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Minor or genetically isolated populations like Turkish-Cypriots (TC) are usually challenging to diagnose and treat for uncommon genetic diseases. TC may exhibit several patterns of unusual genetic disorders based on their unique historical and demographic conditions. The objective of the current study is to identify and investigate the rarest genetic disorders in TC patients. Therefore, between 2019 and 2025, clinical and genetic data, which were confirmed by gene panels and exome sequencing, from 150 TC patients were retrospectively analysed in our clinic. Also, inheritance models and variant types were classified and contrasted. Out of 150 patients, 123 different rare diseases were discovered. Observed in 10 cases (6.7%), neurofibromatosis (type 1) was the most common of these, trailed by spinal muscular atrophy in 6 cases (4%), phenylketonuria in 6 cases (4%), and episodic kinesigenic dyskinesia type 1 in 4 cases (2.7%). Importantly, 114 of the discovered diseases (76%) were observed in only one patient, indicating a vast spectrum of ultrarare or single-case conditions within the group. Autosomal dominant was the most prevalent mode of inheritance; other types also present were autosomal recessive and mitochondrial inheritance. The recurrence of particular gene pathogenic variants in a group of patients may suggest a potential founder effect; however, further population-based haplotype studies are required to confirm this hypothesis within the TC population. The results demonstrate an overrepresentation of particular neurogenetic syndromes and underline the necessity of targeted screening procedures and population-dependent databases to maximise diagnostic yield and genetic counselling in this poorly characterised population.

In various tumor types, cell division cycle-associated 7 (CDCA7) is involved in chromatin remodeling and DNA methylation. However, its biological functions and regulatory mechanisms in gastric cancer (GC) remain unknown. This investigation intended to identify the function of CDCA7 in GC progression and elucidate its epigenetic regulatory mechanisms. Differentially expressed genes (DEGs) were detected from the GSE19826, TCGA-GC, and GSE56807 datasets. Networks of protein-protein interactions (PPI) and hub genes were discovered by the DMNC and Clustering Coefficient algorithms. Receiver operating characteristic (ROC) analysis and expression profiling were undertaken to determine diagnostic performance. In vitro assays, including CCK-8 assays, clonogenic assays, flow cytometry, dot blots, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Western blots, were applied to evaluate the role of CDCA7 and its interaction with helicase, lymphoid-specific (HELLS). 169 overlapping genes were discovered, enriched in Cell adhesion molecules and ECM-receptor interaction. CDCA7 is highly expressed in GC and has high clinical diagnostic value. Knockdown of CDCA7 causes apoptosis and suppresses GC cell invasion, migration, and proliferation. Mechanistically, CDCA7 physically interacts with HELLS and promotes HELLS recruitment to chromatin. Knockdown of CDCA7 reduces global 5 hmC/5 mC levels and histone methylation (H3K9me3 and H4K20me3), while HELLS overexpression partially reverses these effects. Functionally, HELLS overexpression also partially reverses the antiproliferative and proapoptotic effects of CDCA7 knockdown. CDCA7 promotes GC progression by interacting with HELLS to regulate DNA methylation and chromatin stability, suggesting that the CDCA7-HELLS axis may serve as a potential diagnostic biomarker and therapeutic target for GC.

Endometriosis-associated ovarian cancer (EAOC) is a rare subtype of ovarian cancer arising from the malignant transformation of endometriosis (EMS). Despite growing clinical awareness, its underlying pathogenic mechanisms are not fully understood. Epithelial-mesenchymal transition (EMT) plays a crucial role in the progression of various diseases, but the specific EMT changes in EAOC formation remain unclear. We retrieved transcriptomic data for EAOC and single-cell data for EMS from public databases and systematically analyzed EMT levels, EMT subtypes, and factors inducing EMT in both EMS and EAOC. Immunohistochemistry and Masson staining further validated the EMT and fibrosis levels in both EMS and EAOC. The study found that the overall EMT levels in EAOC were significantly lower than in EMS, primarily due to the reduction in type 2 EMT levels associated with fibrosis. Furthermore, this study indicated that the abundant C7 fibroblasts in EMS lesions might contribute to epithelial cell proliferation and EMT. However, the abundance of C7 fibroblasts was significantly reduced in EAOC, suggesting its potential regulatory role in EMT. We found that, during the progression from EMS to EAOC, the level of type 2 EMT decreased, and we also discovered that C7 fibroblasts could act as potential regulators of EMT. These findings expand our understanding of the malignant transformation of EAOC and provide new insights for the development of new diagnostic and therapeutic strategies.

We discovered a thiolate-reactive α,α-gem-dibromo lactam warhead that activates transcription factor Nrf2 and demonstrates anti-inflammatory activities, which have implications in cancer, neurodegeneration, and cardiovascular diseases. Our findings originated from new compounds accessed through aza-oxyallyl cation-mediated [3+2]-cycloadditions of ajmalicine and inspired indoles. RNA-seq and Ingenuity Pathway Analysis illuminated detailed transcriptional profiles of α,α-gem-dibromo lactams to show activation of the antioxidant Keap1/Nrf2 pathway and suppressed NF-κB-mediated inflammatory signaling. We demonstrated the importance of the α,α-gem-dibromo lactam, as the corresponding α,α-gem-dichloro lactam is unable to activate the Nrf2 pathway. Chemical reactions with cysteine-containing compounds suggested α,α-gem-dibromo lactams react with cysteine residues to transfer electrophilic bromine to target molecules, linking unique chemistry to our biological findings. In contrast to electrophiles that activate the canonical Nrf2 pathway by covalently targeting C151 of Keap1, the α,α-gem-dibromo lactams function in a C151-independent manner, indicating a distinct selectivity and consequently mode of action. Pharmacological profiling of several α,α-gem-dibromo lactams compared with ajmalicine against adrenergic receptors revealed substantial differences, indicating tunability and novel pharmacology. Future investigations aim to explore the fundamental activities of the dibromo lactam warhead related to human disease. Installation of this warhead into various molecular scaffolds may be a generalizable method to create cystein-reactive electrophiles.

Survival is highly variable in amyotrophic lateral sclerosis (ALS), complicating prognosis and clinical trial design. Despite advances in biomarker development, accessible prognostic tools are limited. Small non-coding (snc) RNAs are a recently discovered biomarker class showing differential regulation across neurodegenerative diseases, including ALS. Here, we explored changes in sncRNAs over time in ALS. We performed small RNA sequencing in a discovery cohort of 116 longitudinal serum samples from ALS 40 patients collected at 3- to 4-month intervals and identified tRNA-derived stress-induced RNA (tiRNA) tDR-1:34-Gly-GCC as the top sncRNA to increase over time. The finding was validated using TaqMan PCR and replicated in an independent cohort of 35 patients. Both univariate and joint model analyses showed that higher tDR-1:34-Gly-GCC levels correlated with shorter survival. Given that the translation of mRNAs and stress-induced translation inhibition are dysregulated in ALS and linked to familial ALS genes, combined with these findings, serum tDR-1:34-Gly-GCC tiRNA levels hold potential as a prognostic biomarker and outcome measure in clinical trials.

Six new furancarboxylic acids, penidelanones A - F (1 - 6), along with one known analogue, (+)-gregatin B (7), were discovered from the endophytic fungus, Penicillium daleae. Penidelanone A (1) is the first reported furancarboxylic acid with an amide group. Their planar structures were determined by extensive spectroscopic data, and the absolute configurations were assigned by comparison of optical values.

Free-ranging domestic cats (Felis catus) are recognized as invasive and efficient predators on islands, although their impact on continental wildlife remains poorly understood. Predation behavior and space use are key indicators for estimating the influence of these felines on prey populations through direct killings and sublethal effects (landscape of fear). Previous work highlighted-and debated-the importance of biological (sex, age) and environmental (habitat type) factors as well as owner-related habits (feeding, play, hygiene) in shaping hunting and roaming behaviors. However, the influence of individual behavioral characteristics, known as personality, remains largely unexplored. In this study conducted in a suburban area south of Paris, we monitored 23 domestic cats using combined GPS and animal-borne camera devices (or "kittycams") between March and May 2025. Cat predation behavior was analyzed using a detailed ethogram, and space use was studied through two parameters: core range (aKDEc50) and full range (aKDEc95). Although additional data would certainly strengthen our conclusions, our results already reveal that personality affects both range size and hunting propensity. More precisely, cats with high levels of agreeableness and neuroticism have smaller range sizes and hunt less than other individuals. Moreover, animal-borne cameras are far more reliable than the prey-report method to assess predation events and prey diversity, as only one prey was discovered of the 31 caught in total. These results pave the way for tailored, effective, and ethical management measures to mitigate the impact of domestic cats on wildlife.

Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered that the secreted phospholipase PLA2G5 is induced in colon cell types during sepsis. The genetic deletion of Pla2g5 and treatment with a PLA2G5 antibody were both associated with protection from lethal sepsis. Treatment with a PLA2G5 antibody during sepsis was associated with increased splenic red pulp macrophages and improved iron homeostasis, linking PLA2G5 to red blood cell homeostasis during sepsis. Mechanistically, bloodborne PLA2G5 led to intravascular hemolysis through its lipolytic activity on red blood cell membranes. In humans with sepsis due to bacterial, fungal, or viral infections, the serum level of PLA2G5 was elevated and predictive of disease severity and mortality. We conclude that sepsis corrupts PLA2G5 into becoming an intravascular hemolytic factor which is toxic for host red blood cells.

Partially crystalline nodules are occasionally discovered within breccias linked to large ignimbrite-forming eruptions, providing evidence of the fragmentation of the plutonic reservoir and conduit system during such eruptions. These nodules offer valuable insights into the magmatic systems fuelling these highly explosive volcanoes. On Tenerife, crystal-rich samples containing interstitial melt are preserved in several Plinian eruption deposits spanning over ~ 1.8 million years, but the crustal architecture and interactions between magma reservoirs beneath the island remain poorly understood. This study focuses on explosively fragmented juvenile nodules from Tenerife's pyroclastic deposits, which provide snapshots of the mush reservoir preceding caldera-forming events. Petrological, major element and trace element analyses were conducted on juvenile nodules from five major caldera-forming eruptions: Caleta (221 ka), Fasnia (312 ka), San Juan (1.50 Ma), Morteros (~ 1.70 Ma), and Gaviotas (1.84 Ma). These nodules preserve a range of crystallisation stages within Tenerife's alkaline magmatic system, uniquely containing interstitial groundmass that existed in a supra-solidus state at the time of eruption, with an average melt content of ~ 25 vol%. Despite macro-mineralogical variability between eruptions, the juvenile nodules exhibit consistent basanite interstitial groundmass chemistry and lithologies, suggest that the mafic mush reservoir beneath Tenerife has remained both chemically and petrologically stable over ~ 1.8 million years. This study provides a new perspective on the stability of the mafic mush reservoir beneath Tenerife, highlighting its persistent role in the volcano's magmatic plumbing system. The chemical consistency of the mush contrasts with the episodic mobilisation and more chemically diverse evolved phonolite melts, underscoring the importance of understanding mid-crustal processes leading to explosive eruptions. These findings provide evidence for a long-lived, stable mush reservoir and a new perspective on the compositional makeup of the crystal-mush reservoirs at defined points in time, enhancing our temporal understanding of ocean island volcanoes and their crustal magma mush reservoirs. The online version contains supplementary material available at 10.1007/s00410-026-02302-3.

Pancreatic cystic lesions (PCLs) range from benign to malignant, creating diagnostic and therapeutic challenges. While most PCLs are serous or mucinous neoplasms, rare entities such as acinar cell cystadenoma (ACC) remain poorly characterized. This study reports a tertiary center cohort and a systematic literature review. We retrospectively analyzed 23 ACC patients at Karolinska University Hospital. A systematic review was performed following PRISMA guidelines. In our cohort (median age 67.0 years; 73.9% male), ACCs were most often incidentally detected, with abdominal pain being the most frequent indication for imaging. No patients underwent surgery, and no malignant transformation was observed during a median follow-up of 10.4 months. Most patients (87%) underwent both CT and MR imaging, and 65.2% fulfilled proposed imaging diagnostic criteria.The systematic review included 41 studies with 165 patients. Abdominal pain was the most common indication for imaging, and most patients underwent pancreatic surgery. Median follow-up was 1.3 years, with no malignant transformation observed. Imaging typically showed well-circumscribed cystic lesions, usually non-communicating with the main pancreatic duct and mimicking other cystic neoplasms. Histopathology consistently demonstrated an acinar phenotype with low proliferative activity. ACC appears to be an asymptomatic, incidentally discovered lesion, with imaging playing a central diagnostic role. Neither endocrine nor exocrine pancreatic insufficiency nor malignant transformation was observed. However, the relatively short overall follow-up limits conclusions regarding long-term outcomes.

Isolates of the E. coli O101 serogroup collected from bacteremia patients were demonstrated to harbor different glycoforms of the O-antigen polysaccharide. Investigation by high-resolution mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy of the O-antigen structure of the reference E. coli O101 strain H510a and of one naturally occurring variant (Onovel32) confirmed the previously reported simultaneous presence of O-polysaccharide repeat units made up of disaccharides PS1 and PS2. A newly discovered O101 glycoform was shown to be composed of the same backbones modified with a previously unrecognized structure having an additional terminal 4-O-methyl N-acetyl-galactosamine (4-O-Me-GalNAc) residue on the non-reducing end of the PS2 backbone. Another naturally occurring variant (Onovel32MT-) does not contain any PS2 repeat units, nor any 4-O-Me-GalNAc capping. Analyses indicated that the polysaccharide glycoforms from these three O101 strains varied in terms of their ratios of PS1 to PS2 repeat units and the amount of 4-O-Me-GalNAc terminal residue. From the Smith degradation data of the reference O101 strain and the Onovel32MT- variant, it is hypothesized that the PS1 and PS2 repeat units join into a PS1-PS2 block copolymer, which is formed by the addition of the PS2 backbone on the already existing PS1 core backbone. Finally, 4-O-Me-GalNAc acts as a terminal capping residue on the PS2 backbone. Such block copolymer structures have hitherto been reported in galactans of Klebsiella and in Brucella. To our knowledge, this is the first reported occurrence of such a block copolymer O-antigen in E. coli.

Pelviureteric junction obstruction (PUJO) is typically diagnosed through ultrasound and dynamic renal scintigraphy. This report describes a 5-year-old boy with right flank pain diagnosed as PUJO. Imaging revealed a narrowing at the pelvi-ureteric junction, and a subsequent diuretic renal scan indicated obstructed drainage. During surgery, a second narrowing due to congenital mid-ureteral stenosis was discovered, necessitating an excision of the obstructed ureter segment and pyeloplasty. This report highlights the rarity of Congenital Midureteral Stenosis (CMUS) and the challenges in diagnosing it, especially when it coexists with PUJO. Literature search revealed limited previous reports of this dual obstruction, stressing the importance of careful surgical evaluation in suspected cases of urinary obstruction.

Climate change-induced weather variability poses a growing threat to global food security, yet plant resilience is still interpreted through static and reductionist models that treat stress as independent and transient. Here, we introduce a unified quantitative framework grounded in dynamical systems theory. We formalize three novel metrics: (1) the Phenological Weather Memory Index (PWMI), that quantifies exponentially decaying stress memory across developmental stages (with a decay constant α = 0.10 determined by cross‑validation); (2) the Treatment-Weather Resonance Coefficient (TWRC), which measures the alignment of agronomic interventions with favorable weather conditions; and (3) the Physiological State-Space Trajectory (PSST), which maps multi-trait plant physiology into low dimensional attractor basins. Analyzing 288 tomato plants across 24 cultivars under hot, sub-tropical conditions (mean VPD: 2.53 kPa, 65 heat days > 35 °C), we discovered that stress memory is strongly phase-dependent, remaining minimal during vegetative growth (PWMI = 0.009) but increasing sharply during reproductive phase (PWMI = 0.574). Despite the prolonged thermal stress, 97.9% of plants converged into a stable high-yield attractor basin, revealing a fundamental nonlinearity in plant performance. This convergence was driven by dynamic recovery, defined as the capacity of certain cultivars to rapidly forget the stress memory while maintaining internal physiological flexibility. Cultivars such as 'Pony Express', combined low PWMI with effective treatment-weather synchronization, enabling stable productivity under extreme conditions. Together, these results demonstrate that resilience is not a static trait of endurance, but an emergent property arising from temporal synchronization, rapid stress recovery and stable physiological organization. By quantifying stress "forgetting curves" and attractor dynamics, this framework provides a predictive, systems-based foundation for breeding and management strategies that prioritize dynamic recovery over stress tolerance alone.

Cytoplasmic abundant heat-soluble (CAHS) proteins, a stress-responsive intrinsically disordered protein from tardigrades, have been discovered to form gel-like networks providing structural support during dehydration, thus enabling anhydrobiosis. However, the mechanism by which CAHS proteins protect the dehydrating cellular membrane remains enigmatic. Using giant unilamellar vesicles (GUVs) as a model membrane system, here we show that encapsulated CAHS12 undergoes a reversible structural transformation that reinforces membrane integrity and preserves encapsulated components, mimicking natural anhydrobiosis. CAHS12-containing GUVs demonstrated stability for weeks and mechanical robustness under dehydration, elevated temperature, and osmotic stresses. Molecular simulations suggest that CAHS12 forms a filamentous network within the vesicle lumen that mitigates membrane collapse and preserves compartmental architecture. Synthetic cells with cell-free transcription-translation capabilities withstand desiccation and recover biochemical activities, akin to the tun state of the tardigrade. This discovery opens up synthetic cell applications in bioengineering, cold-chain-independent biomanufacturing, and adaptive biointerfaces.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to various antibiotics, and identifying new antibiotics is urgently needed. Based on the structural modification of berberine (BBR), we discovered that 8-octyl berberine (OBBR) had stronger antibacterial activity, especially against MRSA, but its mechanism on MRSA has not been determined. This study revealed that, compared with vancomycin and BBR, OBBR exhibited superior in vitro and in vivo bactericidal activity against MRSA. More importantly, treatment with OBBR didn't develop resistance within 20 round of passages. Mechanistically, via membrane integrity assays and TEM, we observed that OBBR causes significant destruction of the MRSA cell wall and membrane. Transcriptomic and metabolomic analyses revealed that OBBR influenced the peptidoglycan biosynthesis pathway, and the expression of penicillin-binding protein 2a (PBP2a), a peptidoglycan synthesizing transpeptidase, was downregulated in MRSA after OBBR treatment. Further experiments (BOMD, CETSA, DARTs, SPR, GST pull-down and Co-IP) revealed that OBBR can result in an alteration of the spatial conformation of PBP2a and a strong binding interaction between them, and facilitate PBP2a degradation by interacting with ClpC of the AAA+ protease system. Overall, the potential mechanism of the anti-MRSA effect of OBBR is to promote PBP2a protein degradation via the AAA+ protease system rather than inhibiting the transpeptide activity of the PBP2a protein. Therefore, we propose a different bactericidal mechanism from that of β-lactam antibiotics and propose a novel drug candidate against MRSA in clinical settings.

The ClinGen Craniofacial Malformations Gene Curation Expert Panel (Cranio GCEP) was formed in 2020 with an initial target of evaluating genes implicated in craniosynostosis and skull abnormalities. This work summarizes the findings of the Cranio GCEP during its first round of curation, aiming to provide expert guidance for clinical validity of gene-disease relationships in the context of craniofacial malformations. The curation scope of the GCEP was separated into multiple rounds based on frequency of occurrence and uniqueness of associated features. Twelve genes (EFNB1, ERF, FGFR1, FGFR2, FGFR3, MEGF8, MSX2, POR, RAB23, SKI, TCF12, and TWIST1) were selected, based on review of literature, multi-gene sequencing panels from the Genetic Testing Registry (GTR), and expert input. On average, there were two disease relationships per gene, ranging from one to six. In total, the Cranio GCEP curated 23 gene-disease pairs. Of these curations, 17 (74%) classifications reached Definitive, 3 (13%) Moderate, and 3 (13%) Limited. The classification of gene-disease relationships in round one curation of the Cranio GCEP has contributed to systematically evaluating the validity of gene-disease relationships for craniofacial malformations to establish accurate testing panels and improve patient care. By bringing together content experts to focus on gene curation, the Cranio GCEP facilitates education, new collaboration, and encourages publication of clinical cases in previously discovered genes in order to reflect the broadening spectrum of gene-disease relationships in the craniofacial malformation and craniosynostosis literature.

Structural variants (SV) are major drivers of evolutionary processes such as adaptation and speciation, yet their complexity and dynamics in wild populations remain largely unexplored. Avian diversity is highest in the Neotropics, primarily due to the suboscine passerine radiation; however, despite this diversity, genomic resources and studies of SVs in suboscines are scarce compared to their sister clade, the oscine passerines ("songbirds"). Here, we used long-read and chromatin conformation capture sequencing to assemble a high-quality scaffolded reference genome and construct a population-scale pangenome from 5 individuals of the Pearly-vented Tody-Tyrant (Hemitriccus margaritaceiventer), a suboscine bird with plumage variation across its distribution in South American dry forests. Our pangenome graph reveals extensive structural variation, with the chromosomal distribution of SVs strongly predicted by simple and low-complexity repeats - highlighting how specific repeat architecture may influence genome evolution. We discovered intraspecific copy number variation in multigene families, with the most complex instance including beta-keratin genes. Lastly, we identified a 306 kb inversion spanning several melanin pigmentation-associated genes (e.g. MREG, MLPH, RAB17), making it a potential candidate SV for known intraspecific plumage variation. Our study establishes a population-scale pangenome resource for a suboscine bird, enabling characterization of the genome-wide abundance, diversity, and distribution of SVs within this species.

Microbial-derived secondary metabolites (SMs) hold great therapeutic potential but are predominantly discovered from cultured species, representing only a fraction of microbial biodiversity. Advances in metagenomics have unveiled reservoirs of biosynthetic gene clusters (BGCs), but translating genomic sequences into precise chemical structures remains challenging owing to the structural complexity of cryptic BGCs and the context-dependent substrate tolerance and cross-reactivity of modular biosynthetic domains. Here we present DeepSeMS, a transformer-based large language model that accurately predicts secondary metabolite chemical structures from BGC sequences. By encoding biosynthetic genes as functional domains and leveraging a feature-aligned data augmentation, DeepSeMS outperformed existing methods and successfully generated chemically valid predictions for 96.38% of cryptic BGCs. Applying DeepSeMS to a global ocean metagenome, we characterized over 60,000 secondary metabolites, revealing chemical diversity, ecological specificity and considerable biomedical potential, especially as antibiotics. This study underscores the capability of deep learning-driven approaches in revealing hidden biosynthetic potential of Earth's largest, yet largely unexplored, microbial ecosystem.