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We hypothesized that transcriptomic features among disease-driving hematopoietic stem and progenitor cells (HSPC) could improve the current paradigm for risk stratification in myelofibrosis (MF). Therefore, we performed bulk RNA-seq on blood from 358 MF patients split into training and test cohorts (ClinicalTrials.gov Identifier: NCT02760238). Single-cell (sc) RNA-seq data from Lin-CD34+ MF HSPCs were used to guide the development of a prognostic model trained on the bulk RNA-seq data. A...

Phage genomes integrated within bacterial genomes, known as prophages, frequently encode proteins that provide defense against further phage infection. These proteins often function by altering the cell surface and preventing phages from attaching to their host receptor. Here, we describe prophage-encoded proteins that resemble FimU, a component of the Pseudomonas aeruginosa type IV pilus. These phage FimU proteins are incorporated into the pilus without altering its function, yet they mediate...

Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK),...

PURPOSE/BACKGROUND: In patients with major depressive disorder (MDD), anxiety symptoms are common and associated with reduced treatment response. In an 8-week, phase 4, open-label study (ENGAGE), patients with MDD and inadequate antidepressant treatment response showed improvements in patient life engagement, depressive symptoms, and anxiety symptoms following treatment with adjunctive brexpiprazole 0.5 to 2 mg/d. This post hoc analysis of ENGAGE aimed to characterize the utility of adjunctive...

CONCLUSIONS: The inability to enjoy sensory experiences and the lack of interest in food and social activities distinctly predict outcomes with serotonergic versus dopaminergic pharmacotherapy. These findings require replication and extension to other treatments.

INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.

ObjectivesCurrent pharmacological antidepressant treatments suffer from low remission rates and slow initiation of therapeutic effects. In addition, the development of new antidepressant treatments is confounded by the lack of consensus on efficient and valid neurophysiological targets. Temporal complexity is an alternative measure of dynamic brain activity that estimates brain signal variability at several timescales. It can be easily extracted from non-invasive brain recordings and provides...

CONCLUSION: All data, protocols, reagent sets, and chemical tools are made widely available on the AD Knowledge Portal with no intellectual property claims. Target Risk Scores and biodomains are accessible through Agora. For more information and the full target portfolio see www.treatad.org.

CONCLUSION: YCharOS has established characterization standards that align with funding and journal requirements, and is committed to identify reliable and accessible tools for AD research.

Tuberculosis (TB) is an ongoing global health threat that has been exacerbated by the COVID-19 pandemic. People with TB need comprehensive medical and social supports to ensure they can maintain and complete TB treatment. TB programs globally have turned to eHealth to bridge gaps in access and strengthen the circle of care around people with TB. This study evaluates the implementation of an intervention aimed at improving TB care in Shigatse, using the CFIR framework to identify factors...

CONCLUSION: Automated, AI-ENE node number is a novel risk factor for OPC that may better inform pretreatment risk stratification and decision-making.

CONCLUSION: These findings highlight the myelin-axon interface as a critical site of protein aggregation and disrupted neuro-glial communication in AD. The molecular architecture of the myelin-axon interface uncovered in this study provides a foundation for future mechanistic investigations in health and disease.

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The Reactome Pathway Knowledgebase (www.reactome.org) provides expert-curated information on human biological pathways, molecular interactions, and disease mechanisms. However, its complex data model and keyword-based search interface present accessibility barriers for non-expert users. In contrast, general-purpose conversational AI systems offer intuitive natural language interfaces but lack the domain-specificity, transparent sourcing, and factual reliability required for scientific...

Comparative genomics provides a powerful framework to uncover the molecular and evolutionary mechanisms that shape genetic diversity within and across species, revealing how shared and lineage-specific processes influence their evolutionary trajectories through time. The nematode Caenorhabditis briggsae is distributed world-wide and is a comparative model to Caenorhabditis elegans in the biology of development, cellular mechanisms, neurobiology, genetic mappings of complex traits, and genome...

Primary mismatch-repair-deficient high-grade gliomas (priMMRD-HGG) are lethal tumors characterized by hypermutation, resistance to chemoradiation and variable response to immunotherapy. To investigate the mechanisms governing the emergence of driver mutations and their impact on gliomagenesis and patient outcomes, we analyzed genomic and clinical data from 162 priMMRD-HGG. Here we identified three subgroups defined by secondary driver mutations in replicative DNA polymerases or IDH1. These...

Pulmonary fibrosis (PF) is a pathology associated with interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF). Fibrosis promotes continual secretion of extracellular matrix (ECM), producing nonfunctional scar tissue and causing organ failure. This study investigated the tyrosine kinase receptor Ephrin type-B receptor 4 (EphB4) as a mediator of PF. To this end, we generated mice with conditional Col1a2-driven deletion of Ephb4 and used a preclinical mouse model of PF,...

There is considerable heterogeneity in neurodevelopmental disorders (NDDs) that complicates research and clinical support. Although the biological mechanisms of NDDs remain uncertain, emerging studies suggest potential roles of hormone pathways as gonadal, thyroid, glucocorticoid and growth hormones all contribute to brain development. Alterations to these pathways and imbalances of hormones may modulate neural and behavioural development and contribute to the biology of NDDs. Importantly, the...

Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 MB (G3MB) has poor overall survival at <50%, high frequencies of metastases, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling occur frequently in G3MB. Many tumors have no reported mutations, suggesting epigenetic drivers. We here describe novel humanized models for G3MB from human induced...

Mental and substance use disorders profoundly affect global population health, while there is a notable absence of systematic studies focusing on their burden in the Chinese population. We estimated the burden of Global Burden of Diseases (GBD) 2021 for 10 mental disorders and two types of substance use disorders in China from 1990 to 2021. We presented the numbers and rates of prevalence, disability-adjusted life years (DALYs), years of life lost (YLL) and years lived with disability (YLDs),...