states. This atlas is generated using PRO-cap, a highly sensitive method that detects nascent RNA at transcription initiation sites, a critical feature of active TREs. The base-pair resolution of PRO-cap enables systematic dissection of transcription initiation architecture, revealing associations among tissue specificity, evolutionary constraint, transcription factor usage, and regulatory connectivity. Integration with deep learning models such as ProCapNet further provides a framework for prioritizing noncoding variants from GWAS and eQTL studies. Moreover, this tissue-resolved atlas identifies lineage-specific regulatory programs and their alterations in diseases such as metastatic cancer, where TRE landscapes capture regulatory signatures reflecting both tissue of origin and adaptive responses to distant niches. Together, these findings establish transcription initiation at regulatory elements as a defining and mechanistically informative layer of gene regulation across development, physiology, and disease.