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PubMed2026

A systematic review and meta-analysis of the late positive potential and internalizing psychopathology.

The present study leveraged the Hierarchical Taxonomy of Psychopathology (HiTOP) framework to conduct a systematic meta-analysis to determine the association between the late positive potential (LPP) index of emotional reactivity and internalizing psychopathology. PRISMA guidelines were followed. Articles were identified through PubMed, APA PsycInfo, and Web of Science online platforms in May 2025. Included articles examined associations between the LPP to positive and/or negative stimuli and internalizing psychopathology. Risk of bias and publication bias were assessed. Results were examined for individual disorders, distress and fear subfactors, and the internalizing spectrum using two approaches: standard analyses that examined aggregate effects and hierarchical analyses that examined direct and indirect relationships. We conducted moderator analyses for sample, task design, LPP quantification, and psychopathology measurement. We included 63 studies across 5,360 participants (Mage = 19.65, SD = 11.1; 58.7% female). In standard meta-analyses, depression was associated with a smaller LPP to positive stimuli (r = -.06, 95% confidence interval [CI; -.12, -.003]). Specific phobia was associated with a larger LPP to negative stimuli (r = .21, 95% CI [.02, .37]). Distress was associated with a smaller LPP to both positive (r = -.12) and negative (r = -.11) stimuli when measured via clinical interview, and fear was associated with a larger LPP to negative stimuli (r = .10, 95% CI [.03, .16]). Hierarchical analyses indicated that the depression results were specific to the disorder, whereas the fear disorder-level results were due to the higher order fear subfactor. The LPP demonstrates discriminant relationships with distress and fear disorders and subfactors. Results were largely robust against methodological factors. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Humans↗
PubMed2025

Systematic discovery of CRISPR-boosted CAR T cell immunotherapies.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in treating blood cancers, but CAR T cell dysfunction remains a common cause of treatment failure1. Here we present CELLFIE, a CRISPR screening platform for enhancing CAR T cells across multiple clinical objectives. We performed genome-wide screens in human primary CAR T cells, with readouts capturing key aspects of T cell biology, including proliferation, target cell recognition, activation, apoptosis and fratricide, and exhaustion. Screening hits were prioritized using a new in vivo CROP-seq2 method in a xenograft model of human leukaemia, establishing several gene knockouts that boost CAR T cell efficacy. Most notably, we discovered that RHOG knockout is a potent and unexpected CAR T cell enhancer, both individually and together with FAS knockout, which was validated across multiple in vivo models, CAR designs and sample donors, and in patient-derived cells. Demonstrating the versatility of the CELLFIE platform, we also conducted combinatorial CRISPR screens to identify synergistic gene pairs and saturation base-editing screens to characterize RHOG variants. In summary, we discovered, validated and biologically characterized CRISPR-boosted CAR T cells that outperform standard CAR T cells in widely used benchmarks, establishing a foundational resource for optimizing cell-based immunotherapies.

Humans↗
PubMed2025

Genetic Differences in Reactivity to the Environment Impact Psychotic-Like and Affective Reactivity in Daily Life.

BACKGROUND AND HYPOTHESIS: Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. STUDY DESIGN: Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. STUDY RESULTS: PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. CONCLUSIONS: Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Humans↗
PubMed2025

Exploring the causal association between television viewing and meniscal injuries: A two-sample Mendelian randomization analysis.

The aim of this study was to assess whether there is a potential causal relationship between sedentary behavior and meniscal injuries based on the Mendelian randomization (MR) method. This study used a two-sample MR design to integrate pooled data from a large-scale genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) that were significantly associated with sedentary behavior (represented by daily TV-viewing time) and independent of each other were selected as instrumental variables, while focusing on data from populations of European ancestry. To ensure the robustness and reliability of the analyses, 3 mainstream MR analysis methods were combined in this study: inverse variance weighted (IVW), weighted median estimation (WME) and MR-Egger regression. Heterogeneity test, horizontal multivariate analysis, and leave-one-out sensitivity test were also conducted to further validate the stability of causal estimation. The results of the IVW method showed that sedentary behavior was significantly associated with the risk of meniscus injury, with an OR (95% CI) of 2.93 (1.89-4.52), and a P-value of&#x2005;<&#x2005;.001, suggesting that sedentary behavior may be an important risk factor for meniscus injury. No significant bias was found in the heterogeneity test and the assessment of multiple validity, and the sensitivity analysis showed that the effect of individual SNPs on the overall estimation was small, and the results had good robustness. This study provides genetic epidemiological evidence of a positive causal effect of sedentary behavior on meniscal injuries based on a causal inference approach with genetic instrumental variables. The results suggest that reducing sedentary time, especially prolonged TV watching behavior, may reduce the risk of meniscus injury to some extent.

Humans↗
PubMed2026

Identification and genetic validation of potential therapeutic targets for pulmonary hypertension through multi-omics causal inference.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-&#x3b2; signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Hypertension, Pulmonary↗
PubMed2025

Novel Protein-Altering Variants in Cleft Genes Transmitted in Families With NSCL&#xb1;P.

BACKGROUND: Pathogenic protein-altering variants play a role in the etiology of nonsyndromic cleft lip with or without palate (nsCL&#xb1;P), one of the most common craniofacial anomalies. However, the genetic basis of many cases remains unclear, complicating risk prediction for affected families. PURPOSE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL&#xb1;P from sub-Saharan Africa to identify pathogenic risk variants. STUDY DESIGN, SETTING, SAMPLE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL&#xb1;P from sub-Saharan Africa to identify risk variants. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: Genetic variants. MAIN OUTCOME VARIABLES: Nonsyndromic cleft lip with or without palate (nsCL&#xb1;P). ANALYSES: Genomes were sequenced at a mean &#xd7;30 coverage, and variants were prioritized using CADD (&#x2265;20), REVEL (&#x2265;0.5), and ACMG/AMP clinical significance criteria. RESULTS: We identified pathogenic protein-altering variants in CHD7 (p.Arg1345His), LRP2 (p.Asp3245Asn), RYR1 (p.Arg2163Leu, p.Pro2903Thr), SHH (p.Met114Val), and WNT3 (p.Ser112Pro) highlighting the role of hedgehog signaling pathway (FDR=5.32e-12) in nsCL&#xb1;P. These variants were inherited from unaffected parents suggesting an incomplete penetrance of the variant effect. Although mouse data showed that knockout of these genes produces cleft phenotypes, in vivo studies will help us better understand how the consequences of these variants differ from benign mutations. The presence of these protein-altering variants in unaffected parents-incomplete penetrance, provides additional evidence supporting the trait complexity. CONCLUSIONS AND RELEVANCE: This study identified rare, pathogenic protein-altering variants in genes involved in key developmental pathways in African families affected by nsCL&#xb1;P. These findings highlight the critical role of the hedgehog signaling pathway and related networks in the etiology of nsCL&#xb1;P. These findings underscore the importance of whole-genome sequencing in genetically diverse populations to uncover novel risk variants. These findings enhance our understanding of the genetic etiology of nsCL&#xb1;P, particularly in under-represented African populations and support the multifactorial inheritance and the involvement of developmental pathways, such as hedgehog signaling in the etiology of clefting.

Humans↗
PubMed2025

CAUSAL ASSOCIATION BETWEEN SEPSIS AND FIBROBLAST GROWTH FACTORS AS WELL AS THEIR RECEPTORS LEVELS: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY.

Objective: The potential association between sepsis risk and circulating levels of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been a focus of research; however, the causal relationship between them remains to be elucidated. We hypothesize a causal association between genetically predicted FGFs, FGFRs, and sepsis risk, and we conduct a Mendelian randomization (MR) study to validate this hypothesis. Methods: We utilized a two-sample MR design to assess the effect of genetic variants associated with various FGFs (FGF1, FGF2, FGF7, FGF16, FGF19, FGF21, FGF23, FGF5) and FGFRs (FGFR1, FGFR2, FGFR3, &#x3b1;-Klotho) on sepsis risk, using genome-wide association study summary statistics. Our MR analyses employed the inverse-variance weighted (IVW) method, along with weighted median, weighted mode, and MR-Egger regression, supplemented by sensitivity analyses to ensure robustness. Results: The MR analysis identified an unequal number of instrumental variables ranging from 2 to 17 for FGFs and FGFRs when sepsis was the outcome. No significant correlation was found between genetically determined FGF levels and sepsis risk by IVW analysis (all P > 0.05). Correspondingly, similar nonsignificant associations were observed for FGFRs (all P > 0.05). Other MR methods corroborated the IVW findings. Sensitivity analyses, including Cochran's Q test, MR-Egger, and MR pleiotropy residual sum and outlier, indicated no significant heterogeneity or pleiotropy in the relationships, with the exception of a nonsignificant correlation between FGFR1 and sepsis that persisted after the exclusion of an outlier (odds ratio, 0.84; P = 0.34). Conclusion: The analysis found no significant causal associations between FGFs, their receptors, and sepsis risk, indicating a need for further research on their complex interactions.

Humans↗
PubMed2022

Adolescents hospitalised for suicidality: biomarkers, social and affective predictors: a cohort study.

OBJECTIVES: The present research examines genomics and in vivo dynamics of family context and experienced affect following discharge from psychiatric hospitalisation for suicidal thoughts and behaviours (STBs). The purpose of this paper is to provide an overview of a new model, description of model-guided integration of multiple methods, documentation of feasibility of recruitment and retention and a description of baseline sample characteristics. DESIGN: The research involved a longitudinal, multimethod observational investigation. SETTING: Participants were recruited from an inpatient child and adolescent psychiatric hospital. 194 participants ages 13-18 were recruited following hospitalisation for STB. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants underwent a battery of clinical interviews, self-report assessments and venipuncture. On discharge, participants were provided with a phone with (1) the electronically activated recorder (EAR), permitting acoustic capture later coded for social context, and (2) ecological momentary assessment, permitting assessment of in vivo experienced affect and STB. Participants agreed to follow-ups at 3 weeks and 6 months. RESULTS: A total of 71.1% of approached patients consented to participation. Participants reported diversity in gender identity (11.6% reported transgender or other gender identity) and sexual orientation (47.6% reported heterosexual or straight sexual orientation). Clinical interviews supported a range of diagnoses with the largest proportion of participants meeting criteria for major depressive disorder (76.9%). History of trauma/maltreatment was prevalent. Enrolment rates and participant characteristics were similar to other observational studies. CONCLUSIONS: The research protocol characterises in vivo, real-world experienced affect and observed family context as associated with STB in adolescents during the high-risk weeks post discharge, merging multiple fields of study.

Adolescent↗
PubMed2026

Comparison of endothelin-1 levels in plasma from human coronary arteries measured by enzyme linked immunosorbent assay and Olink high-throughput proteomics platform.

Endothelin-1 (ET-1) antagonists are increasingly being approved for new treatments for cardiovascular disease, where elevated ET-1 levels contribute to increased vasoconstriction. Further therapeutic targets, including coronary artery disease, are under investigation. The Olink Explore 3072 Proximity Extension Assay platform enables multiplexed high-throughput measurement of ~3000 plasma proteins, from minimal (&#x2264;6&#x2009;&#xb5;L) sample volumes. However, it is not known if the two oligonucleotide-tagged antibodies raised against preproET-11-212, used in this Olink assay, specifically measure biologically active ET-1 or the other inactive EDN1-encoded peptides, also secreted by human endothelial cells. Paired plasma samples from 29 patients with coronary artery disease were obtained, using a specialised intra-coronary sampling catheter, designed to obtain site specific biochemical information from within coronary arteries. We compared ET-1 concentrations measured with an ET-1 specific ELISA, demonstrated to have no cross-reactivity with other EDN1-encoded peptides versus values obtained using Olink Explore platform. Olink-measured ET-1 correlated significantly with ELISA-derived ET-1 levels (r&#xa0;=&#xa0;0.53, p&#xa0;=&#xa0;0.003), and Olink values predicted ELISA results. Olink ET-1 concentrations also correlated with ETB receptor levels (r&#xa0;=&#xa0;0.40, p&#xa0;<&#xa0;0.05). These findings indicate that the Olink Explore platform can detect relative changes in biologically active ET-1, supporting its use as a biomarker tool in clinical and translational studies.

Humans↗
PubMed2026

Mendelian Randomization Analysis of NETs-Associated Inflammatory Traits and Type 2 Diabetes and its Complications.

Neutrophil extracellular traps (NETs) -associated inflammatory traits play a significant role in type 2 diabetes mellitus (T2DM) and its complications. Notably, IL-6, a key inflammatory cytokine, is intricately linked to the formation of NETs and the pathogenesis of T2DM and its complications. This study aimed to explore the causal association between NETs-associated inflammatory traits and T2DM, as well as its complications, using a Mendelian Randomization (MR) approach. This study utilized a two-sample MR design with data from Genome-Wide Association Studies (GWAS), comprising a large European population-based meta-analysis for T2DM and its complications. The primary method of analysis was the inverse variance weighted (IVW) approach, complemented by MR-Egger regression, weighted median, and weighted mode methods. Sensitivity analyses included MR-Egger, MR-PRESSO, Cochran's Q, and leave-one-out methods to assess the robustness of the findings. The study indicated that genetically predicted levels of interleukin-6 (IL-6) were inversely associated with diabetic coronary artery disease (CAD) (OR = 0.8997, 95% CI: 0.8257-0.9803, P = 0.0158). Additionally, NETs showed significant associations with T2DM with renal complications (OR=0.97, 95% CI 0.9428-0.998, P = 0.0358) and T2DM with peripheral circulatory complications(OR = 1.0342, 95% CI 1.002-1.0673, P = 0.037). The significant IVW associations showed no evidence of heterogeneity or horizontal pleiotropy. This study suggests that genetically predicted NETs-associated inflammatory traits are associated with specific T2DM complications. Genetically predicted IL-6 was inversely associated with diabetic CAD, whereas NETs were associated with renal and peripheral circulatory complications in T2DM.

Diabetes Mellitus, Type 2↗
PubMed1978

[Studies of drugs without randomization (author's transl)].

Post marketing studies of drugs are frequently performed without randomization. In this paper the most important differences between controlled clinical trials and epidemiologic studies are discussed from a cognitive theoretical point of view. It is shown that on the transition of informations from the basic population to the document many biases may arise so that the feasibility of interpreting epidemiologic studies is doubtful. Hence, epidemiologic studies only allow us to make statements on differences between populations but not on the reasons causing them; they merely contribute to the generation of certain hypothesis on the action of drugs. These hypothesis can only be tested in experiments.

Drug Evaluation↗