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Heterozygous loss-of-function variants in Neurabin I (PPP1R9A), responsible for encoding a cytoskeletal scaffolding protein essential for synaptic plasticity, are recurrently associated with neurodevelopmental and neuropsychiatric disorders, yet their direct effects on human neuronal maturation remain unclear. Here, we establish the first comprehensive human mechanistic model of PPP1R9A haploinsufficiency using an isogenic CRISPR/Cas9-engineered iPSC system differentiated into cortical neurons...

CONCLUSIONS: Children and adolescents develop recurrent AVMs at a higher rate than adult patients despite angiographic cure after initial resection. On multivariable analysis, deep venous drainage was independently associated with recurrence. Further work can help elucidate clinical and radiographic predictors of disease recurrence.

CONCLUSIONS: AMR and graft loss following kidney transplantation were defined by compartment-specific disruptions in complement and mitochondrial proteins.

CONCLUSION: The mis-localization and altered post-translational modification of p.(Ala2Val) DKC1 provides functional evidence to clinical laboratories to reclassify p.(Ala2Val) variant as "pathogenic" as per American College of Medical Genetics (ACMG) variant interpretation guidelines.

Endogenous retrotransposable elements (EREs) can modulate immune responses. We explored ERE transcription in relation to response to immune checkpoint inhibition in advanced solid tumors. ERE expression was measured in pre and on-treatment samples from patients treated in a clinical trial with pembrolizumab. We evaluated immune cell infiltration and correlated ERE expression with interferon-stimulated gene profiles and cytolytic activity. Two independent datasets were retrospectively analyzed as...

Comparative genomics provides a powerful framework to uncover the molecular and evolutionary mechanisms that shape genetic diversity, revealing how shared or lineage-specific processes influence their evolutionary trajectories. The nematode Caenorhabditis briggsae is distributed world-wide and is a comparative model to Caenorhabditis elegans in the biology of development, cellular mechanisms, neurobiology, complex trait mappings, and evolution. Following massive collection efforts by the...

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IntroductionWhile there has been a rapid uptake of virtual care in recent years, understanding of its impact on the quality of cancer care remains fragmented due to the heterogeneity of evaluation measures used to date and the lack of a framework to guide the work. We aimed to develop a comprehensive evaluation framework for virtual care in routine oncology practice.MethodsWe conducted separate nominal consensus groups with key informants (knowledge users, policy makers, clinicians, patients,...

Per and polyfluoroalkyl substances (PFAS) have emerged as ubiquitous contaminants in municipal solid waste (MSW) landfill leachates due to their widespread industrial applications, environmental persistence, and the disposal of PFAS-containing waste in landfill. This study presents a multi-regional investigation of PFAS occurrence, influencing factors, and treatment performance in 17 landfill leachates and 9 corresponding effluents across China. Sum PFAS concentrations in raw leachates ranged...

Inflammatory diseases of connective tissues such as periodontitis and rheumatoid arthritis exhibit localized destruction of matrix collagen and loss of tissue function. These diseases are driven by interconnected signaling pathways that determine disease progression and severity. Both periodontitis and rheumatoid arthritis involve the release of extracellular Vimentin (ECV) from stromal and immune cells at diseased sites, but the processes by which ECV binds to cells and promotes inflammatory...

CONCLUSIONS: AI-assisted wbMRI interpretation can improve tumor detection in pediatric cancer surveillance by reducing false negatives. However, its influence on workflow efficiency and interradiologist variability highlights the importance of careful implementation. Successful integration requires addressing challenges such as improving the predictive precision of AI models, offering intuitive end-user designs and instructions, and building trust in AI outputs. AI outputs can influence workflow...

Pathogenic variants in the autoimmune regulator (AIRE) cause autoimmune polyendocrine syndrome type 1 (APS-1), a rare primary immunodeficiency disease with symptoms including hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis. AIRE increases the expression and presentation of tissue-specific genes expressing "self" antigens in the developing T cell niche, thus triggering the elimination of self-reactive T cells and preventing autoimmunity. Earlier diagnoses can...

Transcription factors (TFs) are key players in eukaryotic gene regulation, but the DNA binding specificity of many TFs remains unknown. Here, we assay 284 mostly uncharacterized putative human TFs using selective microfluidics-based ligand enrichment followed by sequencing (SMiLE-seq), revealing 74 new DNA binding motifs. To investigate whether TFs lacking detectable motifs preferably bind epigenetically modified DNA, we develop methylation-sensitive SMiLE-seq (meSMiLE-seq), a microfluidic assay...

The functional impact of a large portion of the human genome known as "dark matter DNA", which is composed mainly of repeat sequences, remains unknown. The genome also encodes many putative and poorly characterized transcription factors. Here, we determine genomic binding locations of 166 poorly characterized human transcription factors in living cells. Nearly half of them associate strongly with known regulatory regions such as promoters and enhancers, frequently co-localizing with each other...

Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs¹. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells². Here we describe a systematic effort ('Codebook') to determine the sequence specificity of 332 putative and poorly...

There is ongoing debate regarding the degree to which transcription factors (TFs) independently specify genomic binding: TF binding motifs are typically short and degenerate, yielding many more binding site predictions than observed in cells. Here we present genomic high-throughput SELEX (GHT-SELEX)-a scalable method that surveys intrinsic binding of purified TFs to the fragmented, naked and unmodified genome. GHT-SELEX peaks for 179 diverse human TFs display surprisingly high overlap with...

Plain Language SummaryResponding to concerns regarding the methods and findings of a study on autism and gender diversity in CanadaDinu and colleagues wrote a letter to the editor about a recently published study that looked at differences in characteristics between autistic and non-autistic adults who were seen by clinicians at a Canadian gender identity clinic. Dinu and colleagues encouraged interpreting the findings of the original article with caution, because they were concerned about the...

CONCLUSIONS: Early program findings suggest that providing hospital-level of care in a community based harm reduction setting may be an acceptable alternative to traditional hospital admission in appropriately selected patients who use drugs.

CONCLUSIONS AND RELEVANCE: In this cohort study of females who underwent BRCA1 or BRCA2 testing, the lifetime cancer risk varied substantially across BRCA test result groups and was further modified by family history. Elevated breast cancer risk among individuals with VUS or negative results highlights the need for individualized risk assessment and management beyond genetic test results alone.

Tioxazafen is an effective nematicide whose commercialization was halted because handlers reportedly developed rashes after working with seeds coated with a tioxazafen-laced cocktail. Here, we show that tioxazafen is bioactivated into toxic products by nematode and human cytochrome P450s. Through systematic analyses, we found that bioactivated tioxazafen disrupts proteasome function, leading to the accumulation of the NRF1 transcription factor ortholog SKN-1A in the nematode C. elegans, and a...