Search Results (279)

Excessive application of chemical fertilisers has led to soil phosphorus immobilisation and aquatic eutrophication, making the development of highly efficient acid/neutral phosphatases crucial for sustainable phosphorus utilisation. In this study, we systematically investigated strain J2, which was isolated from phosphate-contaminated soil in Laoshan, Nanjing, China. 16S rRNA gene sequence analysis identified this strain as Acinetobacter nosocomialis J2, with 99.78% sequence similarity. Whole-genome sequencing generated a 3.83 Mb genome with a GC content of 38.59%, revealing multiple phospho-metabolism-related enzyme genes, including phospholipase C and α/β-hydrolases. A large language model–based protein representation learning strategy was employed to mine acid/neutral phosphatase genes from the genome, in which the model learned contextual and functional features from known phosphatase sequences and was used to identify semantically similar genes within the J2 genome. This approach predicted nine phosphatase candidate sequences, including AnACPase, a putative acid/neutral phosphatase. Biochemical characterisation showed that AnACPase exhibits optimal activity at pH 6.0 and 50 °C, with a K_m value of 0.2454 mmol/L for the p-NPP substrate, indicating high substrate affinity. Mn²⁺ and Ni²⁺ significantly enhanced enzyme activity, whereas Cu²⁺ and Zn²⁺ strongly inhibited it. Soil remediation experiments further validated the application potential of AnACPase, which solubilised 171.56 mg/kg of phosphate within seven days. Overall, this study highlights the advantages of deep learning-assisted genome mining for functional enzyme discovery and provides a novel technological pathway for the bioremediation of phosphorus-polluted soils. Full article

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC; diagnosed before age 50) is rising at an accelerated rate, with a disproportionate impact on underserved populations. While alterations in the receptor tyrosine kinase–RAS (RTK–RAS) signaling pathway play a fundamental role in colorectal cancer (CRC) biology, their prognostic significance in the setting of FOLFOX chemotherapy—particularly across different age groups and ancestral backgrounds—remains insufficiently characterized. We sought to characterize age-, ancestry-, and treatment-specific associations between RTK–RAS alterations and clinical outcomes using an AI-enabled precision oncology framework. Methods: We analyzed 2515 CRC cases, including 266 Hispanic/Latino (H/L) and 2249 non-Hispanic White (NHW) patients, stratified by age at onset, ancestry, and FOLFOX treatment status. Mutation frequencies were assessed using Fisher’s exact and chi-square tests, while overall survival was analyzed with Kaplan–Meier methods. The AI-HOPE and AI-HOPE–RTK–RAS conversational artificial intelligence platforms were used to integrate clinical, genomic, and treatment data via multi-parameter, natural language–based queries. Results: In early-onset Hispanic/Latino patients, ERBB2 and NF1 mutations occurred at significantly lower frequencies in FOLFOX-treated cases compared with untreated cases (p = 0.01 for both). In late-onset H/L patients, NTRK2 mutations were depleted in FOLFOX-treated tumors (p = 0.04). In untreated early-onset H/L patients, MAPK3 and NF1 mutations were enriched relative to NHW counterparts. Among early-onset NHW patients, IGF1R and ERRFI1 mutations were less frequent with FOLFOX exposure, while multiple RTK–RAS genes were reduced in FOLFOX-treated late-onset NHW patients. Survival analyses revealed worse overall survival in FOLFOX-untreated early-onset NHW patients with RTK–RAS alterations (p = 0.029), but improved survival in FOLFOX-treated late-onset NHW patients (p = 0.048). Conclusions: RTK–RAS pathway alterations demonstrate strong age-, ancestry-, and treatment-specific prognostic effects and may serve as precision biomarkers of differential chemotherapy response. AI-enabled analytics substantially accelerated integrative biomarker discovery, supporting their utility for advancing precision oncology in EOCRC. Full article

Alzheimer’s disease (AD) and related dementias (ADRD) are neurodegenerative conditions that cause gradual deterioration of cognition, memory and language in the elderly. AD has been declared as a health priority by the World Health Organization (WHO) considering its severity and unavailability of a permanent cure. Although the global AD/ADRD population is made up of many ethno-racial groups, the majority of AD studies have focused on the Caucasian population. The few AD studies conducted on minority populations in the US have found that significant AD health disparities exist, demonstrating that African Americans and Hispanics have a significantly higher prevalence of AD and related dementias, with their risk often approaching twice that of White individuals. For the past few years, epigenomic research has played an important role in understanding health disparities among diverse racial and ethnic groups. Unlike genetic studies, which focus on the DNA sequence that one is born with, epigenomics investigates how changes in gene expression due to extrinsic environmental exposures may impact disease pathophysiology. Recent epigenomic studies appear to be promising in not only understanding disease pathology but also in developing diagnostic and therapeutic tools for AD with population specificity. However, there is only a handful of studies and review articles available addressing the epigenomic applications in irradicating racial disparities in AD/ADRD. Therefore, the aim of this review is to discuss the recent findings of epigenomic studies in AD and related dementias, their contribution in irradicating racioethnic disparities and insights into the future direction of their application in precision medicine. Full article

Background/Objectives: Speech and language delay (SLD) is one of the most prevalent developmental conditions in childhood, with post-pandemic data indicating a notable increase in identified cases. Within this group, expressive language disorder (ELD) frequently appears alongside neurodevelopmental disorders such as autism spectrum disorder (ASD), epilepsy, and intellectual disability. Although awareness of ELD has grown, the role of genetic testing in its evaluation remains unclear, as such testing is not routinely pursued for isolated expressive language concerns. This gap highlights the need to better define the diagnostic value of genetic analysis and to examine the interval between an ELD diagnosis and the return of genetic testing results. Methods: This study investigated genetic contributions to ELD using the National Brain Gene Registry (BGR), a multisite database of rare neurodevelopmental disorders. Participants with ICD-10 code F80.1 were identified through electronic health records; demographic data, comorbidities, genetic variants, inheritance patterns, age at diagnosis, and timing of interventions were analyzed. Results: Of 687 BGR participants, 32 (4.7%) had documented ELD. The cohort, aged 3–19 years, presented with common comorbidities like developmental delays, ASD, epilepsy, and hypotonia. Across 42 genes, 49 unique variants were identified: 26 pathogenic or likely pathogenic, 22 variants of uncertain significance, and one benign variant. Seventeen variants were de novo, and 10 participants carried multiple variants. Most children (80%) received an expressive language diagnosis prior to genetic testing, with reports returned an average of 1.5 years following the diagnosis. Conclusions: Overall, children with ELD commonly carry genetic variants and neurodevelopmental comorbidities, yet genetic testing is typically pursued well after diagnosis and does not currently alter early management. These findings underscore the need for clearer, evidence-based guidelines to define when genetic testing adds diagnostic or prognostic value in the evaluation of ELD. Full article

This review integrates molecular, clinical, and translational data to provide an updated understanding of GJB2-related deafness and its emerging treatment landscape. Truncating mutations in GJB2 typically cause severe-profound hearing loss (HL) phenotypes, whereas non-truncating alleles are often associated with milder or progressive phenotypes. Geographic variation in variant prevalence contributes to regional differences in disease burden. Beyond the coding region, deletions and cis-regulatory mutations within the DFNB1 locus, including GJB6 and CRYL1, can influence HL severity when compounded with other pathogenic GJB2 variants. DFNB1 hearing loss generally presents as symmetric, bilateral, and flat to gently sloping across frequencies, with preserved cochlear neurons that support excellent cochlear implant (CI) outcomes. Early implantation CI in GJB2-positive children yields superior speech and language development compared with non-GJB2 etiologies. Emerging therapies include dual-AAV (AAV1 + AAV-ie/ScPro) delivery, achieving cell-specific Cx26 restoration, adenine base-editing for dominant-negative variants, and allele-specific suppression using RNA interference or antisense oligonucleotides. Concurrent progress in human iPSC-derived cochlear organoids provides a physiologic model to advance toward clinical trials. By integrating genotype-phenotype correlations, natural history insights, and advances in molecular therapeutics, this review presents a comprehensive update on GJB2-related HL and highlights how gene-based strategies are poised to change the treatment of this condition. Full article

Introduction: Opioids are the most commonly used analgesic drugs for acute and chronic severe pain and are metabolized in the liver via cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs). Methods: A narrative review of the literature was conducted by searching the PubMed database up to December 2025, with English as the only language restriction. Relevant studies were identified using the keywords “opioids,” “pharmacogenetic,” “cytochrome mutations,” and “interactions.” Results: Polymorphisms in CYP2D6 and CYP3A4 genes can affect the pharmacokinetics, clinical effect, and safety of opioids. Furthermore, enzyme induction and inhibition by concomitant drugs or compounds (herbal products or food) are sources of variability factors in drug response that may be predictable. Conclusions: This review article summarizes current evidence on the role of pharmacogenetics and opioid-related interactions, offering a framework to better understand interindividual variability in opioid response and to inform future multimodal approaches. Full article

Six small interference RNAs (siRNAs) have been approved as therapeutics since 2018 making them promising nanosystems due to selective gene knockdown activity. siRNA design is complex due to various factors, where the chemical modifications are crucial to improve its half-life and stability. Machine learning (ML) enabled more efficient analysis of siRNA data, moreover predicting efficacy and off-target effects. This work proposes a novel pipeline for predicting gene knockdown activity of chemically modified siRNAs across the whole range of activities leveraging both descriptors of siRNA chemical composition-aware property matrices and large language model (LLM) embeddings for target gene encoding. Several general-purpose and domain-specific fine-tuned LLMs were benchmarked on the target task, where the Mistral 7B general-purpose model slightly outperformed even the models pre-trained on genomic data. Proposed two-stage probability-enhanced model successfully mitigates data imbalance towards moderate-to-high active constructs and achieves state-of-the-art (SOTA) quality with R² = 0.84 and a RMSE = 12.27% on unseen data, where the probabilistic outputs of classifiers trained with F-scores up to 0.92 were used for regression model supervision. Moreover, leave-one-gene-out (LOGO) experiments show that the model is able to extrapolate on unseen genes, which further shows representativeness of siRNA features and gene embeddings. By filling the gap in the field of advanced chemical composition-aware siRNA design, our model aims to improve the efficacy of developed siRNA-based therapies. Full article

Background: Pathogenic variants in the TRIP12 gene are associated with Clark-Baraitser syndrome, a condition characterized by neurodevelopmental disorders, including intellectual disability, autism spectrum disorder (ASD), and speech delay. Phenotypic expression is variable, and facial features are not consistently present. Familial inheritance is rare. Methods: Whole-exome sequencing (WES) was performed on a proband with speech disorder and ASD, as well as on her parents. Clinical assessment included developmental, cognitive, and physical evaluations. Results: A heterozygous missense variant c.3404A>T (p. Asp1135Val) in the TRIP12 gene was identified in both the proband and her father. Both presented with speech disorder and ASD without facial features or severe intellectual disability. Conclusions: In line with recent genotype–phenotype studies, missense TRIP12 variants tend to be associated with milder neurodevelopmental presentations, typically characterized by mild to moderate intellectual impairment, variable autistic traits, limited or absent facial features, and a low incidence of epilepsy. This familial case further presents the phenotypic spectrum of TRIP12 missense variants and highlights that ASD and speech disorder may occur as isolated neurodevelopmental findings without syndromic features. The report reinforces the relevance of TRIP12 analysis in the differential diagnosis of ASD and language disorders, even in individuals lacking physical traits, supporting more accurate genetic counseling and broader awareness of inherited TRIP12-related conditions. Full article

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition characterized by the degeneration of upper and lower motor neurons. This degeneration leads to a gradual muscle weakness, dysarthria, dysphagia, respiratory insufficiency, and, in some patients, alterations in cognitive and behavioral performance. Regardless of advancements made in pharmacological and gene-targeted interventions, a definitive curative treatment remains elusive. Consequently, rehabilitation plays a pivotal role in preserving autonomy, participation, and overall quality of life. This review outlines the current evidence and clinical approaches related to multidisciplinary rehabilitation in ALS. It covers physical and occupational therapy, respiratory, speech and language, psychological, and palliative care domains. Evidence supports moderate tailored exercise programs, early respiratory therapy, and structured management of mobility deficits, spasticity, pain, dysphagia, and communication impairments as key elements of symptomatic treatment. Psychological and social support, which includes the involvement of caregivers and relatives, enhances emotional well-being and coping resilience. Even with progressive development of gene-targeted and disease-modifying therapies, rehabilitation will stay relevant for maintaining long-term motor function. This review highlights the need for standardized, evidence-based rehabilitation protocols and intensified neurorehabilitation research to strengthen clinical outcomes and quality of life as key therapeutic goals in ALS management. Full article

Background/Objectives: The Mediator (MED) complex is an essential regulator of RNA polymerase II transcription. There is increasing evidence that pathogenic variants in several MED subunits are the cause of neurodegenerative and neurodevelopmental phenotypes, collectively referred to as “MEDopathies”. This review aims to summarize current knowledge on the genetic basis, clinical manifestations, and neuroradiological features of MED-related disorders. Methods: We undertook a narrative synthesis of the literature focusing on the MED subunits most commonly associated with neurological disorders, including MED1, MED8, MED11, MED12/MED12L, MED13/MED13L, MED14, MED17, MED20, MED23, MED25, MED27, and CDK8. Sources included peer-reviewed genetic, clinical, and imaging studies, supplemented by relevant case reports and cohort analyses. In addition, representative facial phenotypes associated with selected MED variants (MED11, MED12, MED13, MED13L, MED25) were visualized for educational purposes using artificial intelligence-based image generation derived from standardized clinical descriptors. Results: All MEDopathies show converging clinical patterns: global developmental delay/intellectual disability, hypotonia, epilepsy, speech disorders, and behavioral comorbidity. Non-neurological involvement, such as craniofacial or cardiac anomalies, is subunit-specific. Neuroradiological features include callosal abnormalities (agenesis, thinning, dysmorphia), delayed or hypomyelination, progressive cerebral and cerebellar atrophy, basal ganglia signaling changes, pontine hypoplasia, and, in MED27 deficiency, a “hot cross bun” sign. Gene-specific constellations emphasize catastrophic infantile progression (MED11), X-linked syndromes with callosal defects (MED12/MED12L), language-dominant phenotypes (MED13), and syndromic intellectual disability with systemic features (MED13L). Conclusions: The growing spectrum of MEDopathies argues for their recognition as a unified nosological group with overlapping clinical and radiological signatures. Characteristic MRI constellations may serve as diagnostic clues and guide targeted molecular testing. Future directions include longitudinal imaging to describe disease progression and the integration of genomic data with curated clinical radiological datasets to refine genotype-phenotype correlations. Full article

Background: Virtual cells are embedded in widely used single-cell generative models. Nonetheless, the models’ implicit knowledge of perturbations remains unclear. Methods: We train variational autoencoders on three gene expression datasets spanning genetic, chemical, and temporal perturbations, and infer perturbations by differentiating decoder outputs with respect to latent variables. This yields vector fields of infinitesimal change in gene expression. Furthermore, we probe a publicly released scVI decoder trained on the $\mathrm{CELL}\times \mathrm{GENE}$ Discover Census ($\sim 5.7$ M mouse cells) and score genes by the alignment between local gradients and an empirical healthy-to-disease axis, followed by a novel large language model-based evaluation of pathways. Results: Gradient flows recover known transitions in Irf8 knockout microglia, cardiotoxin-treated muscle, and worm embryogenesis. In the pretrained Census model, gradients help identify pathways with stronger statistical support and higher type 2 diabetes relevance than an average expression baseline. Conclusions: Trained single-cell decoders already contain rich perturbation-relevant information that can be accessed by automatic differentiation, enabling in-silico perturbation simulations and principled ranking of genes along observed disease or treatment axes without bespoke architectures or perturbation labels. Full article

Peri-implantitis is a multifactorial inflammatory disease that can compromise the longevity of dental implants. Several studies have investigated the association between genetic variants. This systematic review aimed to assess the contribution of genetic polymorphisms to the risk of developing peri-implantitis. A systematic search was conducted in the PubMed database up to 2025 following the PICO strategy and PRISMA guidelines. Eligible studies met the following inclusion criteria: articles written in English, addressing genetic associations with peri-implantitis in human subjects, designed as clinical trials or observational (prospective or retrospective) studies, with full-text availability, and published within the last ten years. Exclusion criteria included studies in languages other than English, those not addressing the main research question, publications older than ten years, studies without full text, and secondary research such as meta-analyses or review articles. Selection and data extraction were performed independently by two reviewers. Risk of bias was evaluated qualitatively for control studies. Twenty-three studies met the inclusion criteria. Polymorphisms in genes related to inflammatory cytokines (e.g., IL-1β +3954 C/T, IL-10, TNF-α), bone metabolism (OPG, BMP4, FGF10), and immune regulation (CD14 rs2569190, miR-27a-3p) were frequently reported. IL-1β +3954 C/T, ET-1 and IL-1β, MMP-8 rs11225395 (T allele), MMP8 (−799 C/T), and CD14 rs2569190 showed consistent associations with increased peri-implantitis risk, while the results for TNF-α −308 G/A were inconsistent across populations. These findings suggest a potential role of genetic predisposition in peri-implantitis development. Identifying genetic biomarkers may help predict susceptibility and personalize management strategies. Full article

Background/Objectives: Preterm infants are at risk for developmental delays due to immature brain development and increased sensitivity to environmental stress. Genetic factors, such as polymorphisms in *OXTR* rs2268490, *COMT* rs4818, and *GRIN2B*, may influence these vulnerabilities and affect neurodevelopment. Methods: We recruited 91 preterm infants (<35 weeks gestation) admitted to the NICU at Hanyang University Seoul Hospital between January 2020 and December 2022. Brain MRIs were conducted at term-equivalent age, and DNA samples were analyzed for SNPs. Neurodevelopmental assessments were performed at 18 months corrected age using the Korean Developmental Screening Test (K-DST) and Bayley Scales of Infant Development, Third Edition (BSID-III). Results: Carriers of the minor alleles in *OXTR* rs2268490 showed significantly lower language and adaptive behavior, and *COMT* rs4818, rs740603 showed significantly lower social–emotional scores on BSID-III. *OXTR* rs2268490 was also associated with altered brain network metrics, including decreased small-worldness (p = 0.012) and increased global (p = 0.038) and local efficiency (p = 0.042). Conclusions: Polymorphisms in the *OXTR* genes are associated with differences in brain network organization and neurodevelopmental outcomes in preterm infants. These variants may influence how environmental factors affect early brain development, highlighting the importance of genetic screening and early intervention. Full article

Objectives: Alexander disease (AxD) is a rare neurodegenerative disorder that represents a group of leukodystrophies with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late-onset phenotypes, symptoms are often milder and difficult to diagnose. We present a diagnostic journey of a teenage male patient with a progressive gait disorder starting at the age of 13 years, with a final diagnosis of Alexander disease. Early in the course of the disease, the boy exhibited distinctive cognitive involvement and neuropsychological deterioration characterized by selective impairment of visual and long-term auditory memory, along with a decline in IQ but preserved reasoning abilities. Methods: The patient underwent an extensive neurological diagnostic workup, which included magnetic resonance imaging (MRI) of the brain, spine, and abdomen, as well as electrophysiological, metabolic, and biochemical tests. Numerous specialist consultations were conducted, including genetic, cardiology, ophthalmology, pulmonology, oncohematology, psychological, and speech–language pathology consultations. In addition, a focused literature review was performed using PubMed, Scopus, Web of Science, and Google Scholar with the search terms “Alexander disease,” “GFAP gene,” “late-onset,” “spastic paraplegia” and “GFAP variant p/Gly18Val”. Results: Whole exome sequencing revealed an extremely rare missense GFAP heterozygous variant NM_002055.5: c.54G>T (p/Gly18Val), confirming the diagnosis of AxD. Conclusions: The presented case highlights the importance of whole-exome sequencing in the diagnosis of unexplained otherwise neurological symptoms, such as progressive spastic paraplegia. Full article