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FANTASIA suite: a reproducible and configurable framework for embedding-based functional annotation of proteins.

Embedding-based annotation transfer is increasingly used for protein function inference due to protein language models capture sequence, structural, and functional signals that may extend beyond conventional pairwise similarity. However, systematic application of these approaches requires control over model choice, reference composition, lookup parameters, evidence traceability, and output formats. We developed the FANTASIA suite, a configurable framework for embedding-based functional annotation of proteins. The suite combines a database-backed implementation for reproducible and extensible analyses with a portable flat-file implementation for rapid local annotation and pipeline integration. Using non-model and model-organism proteomes, we show that larger neighbourhood sizes remain practical for proteome-scale analyses and that taxonomy and sequence-identity filtering support leakage-aware benchmarking. We also compare the supported models with baseline methods through external CAFA5 evaluation and provide practical guidance based on empirical evidence variables. FANTASIA provides a controlled, scalable, and reproducible framework for extending functional annotation across the rapidly expanding diversity of sequenced organisms.

Software↗

TreeFlow: Probabilistic Modelling and Automatic Differentiation for Phylogenetics.

Probabilistic modelling frameworks are powerful tools for statistical modelling and inference. They are not immediately generalizable to phylogenetic problems due to the particular computational properties of the phylogenetic tree object. TreeFlow is a software library for probabilistic modelling and automatic differentiation with phylogenetic trees. It embeds phylogenetic trees in the TensorFlow Probability framework, and implements inference algorithms for phylogenetic models given a fixed tree topology. We demonstrate how TreeFlow can be used to quickly implement and assess new models. We also show that it provides reasonable performance for gradient-based inference algorithms compared to specialized computational libraries for phylogenetics.

Bayesian inference↗

Molecular biomarker profiling in noninfectious uveitis: a chronological review of discovery.

PURPOSE OR REVIEW: Noninfectious uveitis (NIU) encompasses a heterogeneous group of immune-mediated intraocular inflammatory diseases whose complexity has driven systematic molecular biomarker discovery. This review presents NIU molecular biomarkers organized by biological category; autoantigens, human leukocyte antigens (HLA) and genetic markers, cellular immune subsets, cytokines, chemokines, and multiomics platforms including proteomics, microbiome metagenomics, metabolomics, and single-cell transcriptomics with each category presented in strict chronological order of landmark discovery. RECENT FINDINGS: We present a review organized along two nested timelines. Categories are presented in the order they historically emerged in the field, and within each category, landmark discoveries appear in chronological sequence. This allows the reader to trace how each biomarker category evolved: from foundational autoantigen identification in experimental uveitis models, through the genomic revolution of HLA association studies, into cellular immunophenotyping, cytokine profiling of aqueous humor, chemokine mapping of intraocular trafficking, and finally the emerging omics platforms that may potentially anchor precision medicine in NIU. Each biomarker is paired in line with its linked targeted therapeutic. SUMMARY: Biomarker research has transformed the understanding of NIU from a clinically defined syndrome into a group of molecularly distinct immune disorders. Advances spanning autoantigens, genetics, immune-cell profiling, cytokines, chemokines, and multiomics have revealed novel pathogenic mechanisms and therapeutic targets. Integration of these biomarkers with targeted therapies may accelerate the transition toward precision medicine in uveitis care.

cytokines↗

USP6-FISH Negative Nodular Fasciitis: Benign Impostor of the Orbit.

Nodular fasciitis (NF) is a benign, rapidly growing myofibroblastic proliferation that can closely mimic sarcoma clinically, radiographically, and histologically, posing a significant diagnostic challenge. We report a case of an 11-year-old boy presenting with a painless but progressively enlarging periorbital mass initially suspected to be a dermoid cyst. Although his ultrasound was reassuring, MRI showed an enhancing lesion concerning for neoplasm, prompting surgical excision. Histopathologic evaluation revealed spindle-cell proliferation within a myxoid stroma consistent with NF. However, the USP6 fluorescence in situ hybridization analysis was negative. Further genomic analysis identified a rare USP6-PAFAH1B1 fusion. This case highlights a diagnostically challenging subset of NF in which conventional USP6 fluorescence in situ hybridization testing may be negative, necessitating next-generation sequencing for a definitive diagnosis. Increased awareness of NF and its clinical, histologic, genetic, and radiographic presentation is essential to avoid misdiagnosis and to guide appropriate management.

Journal Article↗

Assessment of blinding in pharmacotherapy and noninvasive neuromodulation randomized controlled trials for neuropathic pain in adults.

In randomized controlled trials (RCTs), study participants and research personnel are often blinded to minimize biases related to knowing treatment allocation. To determine if blinding was effective, participants may be asked which treatment they believe they received ("treatment guess"). This descriptive review characterized blinding assessment (BA) reporting in pharmacotherapy and neuromodulation neuropathic pain RCTs. Of 288 papers, 36 (12.5%) reported a BA. One paper reported the results of 2 studies, so in total 37 studies with a BA were assessed. Of these, 19 were crossover, 17 parallel, and 1 partial crossover in design. All 37 studies assessed participant blinding, and 10 also assessed investigator blinding. Approximately 27% included an "unsure" answer option for treatment guess, and 38% asked the reason for the guess. There were no clear patterns in BA reporting across time nor based on treatment type. Seventeen trials provided sufficient data to calculate Bang Blinding Index (BI) to determine blinding success. Participants remained blinded (BI = 0 &#xb1; 0.2) in 10/17 placebo and 10/17 treatment arms, 6 placebo and 5 treatment arms had a BI > 0.2 suggesting possible unblinding, whereas 1 placebo and 2 treatment arms had a BI < -0.2 suggesting misinformed guessing. Overall, we found that BAs are done in a minority of published neuropathic pain trials and with variable methodology. Given the importance of minimizing risk of bias because of treatment unblinding, future studies should consider including BAs, and further consensus building is necessary to determine if and how BAs should be conducted and interpreted in analgesic clinical trials.

Bias↗

Plasma lipid species, immune cell traits, and gastric cancer risk: A Mendelian randomization study.

Plasma lipid composition has been linked to multiple cancers, yet its causal contribution to gastric cancer and the potential intermediary role of immune cells remain unclear. We aimed to clarify these relationships and identify specific lipid and immune cell traits that either protect against or promote gastric cancer. We performed a 2-sample, 2-step Mendelian randomization analysis using summary statistics from large genome-wide association studies of gastric cancer (1423 cases, 3,14,193 controls), plasma lipidomics (179 molecular species), and 731 immune cell phenotypes. Independent, genome-wide significant single-nucleotide variants served as instrumental variables. First, we estimated the causal effects of each plasma lipid on gastric cancer. Then, we explored the potential intermediary role of lipid-associated immune cell traits using a 2-step Mendelian randomization framework. Two lipids - phosphatidylethanolamine (18:0 0:0) and phosphatidylcholine (O-18:0 16:1) - were causally associated with a lower risk of gastric cancer. Three immune cell traits (CD8br and CD8dim %leukocyte, IgD on IgD+ CD38- and CD3 on CD28- CD8br) similarly showed protective effects. In contrast, phosphatidylcholine (O-16:1 18:2), triacylglycerol (49:1), triacylglycerol (56:3), and triacylglycerol (56:4) increased gastric cancer risk, as did immune traits such as TD DN (CD4-CD8-)AC, CD19 on memory B cell, CD28 on CD39+ activated Treg, CD45 on CD4+, CD127 on CD28+DN(CD4-CD8-) and CCR2 on CD14+CD16+ monocyte. Exploratory mediation analyses found no statistically significant evidence that immune cell traits mediated the effects of plasma lipids on gastric cancer risk. Specific phosphatidylethanolamines and phosphatidylcholines confer protection against gastric cancer, whereas several triacylglycerols increase risk. However, exploratory mediation analyses provided no statistically significant evidence that immune cell traits mediated these associations.

Humans↗

Identification of potential key genes involved in iron deficiency for sepsis: A retrospective cohort and transcriptomic study.

Iron overload has been associated with sepsis, but the role of iron deficiency and its molecular links remain unclear. We investigated the association between iron deficiency and sepsis and identified candidate genes potentially linking these conditions. MIMIC-IV data were used to assess the association between serum iron and sepsis status. Transcriptomic datasets from dietary iron-deficient mice (GSE10421), LPS-induced septic mice (GSE267388), and a human blood sepsis cohort (GSE137340) were sequentially analyzed to identify and externally evaluate candidate genes. IEU Open GWAS summary statistics were used for exploratory Mendelian randomization (MR). Exploratory drug prediction was performed using L1000FWD, followed by molecular docking analysis. Patients with sepsis had significantly lower serum iron levels, and restricted cubic spline analysis showed a nonlinear association between serum iron and the odds of sepsis. Cross-tissue transcriptomic analysis identified Sqle, Lss, and Rdh11 as candidate genes. In the human blood cohort, SQLE and RDH11 were significantly increased, whereas LSS was not significantly altered. Exploratory MR showed that genetically proxied SQLE expression was associated with higher odds of sepsis (odds ratio [OR]&#x2005;=&#x2005;1.23, P&#x2005;=&#x2005;1.67&#x2005;&#xd7;&#x2005;10-3), whereas LSS expression was associated with lower odds (OR&#x2005;=&#x2005;0.97, P&#x2005;=&#x2005;8.90&#x2005;&#xd7;&#x2005;10-4); RDH11 showed no significant association (OR&#x2005;=&#x2005;1.01, P&#x2005;=&#x2005;.90). Drug prediction identified ML106 as the top-ranked candidate drug, and molecular docking predicted potential binding poses with SQLE and LSS. Serum iron showed a nonlinear association with sepsis status. SQLE, LSS, and RDH11 emerged as candidate genes, with concordant expression changes of SQLE and RDH11 observed in human blood. MR findings for SQLE and LSS were exploratory and require further validation. ML106 was identified through exploratory drug prediction and requires experimental validation before its therapeutic relevance can be established.

Sepsis↗

A causal relationship between chronic pancreatitis and cardiovascular disease: A two-sample Mendelian randomization analysis.

Current research suggests a link between chronic pancreatitis (CP) and cardiovascular disease (CVD), although the causality remains unclear. The aim of this study was therefore to conduct a 2-sample Mendelian randomization (MR) analysis to determine whether a causal relationship exists between CP and CVD. Summary-level data from publicly available genome-wide association studies of European populations were utilized for the MR analysis. Following quality control measures, independent single-nucleotide polymorphisms associated with CP and CVD were chosen as the genetic instruments. Four complementary MR methods were performed, namely the inverse variance weighted (IVW) method, weighted median, MR-Egger, and leave-one-out sensitivity. The IVW method revealed correlations between alcohol-induced CP and myocardial infarction (odds ratio [OR]&#x2005;=&#x2005;1.001, 95% confidence interval [CI]: 1.000-1.002, P&#x2005;=&#x2005;.0010), as well as with large artery atherosclerosis stroke (OR&#x2005;=&#x2005;1.067, 95% CI: 1.030-1.105, P&#x2005;=&#x2005;.0003). The IVW method also suggested that CP was significantly associated with stroke (OR&#x2005;=&#x2005;1.040, 95% CI: 1.015-1.065, P&#x2005;=&#x2005;.0015) and with ischemic stroke (OR&#x2005;=&#x2005;1.041, 95% CI: 1.005-1.078, P&#x2005;=&#x2005;.0024). These results remained robust and consistent in the sensitivity analysis. This MR study indicates a significant causal relationship between alcohol-induced CP and elevated risks of myocardial infarction and large artery atherosclerosis stroke, and a causal link between CP and stroke as well as ischemic stroke.

Mendelian Randomization Analysis↗

Causal determinants of gout in 614,000 adults: A two-sample Mendelian randomization study of dietary, lifestyle, and metabolic traits.

Gout affects over 55 million people worldwide, with prevalence projected to rise by 70% by 2050. Although observational studies have implicated several dietary, lifestyle, and metabolic risk factors, causal relationships remain uncertain because of confounding and reverse causation. Univariable and multivariable two-sample Mendelian randomization (MR) analyses were performed using genome-wide association data from 2 European cohorts: UK Biobank (6543 self-reported gout cases and 456,390 controls) and FinnGen (3576 cases and 147,221 controls). Genetic instruments for 12 exposures, including dried fruit, salad, and cheese intake; smoking initiation; physical activity; body mass index (BMI); and lipid traits, were derived from established genome-wide association study datasets. Inverse-variance weighted regression with multiplicative random effects was the primary analysis, complemented by weighted median, weighted mode, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier, and 3 predefined multivariable models. Benjamini-Hochberg correction was applied across all 24 tests. BMI showed the strongest and most consistent causal effect on gout (FinnGen: odds ratio [OR]&#x2005;=&#x2005;1.97, 95% confidence interval [CI]&#x2005;=&#x2005;1.51-2.57; UK Biobank: OR&#x2005;=&#x2005;1.006, 95% CI&#x2005;=&#x2005;1.003-1.009; both P&#x2005;<&#x2005;.001) and remained significant in 5 of 6 multivariable models. Triglycerides increased risk in both cohorts (FinnGen: OR&#x2005;=&#x2005;1.34, 95% CI&#x2005;=&#x2005;1.08-1.66; UK Biobank: OR&#x2005;=&#x2005;1.008, 95% CI&#x2005;=&#x2005;1.004-1.012). These associations survived Benjamini-Hochberg correction, as did high-density lipoprotein cholesterol in UK Biobank (OR&#x2005;=&#x2005;0.997, 95% CI&#x2005;=&#x2005;0.994-0.999). Dried fruit intake was inversely associated with gout in FinnGen (OR&#x2005;=&#x2005;0.34, 95% CI&#x2005;=&#x2005;0.13-0.92, P&#x2005;=&#x2005;.034) but not in UK Biobank, and did not survive correction for multiple testing. No other exposure reached significance in either cohort. This study provides genetic evidence that BMI is the dominant modifiable causal determinant of gout, with triglycerides contributing independently. Dietary associations were weaker and did not withstand correction for multiple testing, and should be regarded as hypothesis-generating. These findings support prioritizing weight management and metabolic health in gout prevention.

Gout↗

Randomized controlled trial comparing 7-day fexuprazan-based and 14-day rabeprazole-based triple therapies for Helicobacter pylori eradication.

BACKGROUND: Fexuprazan is a newly developed potassium-competitive acid blocker used for the treatment of acid-related gastrointestinal diseases; however, clinical data regarding its efficacy in Helicobacter pylori eradication are lacking. This study evaluated the efficacy and safety of a 7-day fexuprazan-based triple therapy regimen compared with a 14-day rabeprazole-based triple therapy regimen for H. pylori infection in Korean patients. METHODS: A randomized controlled single-center study was conducted to compare the eradication rates between 7-day fexuprazan (40&#x2009;mg)-based triple therapy (with 1&#x2009;g amoxicillin and clarithromycin 500&#x2009;mg administered twice daily) and 14-day rabeprazole (20&#x2009;mg)-based triple therapy for H. pylori eradication. The primary endpoint was the success rate of H. pylori eradication, determined using the 13C-urea breath test. Safety outcomes were also evaluated. RESULTS: A total of 79 patients were randomly assigned to the fexuprazan and rabeprazole groups. In the full analysis set, eradication rates were 80.00% (32/40) in the fexuprazan group and 82.05% (32/39) in the rabeprazole group. In the per-protocol set, eradication rates were 83.78% (31/37) and 88.89% (32/36), respectively (P = 1.000 and P =.737). The overall incidence of treatment-emergent adverse events was 70.00% (28/40) in the fexuprazan group and 66.67% (26/39) in the rabeprazole group, with no significant difference between groups (P =.812); both regimens were well tolerated. Among patients with clarithromycin-susceptible strains in full analysis set, eradication rates were 93.10% (27/29) in the fexuprazan group and 87.09% (27/31) in the rabeprazole group (P =.672). In the per-protocol set, eradication rates for susceptible strains were 96.42% (27/28) in the fexuprazan group and 93.10% (27/29) in the rabeprazole group (P = 1.000). CONCLUSION: Seven-day fexuprazan-based triple therapy demonstrated eradication efficacy comparable with that of 14-day rabeprazole-based therapy in treatment-na&#xef;ve Korean patients with H. pylori infection. The fexuprazan-based regimen showed a similar safety profile and comparable incidence of adverse events with that of the rabeprazole-based regimen.

Humans↗

Music therapy in artificial insemination by husband: Effects on psychological distress and clinical pregnancy rate.

BACKGROUND: Infertility treatment can be psychologically burdensome. Evidence on music listening during artificial insemination by husband (AIH) remains limited. We evaluated whether a standardized periprocedural music intervention reduced psychological distress and explored its association with clinical pregnancy. METHODS: In this single-center, open-label randomized trial, 254 women undergoing AIH were allocated 1:1 to routine care or routine care plus two 30-minute music-listening sessions, immediately before and after AIH. The prespecified primary outcome was the continuous 21-item Depression Anxiety Stress Scales (DASS-21) score at follow-up; clinical pregnancy was secondary. DASS-21 was completed at baseline and at day 35 after AIH. Clinical pregnancy was assessed by ultrasonography at days 30 to 35. RESULTS: Continuous DASS-21 anxiety, depression, and stress scores did not differ between groups after adjustment for baseline scores (all P&#x2005;&#x2265;&#x2005;.868). Absolute postintervention differences were 0.01 point or less for anxiety and depression and 0.08 point for stress, indicating neither statistical nor clinically meaningful improvement. Clinical pregnancy occurred in 34/127 participants (26.77%) in the intervention group and 14/127 (11.02%) in the control group (exploratory secondary outcome; P&#x2005;=&#x2005;.001). CONCLUSION: The intervention did not improve the primary psychological outcome. The higher clinical pregnancy rate is hypothesis-generating because the trial was not powered for pregnancy, the proposed psychological mechanism was not demonstrated, and nonspecific attention and other unmeasured factors cannot be excluded. Replication using an attention-matched control, immediate state-anxiety and physiological measures, participant-preference assessment, and live-birth follow-up is required.

Humans↗

Effects of a situational interest-based rotational fitness training program on positive affect in university students: A randomized controlled trial.

BACKGROUND: To evaluate whether a 12-week situational interest-based rotational fitness program improved positive emotional states in university students, to compare module-specific effects, and to examine whether the intervention moderated the heart rate-emotion association. METHODS: In this 2-arm randomized controlled trial, 560 freshmen from 10 Chinese universities were assigned to an experimental (n&#x2005;=&#x2005;280) or control group (n&#x2005;=&#x2005;280). The experimental group completed weekly 90-minute sessions covering strength, endurance, speed, and agility modules; controls received regular physical education. Positive emotional states were assessed using the positive well-being subscale of the Subjective Exercise Experiences Scale through ecological momentary assessment at 3 points per session, yielding over 14,000 observations. Linear mixed-effects models tested group, time, group&#x2005;&#xd7;&#x2005;time, heart rate, and heart rate&#x2005;&#xd7;&#x2005;group effects. Assessors and analysts were blinded. Ethical approval for the trial was granted by the Institutional Review Board of Capital University of Physical Education and Sports (2025A055). RESULTS: Improvement was greater in the experimental group than in controls (EMM change: 1.843 vs 0.505; difference&#x2005;=&#x2005;1.338, 95% confidence interval [CI]: 1.275-1.400, P&#x2005;<&#x2005;.001). At week 12, the raw between-group difference was 1.85 (d&#x2005;=&#x2005;2.23), and all group&#x2005;&#xd7;&#x2005;week interactions from weeks 2 to 12 were significant. Heart rate positively predicted emotional states in controls (B&#x2005;=&#x2005;0.005, 95% CI: 0.003-0.007), but this association was attenuated in the experimental group (interaction B&#x2005;=&#x2005;-0.008, 95% CI: -0.011 to -0.005). Strength and agility showed significant improvements, while endurance produced consistently higher emotional states across assessment points. Heart rate moderation was significant for strength and endurance, but not speed or agility. CONCLUSION: The rotational program improved positive emotional states more than regular physical education, although effects varied by module. Strength showed the most robust benefit. The program also weakened, but did not eliminate, the heart rate-emotion association during more demanding activities.

Humans↗

Association of gestational diabetes with other lactation-related disorders: A 2-sample Mendelian randomization analysis of causal effects.

Gestational diabetes mellitus (GDM) is associated with adverse metabolic outcomes and may also be related to postpartum breast and lactation disorders. Observational studies are susceptible to confounding and reverse causation. We used a 2-sample Mendelian randomization design to examine the association between genetic liability to GDM and other disorders of the breast and lactation associated with childbirth. Genetic liability to GDM was associated with higher odds of a composite phenotype of breast and lactation disorders associated with childbirth. Replication using independent samples and more specific clinical outcomes is required. Summary statistics for GDM and the FinnGen outcome "other disorders of breast and lactation associated with childbirth" were obtained from the Integrative Epidemiology Unit open genome-wide association study resource. single nucleotide polymorphisms associated with GDM (P&#x2005;<&#x2005;5&#x2009;&#xd7;&#x2009;10-6) were clumped (R2&#x2005;<&#x2005;0.001) within 10,000&#x2009;kb. The inverse-variance weighted method was the primary analysis; Mendelian randomization-Egger, weighted median, simple mode, and weighted mode analyses were complementary methods. Heterogeneity, directional horizontal pleiotropy, leave-one-out, and Steiger directionality analyses were performed. Nineteen single nucleotide polymorphisms were retained; F statistics ranged from 21.08 to 288.04. Genetic liability to GDM was associated with higher odds of the outcome in the inverse-variance weighted analysis (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.08-2.09; P&#x2005;=&#x2005;.0165). The weighted median (OR, 1.76; 95% CI, 1.09-2.84; P&#x2005;=&#x2005;.0216) and weighted mode estimates (OR, 1.98; 95% CI, 1.21-3.26; P&#x2005;=&#x2005;.0148) were directionally consistent. There was no statistical evidence of heterogeneity or directional horizontal pleiotropy. The Steiger test supported the direction from GDM to the outcome (P&#x2005;=&#x2005;1.30&#x2005;&#xd7;&#x2005;10-11).

Diabetes, Gestational↗

Cost-effectiveness analysis of omeprazole for preventing esophageal stricture in patients with Zargar grade 2b and 3a corrosive esophageal injuries: A trial-based economic evaluation.

BACKGROUND: Corrosive esophageal injury frequently results in esophageal stricture requiring repeated endoscopic dilatation and substantial healthcare expenditure. This study evaluated the cost-effectiveness of omeprazole plus standard treatment compared with standard treatment alone for preventing esophageal stricture in adult patients with Zargar grade 2b and 3a corrosive esophageal injuries. METHODS: A trial-based economic evaluation was conducted alongside a randomized controlled trial from the healthcare provider and patient perspectives. Twenty patients were randomized to receive either standard treatment alone (n&#x2005;=&#x2005;10) or standard treatment plus omeprazole (n&#x2005;=&#x2005;10). Direct medical costs were analyzed using the incremental cost-effectiveness ratio. Deterministic one-way sensitivity analysis and probabilistic sensitivity analysis using Monte Carlo simulation were performed. RESULTS: The incidence of corrosive esophageal stricture was 20% (2/10) in the omeprazole group and 70% (7/10) in the standard treatment group (relative risk, 0.29; 95% confidence interval, 0.08-1.05; Fisher's exact test, P&#x2005;=&#x2005;.070). Omeprazole plus standard treatment reduced healthcare costs by THB 4642.30 per patient from the provider perspective and THB 5476.60 per patient from the patient perspective. The intervention remained the dominant strategy across all deterministic sensitivity analyses. Probabilistic sensitivity analysis demonstrated that 68.3% and 78.8% of simulations favored omeprazole from the provider and patient perspectives, respectively. CONCLUSION: Omeprazole plus standard treatment may represent a cost-effective strategy for adult patients with Zargar grade 2b and 3a corrosive esophageal injuries. However, these findings should be considered preliminary and require confirmation in larger multicenter randomized controlled trials.

Humans↗

From genotype to phenotype: understanding the genetic basis of autism.

PURPOSE OF REVIEW: This paper covers some of the key findings on the topic of genetic influences in autism over the last 12-18&#x200a;months, which consist of significant conceptual shifts and new insights from recent technological advances. RECENT FINDINGS: Autism is a highly heritable condition, with significant heterogeneity of the genes that influence the development of this condition. The heterogeneity of autism, and multiple pathways contributing to the development of an autistic phenotype, create challenges in our understanding, diagnosis, and management of this condition.Recent studies of common genetic variation and polygenic risk scores have focussed on resolving phenotypic heterogeneity and identifying meaningful autism subtypes. Rare-variant discovery has expanded across ancestries, the X chromosome, noncoding loci, structural variants, and tandem repeats, aided by long-read and pangenome-informed sequencing. Single-cell multiomics, spatial perturbation methods and human organoid models have connected genetic variation to cell-type-specific and developmental phenotypes, while also revealing substantial mutation-specific effects and methodological sensitivity. Genetic testing increasingly provides aetiological diagnoses and informs medical surveillance. Recent developments also illustrate the therapeutic potential of gene-first approaches for selected monogenic neurodevelopmental disorders. SUMMARY: Recent developments have expanded our understanding of the way the genetic basis of autism manifests phenotypically.

autism↗

PCR analysis of insertion sequences leads to the generation of artefact amplicons.

Insertion sequences (ISs) are small, self-mobilizing DNA elements widespread across prokaryotic genomes, including chromosomes and plasmids. IS elements frequently co-localize with antimicrobial resistance (AMR) genes and mediate their mobilization, often as part of larger genomic structures that encompass multiple IS elements and antibiotic resistance genes. In this study, we employed Polymerase Chain Reaction (PCR) to amplify DNA sequences containing two copies of an IS26 element from two Escherichia coli ST131 isolates. While the respective PCRs generated products of the expected size, we also observed multiple amplicons of unexpected sizes, which could be misinterpreted as population heterogeneity attributed to IS mobilization. By extracting, re-amplifying and sequencing individual PCR products, we demonstrate that these amplicons of unexpected sizes were indeed artefact products generated during the PCR reaction, likely mediated by within-PCR recombination of the IS26 sequences. Furthermore, PCRs with equally oriented primers, each located close to an IS26 element, also generated artefact amplicons. This research highlights the limitations of using PCR to assess DNA sequences encoding multiple copies of an IS element and therefore, the presence of these genomic structures or the mobilization of the respective IS elements should not be assessed by diagnostic PCR alone but be corroborated with complementary techniques.

ESBL↗

Massively parallel characterization of adolescent idiopathic scoliosis risk variants.

Adolescent idiopathic scoliosis (AIS) is a common pediatric musculoskeletal disorder characterized by lateral spinal curvature, often leading to chronic pain and deformity. Although a significant genetic component to AIS is recognized, the functional impact of most associated genetic variants, particularly those in noncoding regions, remains largely unknown. Using massively parallel reporter assays, we characterize 1664 variant positions in linkage disequilibrium with 26 AIS lead variants identified by genome-wide association studies (GWASs) in chondrocytes, a major cell type implicated in AIS pathogenesis. Using a library of 7173 candidate regulatory sequences, we compare the 1664 reference alleles against 4708 alternate alleles in two human chondrocyte cell lines (TC28a2 and SW1353). Our analysis identifies 92 variants that exhibit significant differential regulatory activity between their reference and alternate alleles, 79 of which are predicted to disrupt transcription factor binding sites, often correlating with their observed regulatory effect. Notably, we validate rs9496392, a single-nucleotide variant near the ADGRG6 locus, which shows consistent differential regulatory activity in both cell lines. ADGRG6 is a key regulator of cartilage homeostasis, and its cartilage-specific knockout in mice results in a scoliosis-like phenotype. The AIS risk allele of rs9496392 (T) is predicted to strongly disrupt several TFBSs, including SP1. This study provides a foundational catalog of functional AIS-associated regulatory variants active in chondrocytes, offering crucial insights into the perturbed gene regulatory networks in AIS. These findings lay the groundwork for identifying biomarkers and potential therapeutic targets for this complex childhood disease.

Journal Article↗

What Uniparental Lineages Tell Us About the Prehistoric Human Colonization of the Americas.

OBJECTIVES: From the perspective of uniparental markers, the view of the human prehistoric settlement of America is that it resulted from a single main migration after the Last Glacial Maximum, following a long or short period of genetic isolation in Beringia. Ancient DNA and whole genome analyses have confirmed this view. My objective here is to demonstrate that humans entered America before the LGM and that the documented post-LGM expansions began in South instead of North America. METHODS: In this work, I have reanalyzed all publicly available mitochondrial DNA and Y-chromosome haplogroups in the American population using simple phylogenetic and phylogeographic methodologies. RESULTS: The arrival of the American settlers occurred more than 30,000 years ago, preceding the LGM. As genomic studies have uncovered, at least two Asian populations contributed to the ancestry of the immigrant population. Low population density and climatic deterioration led to a long period of demographic eclipse, during which small bands of hunter-gatherers made long journeys in search of favorable niches. After the LGM, the climate improved, and demographic expansions occurred in multiple independent centers. The founding and expansion ages of the uniparental haplogroups indicate that these centers were in South America, particularly the Colombian isthmus, the Andean region, the Southern Cone, and the Amazon. Subsequent dispersals occurred in North America, one involving mitochondrial haplogroups A2, C1, and D1, but not B2, and another, of lesser magnitude, represented by the expansion of haplogroups C4c and X2a. CONCLUSION: This work offers a previously unexplored model for the colonization of the Americas.

Native American↗