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At least 19 recordsLinked to original sources
PubMed2025

Genomic mechanism of aroma terpenoids biosynthesis in plants.

BACKGROUND: Aroma terpenoids are crucial plant secondary metabolites with physiological and commercial importance. Interestingly, both closely and distantly related species can synthesize identical aroma terpenoids. With the development of genome sequencing technology, it has become possible to elucidate the genomic mechanism underlying this phenomenon. AIM: This review highlights whole-genome data as a robust strategy for investigating the genomic mechanism of aroma terpenoids biosynthesis in plants, and provides new perspectives on the origin, evolution, and engineering of terpene synthases (TPSs). This aims to significantly benefit plant breeding and enhance suitability for industrial production. KEY SCIENTIFIC CONCEPTS OF REVIEW: Genomic mechanism of aroma terpenoids biosynthesis in plant genomes is the genetic and evolutionary dynamics. We elaborate the genomic mechanism governing the biosynthesis of plant-derived aroma terpenoids in three dimensions: (1) Genome-wide identification and phylogenetic analyses of TPSs. The same aroma terpenoids were produced by numerous plant species with chromosome-level genomes. Based on 34 plant genomes, we identified 1643 TPSs and classified them into seven subfamilies. (2) Functional and structural basis of TPSs. We found that TPSs with identical functions in distant species exhibit low sequence similarity but conserved active cavity architectures. Conversely, functionally distinct TPSs in closely related species cluster phylogenetically but differ in active cavity structures. (3) Patterns of TPS gene origination. Comparative genomic analyses within and between species revealed three patterns enabling TPSs to acquire the same functions: tandem duplications, dispersed duplications, and genes without duplication.

Terpenes↗
PubMed2026

Architectural logic of the 3D genome: mechanisms of dysregulation and emerging cancer therapeutics.

The three-dimensional (3D) genome provides an essential layer of organization that shapes genome function in space and time. Chromatin compartments and topologically associating domains (TADs) arise from the interplay between intrinsic properties of chromatin and architectural factors, including cohesin and CTCF. Despite substantial progress in defining these structural features, whether 3D genome architecture plays a causal role in regulating processes such as transcription, DNA replication, and DNA repair, or instead reflects underlying regulatory activity, remains unresolved. Here, we use the distinction between chromatin-intrinsic features and architectural factors as a framework to evaluate evidence for causality in genome structure-function relationships. We extend this framework to cancer, where both intrinsic alterations (including noncoding mutations, structural variants, and changes in chromatin state) and architectural factor perturbations (such as mutations in architectural proteins and dysregulation of transcriptional machinery) disrupt genome organization and contribute to disease progression. These findings suggest that alterations in genome structure can, in some contexts, actively reshape oncogenic programs. A major limitation in applying 3D genome insights to cancer biology is the cost and complexity of omics assays. Recent advances in artificial intelligence (AI) and machine learning (ML) enable inference and prediction of 3D genome organization from sequence and epigenomic features, providing insight into the extent to which genome folding is encoded intrinsically versus dynamically regulated in architectural factors. This perspective provides a unified view of how genome structure is established, how it relates to function, and how its disruption contributes to tumorigenesis.

3D genome↗
PubMed2026

Molecular and Genomic Mechanisms Linking Diabetes Mellitus and Periodontitis: From Pathogenesis to Translational Opportunities.

Diabetes mellitus and periodontitis are bidirectionally associated chronic disorders linked through metabolic dysregulation, host inflammation, microbial dysbiosis, and impaired tissue remodeling. This review summarizes clinical, molecular, cellular, genomic, epigenomic, transcriptomic, and microbial evidence concerning the mechanisms underlying this relationship and their potential translational relevance. Chronic hyperglycemia is associated with advanced glycation end product signaling through the receptor for advanced glycation end products, mitogen-activated protein kinase/nuclear factor-κB activation, reactive oxygen species production, oxidative stress, and NLR family pyrin domain-containing 3 inflammasome activation, which may contribute to enhanced cytokine responses and periodontal tissue injury. Diabetes is also associated with altered neutrophil and macrophage function, increased T helper 17/interleukin-17 signaling, and an elevated receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio, thereby favoring osteoclastogenesis and alveolar bone loss. Conversely, periodontal inflammation and microbial products may contribute to systemic low-grade inflammation, insulin resistance, and metabolic dysregulation. Multi-omics studies have identified shared susceptibility loci, regulatory networks, and disease-associated cell states, although their causal and clinical significance remains incompletely defined. These findings suggest potential roles for integrated medical-dental care, glycemic screening in dental settings, periodontal inflammation control, host-modulatory therapies, and regenerative biomaterials. Further longitudinal and experimental studies are needed to determine their clinical applicability.

Humans↗
PubMed1978

[Mechanism of genome inactivation in avian erythrocytes. IV. New data on the mechanisms of cytodifferentiation in erythropoiesis].

In was shown earlier (Gazaryan & Kulminskaya, 1975; Kulminskaya & Gazaryan, 1976) that under the conditions of anemia a new (reserve) mechanism of the terminal differentiation of erythroid cells was induced. It was now found that in the course of cell development along this path the basophylic erythroblasts doubled the amount of DNA passed in the peripheral blood where they transformed into basophylic, polychromatophylic and orthochromic reticulocytes. Thereafter they entered the mitosis and transformed into the mature erythrocytes with diploid nuclei. It was shown for the first time that the cell delayed in the G2 phase could actively accumulate the specific product (hemoglobin) and keep its ability to enter the mitotic division.

Animals↗
PubMed2025

Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.

Ferroptosis↗
PubMed2026

Maternal age as a driver of genome instability: mechanisms linking aneuploidy, mutagenesis and mitochondrial dysfunction.

Advanced maternal age is a well-established risk factor for adverse reproductive outcomes due to increased rates of aneuploidy. However, emerging evidence indicates that the genetic consequences of maternal aging extend well beyond chromosome mis-segregation. Aging oocytes acquire a broad spectrum of genetic abnormalities, including maternally derived nuclear de novo mutations (DNMs) and mitochondrial DNA mutations, together with epigenetic dysregulation of DNA methylation and post-translational modification levels. These changes reflect the unique biology of the female germline in which oocytes remain arrested in meiotic prophase I for decades. Age-related deterioration of key processes, such as erosion of cohesion complexes, altered meiotic recombination, and weakened spindle assembly checkpoint surveillance collectively destabilize meiotic chromosome architecture, directly driving chromosome mis-segregation. At the same time, accumulation of endogenous DNA damage and declining DNA damage and repair processes increase the chances of transmitting lesions that can be converted into sequence-level mutations during the earliest embryonic divisions, when genome maintenance relies exclusively on maternal factors. High-resolution sequencing studies further demonstrate that maternal aging is associated with increased DNMs burden in both nuclear and mitochondrial DNA. Together, these findings support a model in which maternal aging is a driver of genome-wide instability that links aneuploidy and mutagenesis through shared defects in meiotic surveillance, declining DNA repair efficiency, and mitochondrial function. This framework positions delayed childbearing as a multifaceted genetic risk factor that extend beyond aneuploidy to include mutations and other genomic alterations that can impact intergenerational genetic risk.

Aneuploidy↗
PubMed2026

Landscape of acquired resistance alterations in gastrointestinal malignancies after genomically targeted therapy.

BACKGROUND: Targeted therapies directed at specific genomic alterations have transformed the management of gastrointestinal (GI) cancers; however, acquired resistance remains inevitable. Circulating tumor DNA (ctDNA) analysis via liquid biopsy provides a non-invasive approach to characterize genomic mechanisms of resistance. We therefore evaluated patterns of acquired genomic resistance in patients with GI cancers treated with targeted therapies. METHODS: Patients with GI cancers treated with standard of care or investigational therapies targeting EGFR, HER2, FGFR, MET, KRAS, BRAF for at least 60 days who underwent both baseline comprehensive genomic profiling and post-progression ctDNA sequencing were retrospectively evaluated. RESULTS: Of 106 patients meeting inclusion criteria, 45 had biliary tract cancer (BTC), 42 colorectal cancer (CRC), and 19 other GI malignancies. At least one putative resistance-associated alteration was detected in ctDNA in 53% of cases. Resistance patterns were heterogeneous with 47% showing no detectable alterations and 33% harboring ≥2 resistance alterations. Among 164 total alterations, the majority were single nucleotide variants (82%), followed by amplifications (17%). Overall, 48% were classified as 'bypass' alterations-activating alternative oncogenic pathways, most commonly MAPK signaling-while 52% were 'on-target' alterations involving secondary changes within the drug target. RAS alterations represented a key mechanism of bypass resistance, accounting for 28% of all resistance alterations. Interestingly, in CRC, bypass alterations predominated (69%), whereas in BTCs, on-target alterations were more frequent (61%). CONCLUSIONS: Liquid biopsies frequently identify acquired resistance following targeted therapy across GI cancers, often revealing multiple concurrent alterations. Patterns of resistance varied by tumor type, with both on-target and bypass mechanisms observed. These findings highlight common themes of resistance and support the growing clinical role of ctDNA analysis in defining resistance and guiding management in GI malignancies.

Gastrointestinal malignancies↗
PubMed2026

Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.

In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.

AAV↗
PubMed2026

Thyroxine enhances breast cancer cell survival and proliferation via TRβ1-Dependent PI3K/AKT signaling.

Thyroid hormones (TH) influence tumor biology through both genomic and non-genomic mechanisms. Specifically, thyroxine (T4) activates signaling pathways linked to cancer progression through interactions with nuclear receptors, such as TRβ1, and membrane receptors, including integrin αvβ3. Nevertheless, the precise role of T4 in breast cancer cell behavior and its underlying molecular mechanisms remain incompletely understood. The effects of physiological concentrations of T4 (10-9 M) on proliferation, cell viability, apoptotic signaling, and activation of intracellular pathways were evaluated in human mammary cell lines. Tumor cell lines (MCF-7 and MDA-MB-231) and the non-tumor mammary epithelial cell line MCF-10A were treated with T4 alone or in combination with the thyroid hormone receptor antagonist 1-850. Cell proliferation was measured using the MTT assay, and viability was determined by trypan blue exclusion. Protein expression and signaling pathways were analyzed by Western blot, including assessment of apoptotic markers (caspases, PARP, Bax, Bcl-2), PCNA, steroid hormone receptors, and signaling mediators such as PI3K, AKT, and ERK. Immunocytochemistry was used to evaluate TRβ1, integrin αvβ3, and Ki67 expression. T4 treatment increased proliferation and survival in hormone-sensitive tumor cells, accompanied by modulation of apoptosis-related proteins and activation of the PI3K/AKT pathway. The antagonist 1-850 selectively attenuated TRβ1-dependent effects, enabling distinction between genomic and integrin-mediated mechanisms. These effects were observed exclusively in hormone-sensitive tumor cells. These findings support a role for T4 in breast cancer progression and identify TH-related signaling pathways as potential therapeutic targets.

Apoptosis↗
PubMed2024

Repeated evolution on oceanic islands: comparative genomics reveals species-specific processes in birds.

Understanding the interplay between genetic drift, natural selection, gene flow, and demographic history in driving phenotypic and genomic differentiation of insular populations can help us gain insight into the speciation process. Comparing patterns across different insular taxa subjected to similar selective pressures upon colonizing oceanic islands provides the opportunity to study repeated evolution and identify shared patterns in their genomic landscapes of differentiation. We selected four species of passerine birds (Common Chaffinch Fringilla coelebs/canariensis, Red-billed Chough Pyrrhocorax pyrrhocorax, House Finch  Haemorhous mexicanus and Dark-eyed/island Junco Junco hyemalis/insularis) that have both mainland and insular populations. Changes in body size between island and mainland populations were consistent with the island rule. For each species, we sequenced whole genomes from mainland and insular individuals to infer their demographic history, characterize their genomic differentiation, and identify the factors shaping them. We estimated the relative (Fst) and absolute (dxy) differentiation, nucleotide diversity (π), Tajima's D, gene density and recombination rate. We also searched for selective sweeps and chromosomal inversions along the genome. All species shared a marked reduction in effective population size (Ne) upon island colonization. We found diverse patterns of differentiated genomic regions relative to the genome average in all four species, suggesting the role of selection in island-mainland differentiation, yet the lack of congruence in the location of these regions indicates that each species evolved differently in insular environments. Our results suggest that the genomic mechanisms involved in the divergence upon island colonization-such as chromosomal inversions, and historical factors like recurrent selection-differ in each species, despite the highly conserved structure of avian genomes and the similar selective factors involved. These differences are likely influenced by factors such as genetic drift, the polygenic nature of fitness traits and the action of case-specific selective pressures.

Animals↗
PubMed2026

In vitro fertilization-conceived offspring exhibit altered Long Interspersed Nuclear Elements-1 retrotransposition dynamics associated with long-term disease risks.

BACKGROUND: In vitro fertilization has transformed reproductive medicine, yet offspring conceived through in vitro fertilization display elevated risks for diverse long-term health conditions, with underlying mechanisms unclear. Long Interspersed Nuclear Elements-1, a mobile genetic element responsive to environmental stress, represents a potential mediator. OBJECTIVE: This study aimed to test the hypothesis that in vitro fertilization procedures may act as an embryonic stressor that alters Long Interspersed Nuclear Elements-1 dynamics, potentially contributing to genomic instability associated with long-term disease susceptibility. STUDY DESIGN: Umbilical cord blood or peripheral blood from 33 in vitro fertilization and 42 naturally conceived neonates were collected for whole-genome sequencing. Total Long Interspersed Nuclear Elements-1 proportion in individual genome was counted with Bowtie2 software. De novo Long Interspersed Nuclear Elements-1 insertion and Long Interspersed Nuclear Elements-1 deletion were detected with Mobile Element Locator Tool. Three parent-matched in vitro fertilization-naturally conceived sibling pairs were included to control for genetic background. Disease association analysis was performed for genes within 500 kb of differential Long Interspersed Nuclear Elements-1 sites in The Database for Annotation, Visualization and Integrated Discovery (DAVID). Statistical analysis was performed using the R language. RESULTS: In vitro fertilization offspring demonstrate elevated global Long Interspersed Nuclear Elements-1 content compared to naturally conceived controls (P=.04). This finding was corroborated in 3 sibling pairs from identical genetic backgrounds, where in vitro fertilization-conceived children consistently exhibited higher Long Interspersed Nuclear Elements-1 levels than their naturally conceived siblings. Eleven genomic loci with differential Long Interspersed Nuclear Elements-1 insertion frequencies and 14 loci with differential Long Interspersed Nuclear Elements-1 deletion frequencies between in vitro fertilization offspring and naturally conceived controls were identified. Notably, these differential Long Interspersed Nuclear Elements-1 sites demonstrated significant enrichment near genes implicated in metabolic, cardiovascular, neuropsychiatric, and neoplastic diseases, conditions associated with in vitro fertilization conception. CONCLUSION: These findings provide preliminary evidence that in vitro fertilization conception is associated with increased Long Interspersed Nuclear Elements-1 content and altered genomic distribution of Long Interspersed Nuclear Elements-1 elements. The proximity of these differential Long Interspersed Nuclear Elements-1 sites to disease-associated genes suggests a plausible genomic mechanism linking in vitro fertilization-associated embryonic stress to elevated disease risk. This work provides valuable molecular insights that may inform the ongoing discussion about assisted reproductive technology safety and suggests that continued attention to genomic integrity in in vitro fertilization-conceived individuals would be beneficial.

Humans↗
PubMed2024

Antibiotic resistance genotype, phenotype, and clinical outcomes in patients with Gram-negative infections at Rabin Medical Center in Israel.

UNLABELLED: Antibiotic resistance is a major cause of morbidity and mortality. However, a better understanding of the relationship between bacterial genetic markers, phenotypic resistance, and clinical outcomes is needed. We performed whole-genome sequencing on five medically important pathogens (Acinetobacter baumannii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) to investigate how resistance genes impact patient outcomes. A total of 168 isolates from 162 patients with Gram-negative infections admitted to Beilinson Hospital at Rabin Medical Center in Israel were included for final analysis. Genomes were analyzed for resistance determinants and correlated with microbiologic and clinical data. Thirty-day mortality from time of culture was 26.5% (43/162). Twenty-nine patients had carbapenem-resistant isolates (29/168, 17.2%), while 63 patients had multidrug-resistant isolates (63/168, 37.5%). Albumin levels were inversely associated with mortality and length of stay, while arrival from a healthcare facility and cancer chemotherapy predicted having a multidrug-resistant isolate. Sequencing revealed possible patient-to-patient transmission events. blaCTX-M-15 was associated with multidrug-resistance in E. coli (OR = 3.888, P = 0.023) on multivariate analysis. Increased blaOXA-72 copy number was associated with carbapenem-resistance in A. baumannii (P = 0.003) and meropenem minimum inhibitory concentration (P = 0.005), yet carbapenem-resistant isolates retained sensitivity to cefiderocol and sulbactam-durlobactam. RJX84154 was associated with multidrug-resistance across all pathogens (P = 0.0018) and in E. coli (P = 0.0024). Low albumin levels were associated with mortality and length of stay in this sample population. blaCTX-M-15 was correlated with multidrug-resistance in E. coli, and blaOXA-72 depth predicted meropenem minimum inhibitory concentration in A. baumannii. RJX84154 may play a role in multidrug-resistance. IMPORTANCE: While there have been several studies that attempt to find clinical predictors of outcomes in patients hospitalized with bacterial infections, less has been done to combine clinical data with genomic mechanisms of antibiotic resistance. This study focused on a hospitalized patient population in Israel with infections due to medically important bacterial pathogens as a way to build a framework that would unite clinical data with both bacterial antibiotic susceptibility and genomic data. Merging both clinical and genomic data allowed us to find both bacterial and clinical factors that impact certain clinical outcomes. As genome sequencing of bacteria becomes both rapid and commonplace, near real-time monitoring of resistance determinants could help to optimize clinical care and potentially improve outcomes in these patients.

Humans↗
PubMed2024

Relaxin Modulates the Genomic Actions and Biological Effects of Estrogen in the Myometrium.

Estradiol (E2) and relaxin (Rln) are steroid and polypeptide hormones, respectively, with important roles in the female reproductive tract, including myometrium. Some actions of Rln, which are mediated by its membrane receptor RXFP1, require or are augmented by E2 signaling through its cognate nuclear steroid receptor, estrogen receptor alpha (ERα). In contrast, other actions of Rln act in opposition to the effects of E2. Here we explored the molecular and genomic mechanisms that underlie the functional interplay between E2 and Rln in the myometrium. We used both ovariectomized female mice and immortalized human myometrial cells expressing wild-type or mutant ERα (hTERT-HM-ERα cells). Our results indicate that Rln modulates the genomic actions and biological effects of estrogen in the myometrium and myometrial cells by reducing phosphorylation of ERα on serine 118 (S118), as well as by reducing the E2-dependent binding of ERα across the genome. These effects were associated with changes in the hormone-regulated transcriptome, including a decrease in the E2-dependent expression of some genes and enhanced expression of others. The inhibitory effects of Rln cotreatment on the E2-dependent phosphorylation of ERα required the nuclear dual-specificity phosphatases DUSP1 and DUSP5. Moreover, the inhibitory effects of Rln were reflected in a concomitant inhibition of the E2-dependent contraction of myometrial cells. Collectively, our results identify a pathway that integrates Rln/RXFP1 and E2/ERα signaling, resulting in a convergence of membrane and nuclear signaling pathways to control genomic and biological outcomes.

Female↗
PubMed2026

Genomic determinants of fluoroquinolone resistance in Escherichia coli in Nigeria: dominance of QRDR mutations and limited contribution of PMQR in a cross-sectional study.

BACKGROUND: Fluoroquinolone-resistant Escherichia coli is a major global clinical threat, particularly in low- and middle-income countries like Nigeria. However, the full genomic landscape, including the relative contributions of chromosomal mutations, plasmid-mediated resistance, and the role of high-risk clones, remains poorly characterized in this setting. This study aimed to define the genomic mechanisms, clonal distribution, and genotype-phenotype relationships of fluoroquinolone resistance in clinical E. coli isolates from Nigeria. METHODS: A cross-sectional study of 107 clinical E. coli isolates was conducted. Phenotypic susceptibility to ciprofloxacin and nalidixic acid was determined using VITEK 2 and broth microdilution. Whole-genome sequencing was performed, and analysis included detection of quinolone resistance determining region (QRDR) mutations (gyrA, parC, parE) and plasmid-mediated quinolone resistance (PMQR) genes, multilocus sequence typing (MLST), and phylogenetic analysis. Statistical associations were evaluated using chi-squared tests or Fisher's exact tests. RESULTS: Ciprofloxacin non-susceptibility was high at 86.0%. Resistance was primarily driven by a conserved chromosomal mutation profile; the combination of gyrA S83L, gyrA D87N, and parC S80I was present in 85 isolates and was associated with ciprofloxacin non-susceptibility in all affected isolates in this cohort. Isolates with only gyrA mutations were resistant to nalidixic acid but susceptible to ciprofloxacin, consistent with a stepwise resistance pathway. In this cohort, the triple QRDR signature (gyrA S83L + gyrA D87N/Y + parC S80I) was a perfect positive predictor of ciprofloxacin non-susceptibility (85/85; 100%). The ST131 lineage dominated, accounting for 21.5% of isolates and universally carrying the complete triple QRDR profile; notably, no ST131 isolate carried a PMQR determinant. Plasmid-mediated quinolone resistance (PMQR) genes were detected in 15.0% of isolates but were not independently associated with ciprofloxacin non-susceptibility in this cohort in the absence of concomitant QRDR mutations. Efflux pump genes were ubiquitous and non-predictive. Notably, six isolates, all from urine, were non-susceptible (R/I) despite lacking all known QRDR and PMQR determinants, pointing to uncharacterized mechanisms. In a multivariable logistic regression model that included ST131 status, PMQR carriage, and parE mutation status, ST131 was associated with ciprofloxacin non-susceptibility (adjusted OR 5.96, 95% CI 1.21-29.4, p = 0.028), whereas PMQR carriage was not (adjusted OR 0.94, 95% CI 0.18-4.85, p = 0.94). The triple QRDR signature was not included in this model because it perfectly predicted ciprofloxacin non-susceptibility in this cohort. Resistance patterns varied by clinical source, with the highest burden in bloodstream and wound infections. This stepwise hierarchy from first-step gyrA mutations to the classic triple QRDR profile is summarised in the graphical abstract, Fig. 1. CONCLUSIONS: Fluoroquinolone resistance in Nigerian clinical E. coli is predominantly driven by chromosomal QRDR mutations within successful clones like ST131. PMQR genes and efflux pumps appeared to play a supplementary role rather than being independent drivers of ciprofloxacin resistance in this cohort. These data support prioritising key QRDR mutations in genomic reporting and local stewardship decisions, while the QRDR-negative resistant urine isolates require further investigation.

Escherichia coli↗
PubMed2026

Cardiovascular Disease and Androgens: Clinical Trends, Potential Mechanisms, and Considerations for Engineering Solutions.

This review summarizes the current understanding of androgen physiology, relationships between androgens and cardiovascular (CV) diseases, and novel engineering approaches to study the effect of androgens on CV system. Testosterone (T), the primary sex hormone in biological males and a potent sex hormone in females, is the androgen of focus for this review. In the cardiovascular system, T signaling is seen through varying genomic and non-genomic mechanisms, which are further detailed in this review. Varying androgen levels in aging adults can significantly impact CVD outcomes, particularly for males. We also consider the implication of exogenous T treatment and androgen deprivation treatments on CVD. Furthermore, androgen-related trends in different CVD processes such as cardiac hypertrophy, congestive heart failure, atherosclerosis, calcific aortic valve disease, and aneurysms are explored. To that end, we present opportunities for novel tissue engineered approaches to discovering mechanisms and potential therapeutic pathways for androgen-related CV conditions.

Androgen deprivation↗
PubMed2026

Haplotype Blocks Are Associated With Rapid Local Adaptation to Environmental Shifts in Wild Barley.

Genomic mechanisms of local adaptation must be highly responsive in geographic regions where climate is changing rapidly. The Levant region is a critical biodiversity hotspot and the distribution edge for many species, including the wild ancestor of domesticated barley. This region is under an accelerated desertification process, thus enforcing a rapid genomic response to the projected environmental changes. To elucidate the genomic basis of rapid local adaptation, we studied wild barley populations using an ecological-genetic sampling design that decouples environmental variation from demographic background. We collected and sequenced 300 wild barley individuals and evaluated the phenotypes of 3600 progeny plants over 3 years. Our genomic analyses revealed that local adaptation is associated with clusters of candidate genes forming haplotype blocks. These clusters are enriched with environment and stress responsive genes, including flowering time regulators, drought and heat responsive genes. We identified six candidate adaptive haplotype blocks which span 1-8 Mbp and are distributed across chromosomes 1H, 2H, 4H and 5H, each segregating as two major haplotypes. Additionally, we integrated over 2600 occurrence records into ecological and evolutionary modelling to assess the genomic vulnerability of populations to projected future climates. Our study identifies candidate genomic regions and environmental drivers of local adaptation in wild barley and highlights the advantage of haplotype blocks architecture in orchestrating an efficient response to rapid environmental change. We highlight the ecological factors most strongly associated with the observed evolutionary responses and provide insights and guidelines for biodiversity conservation and implementation of crop wild relatives in breeding.

Hordeum↗
PubMed2026

Tandem Double Inversion Resolves the Structural Paradox Underlying Recurrent KAT6A::NCOA2 Fusion in Acute Myeloid Leukemia.

The KAT6A::NCOA2 (formerly MOZ::TIF2) fusion is an extremely rare recurrent genetic abnormality in acute myeloid leukemia (AML), with only nine cases reported to date. It has consistently been associated with inv(8)(p11q13). However, the genomic mechanism underlying this fusion has remained unresolved. Because both KAT6A and NCOA2 are transcribed in the same reverse orientation on chromosome 8, a simple inversion is structurally insufficient to generate a transcriptionally competent fusion transcript, creating a long-standing cytogenetic paradox. We analyzed an AML case harboring a KAT6A::NCOA2 fusion using targeted genomic profiling and breakpoint-level validation. In addition to the canonical KAT6A::NCOA2 fusion, sequencing identified an unexpected MTFR1::KAT6A rearrangement. Since MTFR1 is located between KAT6A and NCOA2 on chromosome 8, we hypothesized a complex intrachromosomal rearrangement. Genomic breakpoint analysis revealed that the fusion was generated not by a single inv(8), but by two adjacent intrachromosomal inversions forming a tandem double inversion. This rearrangement reoriented genomic segments to place KAT6A and NCOA2 in a transcriptionally compatible configuration, enabling fusion formation. These findings resolve the structural paradox of KAT6A::NCOA2-positive AML by demonstrating that a cytogenetically apparent inv(8)(p11q13) can conceal a tandem double-inversion architecture that reorients KAT6A and NCOA2 into a transcriptionally compatible configuration.

Humans↗
PubMed2026

The Thyroid-Brain Network: Exploring Inflammation, Immune Mechanisms and Common Triggers in Thyroid-Related Neurological Dysfunction.

Autoimmune thyroid diseases (AITD), including Hashimoto's thyroiditis and Graves' disease, represent the most prevalent endocrine disorders worldwide, affecting hundreds of millions with profound but often under recognized neurological consequences. There are emerging lines of evidence establishing inflammation and immunity as the critical missing link connecting peripheral thyroid dysfunction to central nervous system manifestations. Thyroid hormones function as essential neuromodulators governing neurodevelopment, synaptic plasticity, and cognitive processing through integrated genomic and non-genomic mechanisms, with region-specific cerebral metabolic disturbances correlating with distinct neuropsychiatric symptoms. The immunological perspective reveals that AITD propagates neuroinflammation through convergent pathways: molecular mimicry enabling cross-reactivity between thyroid and neural antigens, cytokine-mediated disruption of neurotransmitter metabolism, HMGB1-driven glial activation, and blood-brain barrier compromise facilitating immune cell infiltration. The thyroid-gut-microbiota axis emerges as a critical mediator wherein dysbiosis perpetuates both thyroid autoimmunity and neuroinflammation through impaired serotonin precursor availability and increased intestinal permeability. Mitochondrial dysfunction represents an energetic common denominator, as thyroid hormone dysregulation directly impairs oxidative phosphorylation, producing region-specific cerebral metabolic disturbances. Simultaneous compromise of monoamine systems, cholinergic signaling abnormalities, and glutamate excitotoxicity creates a particularly toxic neurochemical state in untreated thyroid dysfunction. Common triggers such as psychological stress, gut dysbiosis, and mitochondrial impairment may activate interconnected pathways that simultaneously compromise thyroid and brain function, revealing that these disorders share fundamental mechanistic origins. These insights have been discussed in the current review to enhance the understanding of thyroid-brain function, the core mechanisms and consequences of functional deficits.

Journal Article↗