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Nontuberculous mycobacteria (NTM) are environmental microorganisms for which large, systematic studies of niche diversity are lacking. We performed a semi-longitudinal state-wide sampling campaign (2015-2019) for environmental NTM across Hawai'i. A volunteer network collected 2,334 water biofilms, soil, and dust samples from built (n = 1,946) and natural (n = 388) sites. Of these, 541 contained culturable NTM (23%) and per island hotspots identified. Of 74 NTM species recovered, the most prevalent rapid growing mycobacteria (RGM) were Mycobacterium porcinum, Mycobacterium chelonae, and Mycobacterium abscessus. Mycobacterium intracellulare subsp. chimaera was the most frequently isolated slow growing mycobacteria (SGM). Our longitudinal analyses indicate widespread colonization of diverse niches by species less associated with lung infections such as M. chelonae. In contrast, household water biofilms tended to be reliable niches for M. abscessus and M. avium complex species colonization across the 5-year study. Analysis of 590 deidentified lung samples from Hawai'i and other Pacific Islands revealed M. chimaera as the most frequently isolated species (40%, 238/590). Phylogenetic analysis of environmental and lung M. abscessus suggests most cluster within dominant circulating clone 1 (DCC1). Contrastingly, most Hawai'i and other Pacific Island M. chimaera were distinct from previously studied European isolates, leading to the identification of two novel clusters of phylogenetically related strains we have termed Pacific Island Circulating Cluster 1 and 2 (PCC1, PCC2). PCC1 consists exclusively of Hawai'i/Pacific Island isolates, while PCC2 was enriched by lung samples and was mostly collected from Hawai'i/Pacific Islands. These data reveal the genetic diversity, ecological niches, and potential reservoirs of NTM in varied Hawai'i ecosystems.IMPORTANCENearly one in four environmental Hawai'i samples tested positive for any NTM species, with hotspots often overlapping population centers. Recovery of any NTM species occurred just as often from natural settings as homes and public buildings, highlighting exposures as a normal part of life. Soil was the most common reservoir for NTM colonization, but we distinguish NTM species pertinent to lung disease that were far more likely to be found in water biofilms, such as showerheads and kitchen sinks. No single species dominated the environment; yet, the type of NTM found in water systems closely mirrored those recovered from patients' lung samples. Genetic analyses revealed that Hawai'i harbors distinct, locally circulating strains, including lineages not linked to known hospital outbreaks. Together, these findings improve our understanding of where precarious exposures can occur and inform public health strategies to reduce exposures by highlighting niches that are common hotspots for NTM colonization.

Transposable elements (TEs), particularly retrotransposons that dominate mammalian genomes, are pervasive components of mammalian genomes whose activation is constrained by multilayered repression systems. In germ cells, this repression architecture is particularly elaborate, integrating chromatin-based silencing, DNA methylation, and small RNA-guided pathways to safeguard genome integrity during epigenetic reprogramming. These mechanisms are coordinated yet mechanistically specialized, targeting distinct phases of the transposon life cycle and different TE families across developmental stages. Yet the distinctive chromatin landscape of germ cells also creates windows of developmental permissiveness during which TE transcription can occur. Beyond the germline, TE expression can emerge in defined stages of early embryogenesis, extraembryonic development, neural differentiation, and aging, with consequences ranging from chromatin remodeling and regulatory co-option to inflammatory signaling and genome instability. Together, these observations raise a central question: how do different mammalian lineages balance epigenetic plasticity with genome defense? Here, we synthesize current understanding of the molecular logic of TE repression, emphasizing the germline, and integrate evidence across development and aging. We highlight shared principles-such as epigenetic permissiveness and RNA-guided targeting-while underscoring a key difference in regulatory outcome: somatic contexts may tolerate, co-opt, or pathologically amplify TE activity, whereas the germline converts transient activation into heritable, sequence-specific silencing. Transposable elements are repeated DNA sequences that can move or copy themselves within the genome. Because of this ability, they can damage DNA and disrupt normal cell function. For many years, they were mainly viewed as harmful “genetic parasites.” However, recent studies have shown that they can also contribute to normal biological processes, including early development and gene regulation. This review discusses how mammals control transposable elements, with a particular focus on reproductive cells that give rise to sperm and eggs. These cells undergo major changes in their DNA packaging and gene regulation during development. Such changes can temporarily weaken the systems that normally keep transposable elements silent, creating periods when these elements become more active. To prevent harmful effects, reproductive cells use several layers of protection, including chemical modifications of DNA and RNA-based defense systems. We also compare transposable element activity in reproductive cells with other biological settings, including early embryos, the placenta, the nervous system, and aging tissues. In some situations, transposable element activity may contribute to normal development or gene control. In others, excessive activation is linked to infertility, inflammation, aging, and disease. Together, these findings show that mammals must carefully balance two competing needs: allowing enough flexibility in the genome for development and adaptation, while still protecting the genome from harmful transposable element activity. Understanding this balance may improve our knowledge of fertility, aging, and human disease.

To identify genetic and phenotypic determinants of migraine susceptibility and progression using a large-scale, hypothesis-free approach. Migraine is a common neurological disorder with a substantial individual and societal burden. While risk factors are known, hypothesis-driven approaches may overlook contributors. We analyzed data from 502,364 UK Biobank participants (aged 37-73 years; recruited 2006-2010) to assess associations between migraine and 2824 phenotypes, including observational associations and associations with migraine polygenic risk scores. Time-dependent associations were evaluated, and causality was assessed. Follow-up extended from baseline through to November 30, 2024, with a median of ~14.7 years. Our analyses identified 253 phenotypes significantly associated with migraine risk, 191 phenotypes associated with migraine PRS, and 87 overlapping between the two approaches. Cox regression analysis confirmed 84 robust time-dependent associations and highlighted novel risk factors, such as oral ulcers (adjusted hazard ratio [aHR] = 1.14, 95% confidence interval [CI]: 1.02-1.28, q = 2.54 × 10-2), lower limb obesity (aHR = 1.01, 95% CI: 1.00-1.02, q = 3.52 × 10-4), and hormone replacement therapy (aHR = 1.39, 95% CI: 1.29-1.50, q = 1.95 × 10-17). MR analysis also revealed causal associations with emotional fluctuations (inverse-variance weighting odds ratio [IVW OR] 4.10, 95% CI = 1.76-9.53, q = 1.00 × 10-2), neuroticism (IVW OR = 1.12, 95% CI = 1.07-1.08, q = 1.24 × 10-5), general health ratings (IVW OR = 1.81, 95% CI = 1.43-2.29, q = 3.30 × 10-2), and fatigue (IVW OR = 1.94, 95% CI = 1.35-2.79, q = 5.73 × 10-36). However, the association with paracetamol use (IVW OR = 9.65 × 104, 95% CI = 1.67 × 104-5.57 × 105, q = 5.73 × 10-36) had uncertain directionality on Steiger testing and should be interpreted cautiously. In total, 87 genetic and phenotypic determinants of migraine were identified, offering new therapeutic targets involving inflammatory and insulin-like growth factor 1 (IGF-1) -related pathways. This comprehensive analysis provides new insights into the genetic and phenotypic factors that influence migraine. The findings suggest new targets for therapeutic intervention and provide a basis for the development of precision prevention and clinical management strategies. Migraine is a complex disorder influenced by many factors, but a complete picture of all potential risks is still needed. In this study of over 500,000 people, we used a large repository of data (the UK BioBank) to search for connections between migraine and hundreds of health, lifestyle, and genetic traits. We found that mental health factors such as depression and some biological factors such as the presence of mouth ulcers and body fat distribution may increase migraine risk, offering new potential clues for understanding and preventing migraine.

Recurrent pregnancy loss (RPL) is a multifactorial condition with varying definitions across professional societies and is often misunderstood. This review summarizes recent insights into genetic, paternal, anatomic, metabolic, immunologic, and infectious contributors that may explain otherwise unexplained RPL. In most RPL cases, a cause can be identified when standard evaluation is combined with genetic testing of products of conception (POC). When no clear etiology emerges, additional factors should be considered, including the couple's metabolic health, chronic endometritis, adenomyosis, and paternal contributors. Preimplantation genetic testing for aneuploidy appears beneficial, particularly for older patients and those with recurrent aneuploid losses despite normal evaluations. Conversely, emerging evidence suggests that many empiric treatments for unexplained RPL have limited or no benefit. Comprehensive RPL evaluation should include POC genetic testing and assessment of both partners. An individualized, targeted approach improves outcomes while reducing costs, delays, and exposure to ineffective therapies. Paternal factors are increasingly recognized as important and should be included in both evaluation and management strategies when possible.

Carbonic anhydrases are classically defined as zinc-dependent enzymes that catalyze the reversible hydration of carbon dioxide and play essential roles in acid-base homeostasis. However, carbonic anhydrase VIII (CA VIII) represents a catalytically inactive member of this family due to the absence of one of the three histidine residues required for enzymatic activityStructural analyses further indicate that, despite this loss of catalytic function, CA VIII retains the conserved carbonic anhydrase fold, suggesting functional repurposing rather than structural degeneration. Despite this catalytic silencing, CA VIII is evolutionarily conserved and highly expressed in neuronal tissues, indicating important biological functions beyond enzymatic catalysis. Converging structural, biochemical, and genetic evidence supports the view that CA VIII functions as a pseudoenzyme that regulates intracellular signaling pathways. Mechanistically, CA VIII interacts with the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), modulating intracellular calcium release and thereby influencing neuronal excitability, synaptic function, and cerebellar development. Disruption of CA VIII has been consistently associated with altered calcium homeostasis and impaired neuronal signaling. Importantly, human genetic studies provide direct evidence for the physiological significance of CA VIII. Mutations identified in affected families, including reports from Iraqi and Saudi Arabian populations, are associated with cerebellar ataxia and neurodevelopmental abnormalities, linking CA VIII dysfunction to human disease. These findings establish CA VIII as a critical regulator of neuronal calcium signaling with clear clinical relevance. In this review, we integrate structural, molecular, and genetic evidence to position CA VIII as a functionally repurposed pseudoenzyme that operates as a signaling regulator rather than a catalytic enzyme. We further discuss its emerging roles in neuronal physiology and disease, and highlight broader implications for pseudoenzyme biology and the evolution of protein function.

The ancient Overland Silk Road connected distant regions through commerce and movement, enabling large-scale dispersal of domesticated animals alongside goods. However, the evolutionary and demographic trajectories of domestic camels, vital transport animals within this trade network, remain poorly understood due to a scarcity of paleogenomic data. In the present study, complete mitochondrial genomes (mitogenomes) and low-coverage nuclear genomes were obtained from three Camelus specimens excavated in Xi'an, a major eastern hub of the ancient Overland Silk Road, with calibrated radiocarbon ages of approximately 2 300-2 000, 900-700, and 300-0 years before present (cal BP). Phylogenetic analyses identified two individuals as domestic Bactrian camels and one individual as an Arabian camel, yielding the first genetically validated Arabian camel bone remain reported from China. Maternal haplotypes showed limited phylogeographic partitioning, consistent with extensive human-mediated dispersal. Notably, admixture analysis provided potential evidence of ancient interspecific hybridization, with 7.3% Arabian-related ancestry detected in the ~2 300-2 000 cal BP domestic Bactrian camel and 45.1% domestic Bactrian-related ancestry in the ~900-700 cal BP Arabian camel. This bidirectional introgression pattern suggests intentional breeding and circulation of hybrid camels for trade caravans. Overall, these findings support a model in which the ancient Overland Silk Road acted as a genetic corridor, repeatedly reshaping the demographic history of domestic camels through sustained mobility and recurrent admixture. 古丝绸之路不仅促进了经济交流，也推动了家养动物在该贸易网络沿线地区间的扩散。然而，作为古丝绸之路上重要运输工具的骆驼，其遗传历史因古基因组数据的匮乏而未被充分了解。该研究对出土于古丝绸之路东部重要枢纽——西安市的3件骆驼遗存材料（分别距今2300–2000、900–700和300–0年）进行了测序，获得了其完整线粒体基因组及低覆盖度核基因组。线粒体及核DNA系统发育分析将其中的2个标本归入家养双峰驼，另一个标本归入家养单峰驼，后者代表了在中国首次通过遗传学方法鉴定的家养单峰驼骨骼遗存。研究结果还表明家养双峰驼母系谱系缺乏系统地理结构，这与历史时期广泛的人为迁移相一致。值得注意的是，该研究祖先成分分析为古代家养骆驼种间杂交提供了直接证据：在1个约2300–2000年历史的家养双峰驼中检测到约7.3%的家养单峰驼遗传成分，而在1个约900–700年历史的家养单峰驼中检测到45.1%的家养双峰驼相关成分。这种潜在的双向基因流强调了在历史时期人们为贸易活动而进行的有意杂交骆驼育种。综上，该研究结果揭示古丝绸之路很可能充当了一个遗传走廊，通过反复的迁移与混合，塑造了家养骆驼的种群演化历史。.

Sanjad-Sakati syndrome (SSS), also known as hypoparathyroidism-intellectual disability-dysmorphism syndrome, is a rare autosomal recessive disorder caused by a TBCE founder mutation. The full disease spectrum remains poorly understood. To comprehensively analyze growth, phenotype, endocrine manifestations, and mortality in a large multicenter SSS cohort. Clinical and genetic data were collected from 135 individuals across centers in the Gulf region using a REDCap survey. The median age at inclusion was 9.1 years (range: birth-30 years; 50.3% female). The homozygous TBCE founder mutation (c.155_166del; p.Ser52_Gly55del) was detected in all genetically tested individuals (n = 68). Intrauterine growth restriction (mean birth weight -3.0 SD, length -3.3 SD) and dysmorphic features were universal. Postnatal growth showed severe failure to thrive during infancy, followed by persistently low height z-scores (-7 to -8). Endocrine features included hypoparathyroidism in all patients, primary hypothyroidism (16.5%), hypoglycemia (27.8%), non-autoimmune insulin-dependent diabetes (1.6%) and pituitary hormone deficiencies. Other findings included developmental delay (100%), hypocalcemic seizures (64.2%), tetany (53.3%), nephrocalcinosis (62.1%), gastroesophageal reflux (29.1%), and recurrent respiratory (63.7%) and bacterial infections (53.8%). Antibiotic prophylaxis was used in 35% of patients. Kaplan-Meier analysis estimated a median survival of 27.2 years, with respiratory failure causing 84% of deaths (21/25). The estimated overall survival at an age of 18 years was 62.4%. This largest reported SSS cohort highlights the high prevalence of associated endocrine, respiratory, and gastrointestinal manifestations, with respiratory failure as the leading cause of death. These data support the need for multidisciplinary care guidelines.

Excessive extracellular accumulation of K+ plays a key role in the induction and propagation of seizures associated with temporal lobe epilepsy (TLE), and astrocytes are largely responsible for K+ clearance from the extracellular space. Here, we review the TLE-related changes in the content and/or activity of proteins contributing to K+ transport across the astrocytic cell membranes. Seizures, whether genetic or acquired, are linked with decreased expression and/or mislocalization of the two key astroglia-specific drivers of K+ uptake: the inward rectifying potassium channel Kir4.1 and its spatial and functional partner, the water channel aquaporin 4 (AQP4). Among neural cells of the CNS, the high K+-responsive α2 isoform of Na+/K+-ATPase is specific for astrocytes and is substantially inactivated in the brains of TLE patients and experimental animals, albeit not always in epilepsies with a genetic background. The above data consistently support the involvement of malfunctional astrocytic K+ transport as a factor facilitating seizures. By contrast, complex and variable, region-dependent dynamics of the two-pore domain potassium channels (K2P; TWIK, TASK, and TREK) were observed in astrocytes in the hippocampus, rendering their contribution to seizures difficult to interpret. Anti-seizure medication targeting metabolic processes not directly related to astrocytic K+ transport often reversed the unfavorably changed status of the astrocytic mediators of K+ buffering.

The coexistence of mosaic trisomy 18 and Turner syndrome represents an extremely rare genetic constellation, with only a few cases reported in the literature to date. We present the case of a 7-year-old girl with esophageal atresia, full trisomy 18 in lymphocytes, and mosaic copy number changes involving trisomy 18 with coexisting monosomy X in fibroblasts, suggesting the presence of additional cell populations lacking trisomy 18. In addition, we provide a review of the relevant literature. This case is of particular clinical significance, as it describes long-term survival in a child with Edwards syndrome and illustrates the diagnostic challenges associated with tissue-limited mosaicism. Furthermore, it underscores that an established diagnosis of one genetic disorder does not preclude the coexistence of another, particularly when the clinical phenotype deviates from the classical presentation of the primary syndrome. Adequate analysis of a sufficient number of metaphases in karyotyping is essential to reliably detect or exclude mosaicism in Edwards syndrome, as the distinction between full and mosaic trisomy 18 carries important prognostic implications.

Phase variation (PV) allows bacterial pathogens to rapidly modify surface structures through reversible mutations-often driven by simple sequence repeats (SSRs)-thereby facilitating immune evasion and environmental adaptation. In Campylobacter jejuni, SSR-mediated PV regulates numerous surface-exposed molecules, including capsular polysaccharides and lipooligosaccharides, which play key roles in host interaction and immune resistance. However, the stochastic nature of PV has made it difficult to systematically analyze the functions of individual phase-variable genes (PVGs). Here, we introduce PV-GenShift (Phase Variation Genomic Shift), a genome-scale screening platform built on a genetically stabilized library of phase-locked C. jejuni variants. Using multiplex genome editing via natural transformation, we fixed the ON/OFF states of 15 SSR-containing PVGs, enabling reproducible, high-resolution analysis of phasotypes, defined as unique combinations of ON/OFF states across multiple PVGs, under defined selective pressures. Applying PV-GenShift to models of human serum exposure, murine colonization, and chicken gut passage, we identified distinct phasotypes linked to serum resistance and enrichment during mouse colonization-particularly those involving capsular polysaccharide modifications such as O-methyl phosphoramidation and methylation. In contrast, chicken passage produced heterogeneous ON/OFF patterns without a dominant phasotype. These findings underscore the combinatorial influence of SSR-mediated PVG expression states on bacterial adaptation and establish PV-GenShift as a versatile framework for dissecting PV-driven phenotypic diversity. This approach offers a scalable strategy for mapping genotype-phenotype relationships and provides insights with implications for vaccine development, diagnostic design, and targeted therapeutics. Phase variation allows bacteria to rapidly generate phenotypic diversity, but its randomness has long limited efforts to define how specific gene combinations influence adaptation. In Campylobacter jejuni, phase-variable genes control numerous surface structures that affect host interactions and immune resistance, yet their coordinated contributions remain poorly understood. PV-GenShift (Phase Variation Genomic Shift) overcomes this challenge by genetically stabilizing the ON/OFF states of multiple phase-variable genes, enabling systematic, reproducible analysis of phasotypes under defined selective pressures. Using this approach, we identified combinations of gene states that enhance serum resistance and promote colonization in mice, particularly those involving modifications to capsular polysaccharides. In contrast, chicken passage produced heterogeneous patterns consistent with weak or non-specific selection. These findings demonstrate that the interplay of multiple phase-variable loci shapes host adaptation and highlight PV-GenShift as a broadly applicable strategy for dissecting phase variation in diverse pathogens, with implications for vaccine design and targeted therapies.

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular hypertrophy and progression to heart failure (HF). Approximately 40% of cases are caused by variants in genes encoding sarcomere proteins. This study sought to determine the relationship between genotype and other clinical predictors of HF outcomes in HCM patients. This observational, single-center cohort comprised 505 genotyped HCM patients (52 years of age [Q1-Q3: 41-62 years], 33% women). Patients were stratified into gene-positive (G+) and gene-elusive (G-) groups. The primary endpoint was HF-related death or cardiac transplantation. Secondary endpoints included cardiac death, arrhythmic events, and all-cause mortality. Proportional hazards models were used to evaluate predictors of outcomes, including genetic status, log-transformed N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, peak VO2, and left ventricular ejection fraction (LVEF). During a median follow-up of 10.6 years (Q1-Q3: 4.6-15.0 years), 34 patients (6.7%) experienced the primary outcome (HF-related death: 22 [4.4%] and heart transplantation: 12 [2.4%]). The HF endpoint occurred in 12.8% (28 of 219) of the G+ group compared with 2.1% (6 of 286) of the G- group. In multivariable Cox analysis, G+ status (HR: 5.86; 95% CI: 2.26-15.25; P < 0.001), log NT-proBNP (HR: 2.46; 95% CI: 1.59-3.80; P < 0.001), peak VO2 (HR: 0.90; 95% CI: 0.82-0.98; P < 0.001), and LVEF (HR: 0.74 per 5% increment; 95% CI: 0.63-0.86; P < 0.001) were independently associated with HF outcomes. For secondary endpoints, 60 patients (11.9%) died of cardiac causes, 34 (6.7%) experienced arrhythmic events, and 115 (22.8%) died of any cause. Genetic status, peak VO2, log NT-proBNP, and LVEF independently predict HF outcomes in HCM. Combining genotype with HF biomarkers and functional capacity measures identifies patients at increased risk of HF-related death or transplant and may support targeted monitoring and selection for disease-modifying trials.

A combination of structure-function and genetic analyses of viruses is unveiling a wide repertoire of adaptive mechanisms for restoring biological function in the face of negative selection pressures. The fixation of second-site compensatory mutations in highly heterogeneous RNA virus populations constitutes a frequent and versatile response to recover infectivity in the presence of deleterious mutations. In this study, we explored the following: (i) survival mechanisms of human rhinovirus (RV) when infectivity-impairing amino acid substitutions were introduced at either capsid protein-protein interfaces or capsid protein-RNA interfaces involved in virion assembly and viral RNA uncoating, and (ii) whether recovery of infectivity through compensatory amino acid substitutions in different functional elements in the same virion may be constrained to different extents. Specific interactions between capsid subunits or between the capsid and the genomic RNA in the RV virion were disrupted by replacement of individual amino acid residues with alanine, and the resulting crippled viruses were left to recover normal infectivity during serial infections of human cells. Identification of compensatory amino acid substitutions acquired during virus multiplication revealed that RV can use different genetic mechanisms to recover infectivity, depending on whether the deleterious substitution was localized at either pentamer-pentamer or capsid-RNA interfaces. Moreover, severe constraints to restore infectivity were found when deleterious substitutions were introduced at capsid-RNA interfaces instead of inter-pentamer interfaces. Because of those constraints, the capsid-RNA interface may constitute a preferential target for the design of anti-RV drugs that can interfere with viral assembly and uncoating, while minimizing opportunities for virus escape.IMPORTANCEHuman rhinoviruses cause most common colds and originate serious socioeconomic problems every year. In addition, they are associated with or exacerbate severe respiratory diseases, including chronic obstructive pulmonary disease, a major cause of death worldwide. No vaccines or drugs against rhinovirus infection are currently available. This study shows that when deleterious amino acid substitutions are introduced at interfaces between rhinovirus capsid subunits, infectivity is readily recovered through the fixation of second-site compensatory mutations that restore virion assembly and conformational stability. In contrast, severe difficulties were encountered for the recovery of infectivity when similar deleterious substitutions that impair virion assembly and stability and disregulate genome uncoating are introduced at capsid-viral RNA interfaces. The results suggest that the capsid-RNA interface may constitute a promising target for the design of anti-rhinoviral drugs that impair virus assembly and uncoating, while restraining the emergence of drug-resistant variant viruses.