Recent ucsf_postprints items

Rapid two-step target capture ensures efficient CRISPR-Cas9-guided genome editing

Mon, 28 Jul 2025 00:00:00 +0000

RNA-guided CRISPR-Cas enzymes initiate programmable genome editing by recognizing a ∼20-base-pair DNA sequence next to a short protospacer-adjacent motif (PAM). To uncover the molecular determinants of high-efficiency editing, we conducted biochemical, biophysical, and cell-based assays on Streptococcus pyogenes Cas9 (SpyCas9) variants with wide-ranging genome-editing efficiencies that differ in PAM-binding specificity. Our results show that reduced PAM specificity causes persistent non-selective DNA binding and recurrent failures to engage the target sequence through stable guide RNA hybridization, leading to reduced genome-editing efficiency in cells. These findings reveal a fundamental trade-off between broad PAM recognition and genome-editing effectiveness. We propose that high-efficiency RNA-guided genome editing relies on an optimized two-step target capture process, where selective but low-affinity PAM binding precedes rapid DNA unwinding. This model provides a foundation...

Rapid two-step target capture ensures efficient CRISPR-Cas9-guided genome editing

Mon, 28 Jul 2025 00:00:00 +0000

Single-atom bridges across biotic-abiotic interfaces facilitate direct electron transfer for solar-to-chemical conversion.

Thu, 24 Jul 2025 00:00:00 +0000

Biotic-abiotic hybrid systems show significant promise for solar-to-chemical conversion by integrating intracellular biocatalytic pathways with artificially synthesized semiconductors. However, due to intricate interfacial connection and ubiquitous heterogeneities between microorganisms and materials, it remains challenging to achieve atomically precise interface contact and elucidate electron transport mechanism at the single-/sub-cell levels for efficient solar energy transformation. Herein, we report a general design of facilitating direct electron transfer pathway through constructing single-atom bridges across biotic-abiotic interfaces to enhance solar-to-chemical conversion. Specifically, using C₃N₄/Ru-Shewanella hybrid system as a demonstration, we discover that single-atom bridges promote effective charge separation and reduce electron transfer barriers at the biohybrid interfaces. Moreover, operando single-cell photocurrent technique and theoretical...

Mapping global brain reconfigurations following local targeted manipulations

Tue, 22 Jul 2025 00:00:00 +0000

Understanding how localized brain interventions influence whole-brain dynamics is essential for deciphering neural function and designing therapeutic strategies. Using longitudinal functional MRI datasets collected from mice, we investigated the effects of focal interventions, such as thalamic lesions and chemogenetic silencing of cortical hubs. We found that these local manipulations disrupted the brain's ability to sustain network-wide activity, leading to global functional connectivity (FC) reconfigurations. Personalized mouse brain simulations based on experimental data revealed that alterations in local excitability modulate firing rates and frequency content across distributed brain regions, driving these FC changes. Notably, the topography of the affected brain regions depended on the intervention site, serving as distinctive signatures of localized perturbations. These findings suggest that focal interventions produce consistent yet region-specific patterns of global FC...

Key Connectomes and Synaptic‐Compartment‐Specific Risk Genes Drive Pathological α‐Synuclein Spreading

Tue, 22 Jul 2025 00:00:00 +0000

Previous studies have suggested that pathological α-synuclein (α-Syn) mainly transmits along the neuronal network, but several key questions remain unanswered: 1) How many and which connections in the connectome are necessary for predicting the progression of pathological α-Syn? 2) How to identify risk genes that affect pathology spreading functioning at presynaptic or postsynaptic regions, and are these genes enriched in different cell types? Here, these questions are addressed with novel mathematical models. Strikingly, the spreading of pathological α-Syn is predominantly determined by the key subnetworks composed of only 2% of the strongest connections in the connectome. Genes associated with the selective vulnerability of brain regions to pathological α-Syn transmission are further analyzed to distinguish those functioning at presynaptic versus postsynaptic regions. Those risk genes are significantly enriched in microglial cells of presynaptic regions and neurons of postsynaptic...

Insights from Drug Checking Programs: Practicing Bootstrap Public Health Whilst Tailoring to Local Drug User Needs

Tue, 22 Jul 2025 00:00:00 +0000

The year 2021 was the most deadly year for overdose deaths in the USA and Canada. The stress and social isolation stemming from the COVID-19 pandemic coupled with a flood of fentanyl into local drug markets created conditions in which people who use drugs were more susceptible to accidental overdose. Within territorial, state, and local policy communities, there have been longstanding efforts to reduce morbidity and mortality within this population; however, the current overdose crisis clearly indicates an urgent need for additional, easily accessible, and innovative services. Street-based drug testing programs allow individuals to learn the composition of their substances prior to use, averting unintended overdoses while also creating low threshold opportunities for individuals to connect to other harm reduction services, including substance use treatment programs. We sought to capture perspectives from service providers to document best practices around fielding community-based...

Understanding the complex interplay between tau, amyloid and the network in the spatiotemporal progression of Alzheimer’s disease

Tue, 22 Jul 2025 00:00:00 +0000

Introduction

The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success.

Methods

We tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI.

Results

Although network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best.

Discussion

This mathematical exposition of the "pas de deux" of co-evolving proteins provides quantitative, whole-brain support to the concept of amyloid-facilitated-tauopathy...

Modelling pathological spread through the structural connectome in the frontotemporal dementia clinical spectrum

Tue, 22 Jul 2025 00:00:00 +0000

The ability to predict the spreading of pathology in patients with frontotemporal dementia (FTD) is crucial for early diagnosis and targeted interventions. In this study, we examined the relationship between network vulnerability and longitudinal progression of atrophy in FTD patients, using the network diffusion model (NDM) of the spread of pathology. Thirty behavioural variant FTD (bvFTD), 13 semantic variant primary progressive aphasia (svPPA), 14 non-fluent variant primary progressive aphasia (nfvPPA) and 12 semantic behavioural variant FTD (sbvFTD) patients underwent longitudinal T1-weighted MRI. Fifty young controls (20-31 years of age) underwent multi-shell diffusion MRI scan. An NDM was developed to model progression of FTD pathology as a spreading process from a seed through the healthy structural connectome, using connectivity measures from fractional anisotropy and intracellular volume fraction in young controls. Four disease epicentres were initially identified from...

Directionality bias underpins divergent spatiotemporal progression of Alzheimer‐related tauopathy in mouse models

Tue, 22 Jul 2025 00:00:00 +0000

Introduction

Trans-synaptic connectome-based spread is a shared mechanism behind different tauopathic conditions, but they exhibit divergent spatiotemporal progression. One explanation is that conditions may incur directional biases in tau transmission along fiber tracts.

Methods

We examined this hypothesis using tau data from 11 distinct mouse models across four experimental studies. For this purpose, we extended a network-based spread model by incorporating net directionality along the connectome.

Results

Retrograde bias better predicted tau progression than anterograde bias, but our best-fitting biophysical models incorporate the mixed effects of both retrograde- and anterograde-directed spread, with notable tau-strain-specific differences. There was a nontrivial association between directionality bias and tau aggressiveness, with more virulent strains exhibiting less retrograde character.

Discussion

Our study implicates directional bias in tau...

Integrating Event-Based and Biophysical Models to Predict Individual Tau Progression in Alzheimer's Disease

Tue, 22 Jul 2025 00:00:00 +0000

Alzheimer's Disease (AD) is characterized by the accumulation of tau neurofibrillary tangles, which spread along the brain's white matter tracts and correlate with cognitive de-cline. Modeling and predicting tau progression is crucial for developing of therapeutic treatments, but current approaches provide limited insight into individual variation. This study combines statistical and biophysical modeling approaches to capture individuals' longitudinal tau spread. We employed an event-based model (EBM) to identify time-evolving pathology patterns in 650 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. We then fit a biophysical network diffusion model (NDM) to the resulting tau trajectories. By optimizing the initial tau pattern of the NDM, we achieved a strong fit to individuals' empirical data, enabling predictions of past and future tau. Our findings reveal a phenomenon of convergence of inter-region and inter-subject tau over time, as well as two underlying seed...

How do we understand the value of drug checking as a component of harm reduction services? A qualitative exploration of client and provider perspectives

Tue, 22 Jul 2025 00:00:00 +0000

Background

Mortality related to opioid overdose in the U.S. has risen sharply in the past decade. In California, opioid overdose death rates more than tripled from 2018 to 2021, and deaths from synthetic opioids such as fentanyl increased more than seven times in those three years alone. Heightened attention to this crisis has attracted funding and programming opportunities for prevention and harm reduction interventions. Drug checking services offer people who use drugs the opportunity to test the chemical content of their own supply, but are not widely used in North America. We report on qualitative data from providers and clients of harm reduction and drug checking services, to explore how these services are used, experienced, and considered.

Methods

We conducted in-depth semi-structured key informant interviews across two samples of drug checking stakeholders: “clients” (individuals who use drugs and receive harm reduction services) and “providers” (subject matter experts...

Structured noise champagne: an empirical Bayesian algorithm for electromagnetic brain imaging with structured noise

Tue, 22 Jul 2025 00:00:00 +0000

Introduction

Electromagnetic brain imaging is the reconstruction of brain activity from non-invasive recordings of electroencephalography (EEG), magnetoencephalography (MEG), and also from invasive ones such as the intracranial recording of electrocorticography (ECoG), intracranial electroencephalography (iEEG), and stereo electroencephalography EEG (sEEG). These modalities are widely used techniques to study the function of the human brain. Efficient reconstruction of electrophysiological activity of neurons in the brain from EEG/MEG measurements is important for neuroscience research and clinical applications. An enduring challenge in this field is the accurate inference of brain signals of interest while accounting for all sources of noise that contribute to the sensor measurements. The statistical characteristic of the noise plays a crucial role in the success of the brain source recovery process, which can be formulated as a sparse regression problem.

Method

In...

“Everyone says ‘safe sex’ but no one ever says ‘safe drugs’, you know?”: Perspectives on the intersection of drug checking services, drug policy and the overdose crisis

Tue, 22 Jul 2025 00:00:00 +0000

Background

Overdose deaths have continued to rise in the US despite heightened public attention and resources. Drug checking shows promise for integration into existing services for people who use drugs (PWUD) across North America. Amidst the backdrop of rising overdose deaths and emerging funds for harm reduction initiatives, this manuscript explores the landscape of drug checking services in North America and perspectives on improved integration with a diverse set of PWUD based in San Francisco and North American drug checking experts.

Methods

Two separate samples of drug checking stakeholders, ‘providers’ and ‘clients’ were recruited. Providers participated in in-depth semi-structured qualitative interviews over Zoom on their experiences advocating for and operating drug checking services in the US and Canada. Clients were people who used drugs and lived in or commuted to the San Francisco Bay Area and participated in semi-structured interviews in November 2022. Interviews...

A network-level transport model of tau progression in the Alzheimer’s brain

Tue, 22 Jul 2025 00:00:00 +0000

One of the hallmarks of Alzheimer's disease (AD) is the accumulation and spread of toxic aggregates of tau protein. The progression of AD tau pathology is thought to be highly stereotyped, which is in part due to the fact that tau can spread between regions via the white matter tracts that connect them. Mathematically, this phenomenon has been described using models of 'network diffusion,' where the rate of spread of tau between brain regions is proportional to its concentration gradient and the amount of white matter between them. Although these models can robustly predict the progression of pathology in a wide variety of neurodegenerative diseases, including AD, an underexplored aspect of tau spreading is that it is governed not only by diffusion but also by active transport along axonal microtubules. Spread can therefore take on a directional bias, resulting in distinct patterns of deposition, but current models struggle to capture this phenomenon. Recently, we have developed...

Impacts of COVID-19 on HIV/AIDS-Related Services in California

Tue, 22 Jul 2025 00:00:00 +0000

The degree to which COVID-19 has disrupted the advances in reducing new HIV infections and preventing AIDS-related deaths is unknown. We present findings related to the effect COVID-19 had on HIV, sexual health and harm reduction service delivery in the state of California. We conducted a qualitative rapid assessment with health care providers, as well as representatives from non-medical support service agencies serving clients living with HIV in a range of counties in California. Some organizations adapted fairly easily while others struggled or were unable to adapt at all. Clinics were better positioned than community-based organizations to accommodate COVID restrictions and to quickly reestablish services. Influential forces that softened or calcified the hardships created by COVID-19 included influx of funding, flexibility in managing funds, networking and relationships, and workforce vulnerabilities. These data clearly suggest that an enhanced level of flexibility within...

Selective vulnerability and resilience to Alzheimer's disease tauopathy as a function of genes and the connectome

Tue, 22 Jul 2025 00:00:00 +0000

Brain regions in Alzheimer's disease exhibit distinct vulnerability to its hallmark pathology with the entorhinal cortex and hippocampus succumbing early to tau tangles while others like the primary sensory cortices remain resilient. The quest to understand how local/regional genetic factors, pathogenesis and network-mediated pathology spread, together govern this selective vulnerability (SV) or resilience (SR) is ongoing. Although many Alzheimer's risk genes are known from gene association and transgenic studies, it is still unclear whether and how their baseline expression confers SV/SR to pathology. Prior analyses have yielded conflicting results, pointing to a disconnect between the location of genetic risk factors and downstream tau pathology. The spatial distribution of vulnerability doesn't always align with genetic factors, suggesting a role for non-cell-autonomous mechanisms like transneuronal tau transmission. We hypothesize that a full accounting of the role of genes...

Spatial cell-type enrichment predicts mouse brain connectivity

Tue, 22 Jul 2025 00:00:00 +0000

A fundamental neuroscience topic is the link between the brain's molecular, cellular, and cytoarchitectonic properties and structural connectivity. Recent studies relate inter-regional connectivity to gene expression, but the relationship to regional cell-type distributions remains understudied. Here, we utilize whole-brain mapping of neuronal and non-neuronal subtypes via the matrix inversion and subset selection algorithm to model inter-regional connectivity as a function of regional cell-type composition with machine learning. We deployed random forest algorithms for predicting connectivity from cell-type densities, demonstrating surprisingly strong prediction accuracy of cell types in general, and particular non-neuronal cells such as oligodendrocytes. We found evidence of a strong distance dependency in the cell connectivity relationship, with layer-specific excitatory neurons contributing the most for long-range connectivity, while vascular and astroglia were salient for...

Efficacy of Augmented Food Pantry Services in Addressing Food Insecurity

Mon, 21 Jul 2025 00:00:00 +0000

Abstract

Objectives

Almost 1 in 9 Americans obtain food from a food bank or food pantry every year to help make ends meet. Despite this scope and scale, the efficacy of the charitable food system at alleviating food insecurity is still unclear. This study aimed to determine whether food distributed at food pantries as part of a comprehensive diabetes self-management support program, changed food security status for adults with diabetes.

Methods

This is a secondary, prespecified analysis of a larger randomized, controlled study (the FAITH-DM trial) conducted in 27 food pantries in Detroit MI; Houston, TX; and Oakland, CA (2015–2018). We screened 5329 adults for diabetes, and individually randomized 568 participants with hemoglobin A1c (HbA1c) 7.5% or greater to an immediate 6-month intervention (including bimonthly food, diabetes education, health care referral and glucose monitoring) or to receive the intervention after a 6-month delay (cross-over design). For...

Behavioral Drivers Influencing Women’s Decision to Use Self-Injectable Contraception Provided by Community Health Surveillance Assistants in Rural Malawi

Mon, 21 Jul 2025 00:00:00 +0000

Introduction

Self-injection (SI) for contraceptive use is recommended for its proven ability to empower women and overcome barriers to contraceptive access. The World Health Organization endorsed SI as a self-care approach in 2019. Despite the increase in Malawi's modern contraceptive prevalence rate from 38.1% in 2012 to 48.9% in 2020, it remains below the government's 60% target. Injectable contraceptives, including depot medroxyprogesterone acetate subcutaneous (DMPA-SC), introduced in 2018, are the most popular contraceptive method in Malawi, particularly among adolescents, representing 49.8% of the contraceptive method mix. However, utilization of SI remains limited, especially in rural areas where access challenges persist. This study explores the behavioral drivers influencing women's decision to use self-injectable contraception provided by community health surveillance assistants (CHSA) in rural Malawi.

Methods

Using the capability, opportunity, motivation-behavior...

Comparative Analysis of Ultrasonography and MicroCT Imaging for Organ Size Evaluation in Mice

Mon, 21 Jul 2025 00:00:00 +0000

In this work, the authors compared microCT and in vivo ultrasonography in terms of accuracy and efficacy for measuring the volume of various organs in mice. Two quantification protocols were applied: ellipsoidal volume measuring maximum diameters in all three axes in both imaging systems and manual delineation of organ borders in microCT studies. The results were compared with ex vivo volumes. In general, both imaging techniques and quantification protocols are accurate, but ultrasound is faster in both acquisition and analysis. The only accurate method for heart volume measurement is manual segmentation on microCT. For the ovary, none of the techniques and protocols had a positive correlation with ex vivo volume. The three-diameter method can be used for ellipsoid organs because of its rapidity, but for more irregular structures, manual segmentation is recommended, although it is time-consuming.

Knowledge, confidence and social support: Kenyan women’s priority needs for contraceptive self-injection learning through a social cognitive theory lens

Mon, 21 Jul 2025 00:00:00 +0000

Background

Self-injectable contraceptives provide individuals the opportunity to prevent pregnancy with a self-controlled method that helps enhance self-care. Kenya is in the process of making self-injectable subcutaneous depot medroxyprogesterone acetate (DMPA-SC) widely available. We know little about what would make women in Kenya feel that contraceptive self-injection (SI) is feasible. Applying the social cognitive theory, we sought to understand what SI-naïve reproductive-aged women wanted to learn about SI, how they desired to learn it, and with whom.

Methods

We conducted sixty-one in-depth interviews with women aged 15-45 years, residing in Nairobi and Kisumu, Kenya. Participants were purposively sampled to ensure diverse representation by age, contraceptive use or non-use, and previous experience with SI of DMPA-SC. Audio recordings of the in-depth interviews were transcribed and translated into English as necessary. Transcripts were coded in Dedoose...

Ugandan physician attitudes towards a potential, local trauma fellowship program

Mon, 21 Jul 2025 00:00:00 +0000

Introduction

In low-income countries, clinicians trained through a context-specific trauma surgery fellowship program (TFP) can help reduce injury-related mortality to levels closer to those observed in higher-resource settings. Successful implementation, however, hinges on buy-in from local clinicians. We assessed clinician support for a potential TFP in Uganda, considering perceived need, curricular recommendations, barriers, and motivating factors.

Methods

After cognitive interviews with experts and questionnaire pilot testing, we cross-sectionally surveyed Ugandan consultants (general surgeons and procedural specialists involved in trauma care) and surgical residents at a tertiary, national referral hospital. Respondent percentages were calculated for multiple-choice answers, and we performed thematic analysis of free-text responses using a primarily inductive approach.

Results

Among 46 faculty (from 13 specialties) and 42 resident respondents, 86% supported...

Anti-Obesity Medication Prescriptions by Race/Ethnicity and Use of an Interpreter in a Pediatric Weight Management Clinic

Mon, 21 Jul 2025 00:00:00 +0000

Abstract Background: Healthcare disparities associated with race/ethnicity and low English proficiency are well established in the US. We sought to determine if there are race/ethnic differences in anti-obesity medication prescription rates among youth with severe obesity (body mass index (BMI) ≥1.2 times the 95th percentile and/or BMI ≥35 kg/m2) treated in a pediatric weight management clinic (PWMC). We secondarily sought to determine if, among youth from families in whom English was not the primary language, there are differences in prescription rates between those using an interpreter during visits and those not. Methods: We reviewed electronic health records of youth 2–18 years old with severe obesity seen at a PWMC from 2012–2020. Race/ethnicity was self-reported and categorized as Non-Hispanic White (NHW), Hispanic/Latino, Non-Hispanic Black (NHB), Asian, American Indian/Alaska Native and Mixed. Anti-obesity medicines included stimulants (i.e. phentermine, lisdexamfetamine),...

Kidney Function: Supply and Demand.

Sat, 19 Jul 2025 00:00:00 +0000

Kidney Function: Supply and Demand.

The effect of nasal douching by hypertonic 2.3 per cent sea water with algae extracts on the concentration of epidermal growth factor, transforming growth factor-α and interleukin-8 in nasal secretions of patients with nasal polyposis following endoscopic surgical treatment.

Fri, 18 Jul 2025 00:00:00 +0000

Objective

To investigate epidermal growth factor, transforming growth factor-α and interleukin-8 production in nasal mucosa irrigated with hypertonic 2.3 per cent solution with algae extracts, in comparison to 0.9 per cent NaCl during the first two weeks after surgery for nasal polyposis, in relation to symptoms and local findings.

Methods

This prospective study included 20 nasal polyposis patients postoperatively irrigated with hypertonic solution and 20 nasal polyposis patients postoperatively irrigated with isotonic solution. We evaluated nasal symptom score, endoscopic score and mediator levels in nasal secretions before and after irrigation.

Results

Following treatment, nasal symptom score and endoscopic score were significantly lower in the hypertonic solution group (p = 0.023; p < 0.001, respectively). The increase in the epidermal growth factor and the decrease in the transforming growth factor-α and interleukin-8 concentration were...

Announcing the Biomedical Data Translator: Initial Public Release.

Fri, 18 Jul 2025 00:00:00 +0000

The growing availability of biomedical data offers vast potential to improve human health, but the complexity and lack of integration of these datasets often limit their utility. To address this, the Biomedical Data Translator Consortium has developed an open-source knowledge graph-based system-Translator-designed to integrate, harmonize, and make inferences over diverse biomedical data sources. We announce here Translators initial public release and provide an overview of its architecture, standards, user interface, and core features. Translator employs a scalable, federated, knowledge graph framework for the integration of clinical, genomic, pharmacological, and other biomedical knowledge sources, enabling query retrieval, inference, and hypothesis generation. Translators user interface is designed to support the exploration of knowledge relationships and the generation of insights, without requiring deep technical expertise and gradually revealing more detailed evidence, provenance,...

DDIS-02. DEVELOPMENT OF NOVEL SPRAY-TYPE FLUORESCENT PROBES FOR GLIOBLASTOMA DETECTION

Fri, 18 Jul 2025 00:00:00 +0000

Abstract PURPOSE: ALA is commonly used as an intraoperative tool in malignant glioma surgery, which has been proven effective for radical tumor resection and extended progression-free survival. However, there are some limitations in its use, such as false positivity, false negativity, and inability of re-administration. We aim to develop a novel fluorescent labeling system which can be repeatedly administered by spray during surgery, using hydroxymethyl rhodamine green (HMRG) as fluorescent scaffold originally designed at our university for cancer detection. [Methods]Primary probe screening was performed using the homogenized glioblastoma (GBM) samples with the fluorescent probe library comprised of more than 320 kinds of HMRG fluorescent scaffold combined with various types of dipeptides. Second probe screening was performed using fresh GBM specimens and the selected probes in primary screening. To identify the responsible enzymes, diced electrophoresis gel (DEG) assay was performed....

Cravings, Control, and Cessation: A Scoping Review of Perceptions of Nicotine Addiction.

Fri, 18 Jul 2025 00:00:00 +0000

Purpose of review

Nicotine addiction is the result of repeated tobacco use and subsequently promotes continued consumption, potentially acting as both cause and consequence of tobacco use. This scoping review aims to describe the literature and catalogue existing measures regarding perceptions of nicotine addiction with special attention to scales that recognize its multidimensionality.

Recent findings

Following a comprehensive review of 923 empirical articles, we found 252 articles that assessed perceptions of nicotine addiction, five of which utilized a validated measure. Single item assessments were categorized into affective concern, knowledge that tobacco is addictive, personal perceptions of addiction, other peoples addiction, and comparative addictiveness. Scaled measures of perceptions of nicotine addiction largely assessed perceived susceptibility and severity.

Summary

Despite decades of research demonstrating the importance of perceptions of risk...

The development of aperiodic neural activity in the human brain.

Fri, 18 Jul 2025 00:00:00 +0000

The neurophysiological mechanisms supporting brain maturation are fundamental to attention and memory capacity across the lifespan. Human brain regions develop at different rates, with many regions developing into the third and fourth decades of life. Here, in this preregistered study ( https://osf.io/gsru7 ), we analysed intracranial electroencephalography recordings from widespread brain regions in a large developmental cohort. Using task-based (that is, attention to to-be-remembered visual stimuli) and task-free (resting-state) data from 101 children and adults (5.93-54.00 years, 63 males; n electrodes = 5,691), we mapped aperiodic (1/ƒ-like) activity, a proxy of neural noise, where steeper slopes indicate less noise and flatter slopes indicate more noise. We reveal that aperiodic slopes flatten with age into young adulthood in both association and sensorimotor cortices, challenging models of early sensorimotor development based on brain structure. In the prefrontal cortex...

IMMU-23. A NOVEL MASS CYTOMETRY-BASED MULTI-PARAMETER CHARACTERIZATION OF NEOANTIGEN-REACTIVE CD8+ T-CELLS IN PATIENTS PARTICIPATING IN PNOC007 H3.3K27M PEPTIDE VACCINE CLINICAL TRIAL

Fri, 18 Jul 2025 00:00:00 +0000

Abstract

BACKGROUND

We have identified an HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a multi-center clinical trial of the peptide vaccine through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007) for patients with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG). We sought to characterize vaccine-reactive CD8+T-cells subpopulations using their precise activation and developmental status to find their associations with clinical outcomes.

METHODS

Mass cytometry (CyTOF) analysis was performed on patient-derived peripheral blood mononuclear cells collected at baseline as well as pre-specified time points throughout the study. Each cell subtype was characterized via tSNE-clustering based on their expression profiles and quantified as a fraction of total CD45+cells. H3.3K27M-reactive CD8+T-cells were evaluated using an H3.3K27M-HLA-A2 dextramer along with a panel of T-cell and...

PDCT-17 (LTBK-11). PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINE COMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLY DIAGNOSED HLA-A2+ H3.3K27M MIDLINE GLIOMAS

Fri, 18 Jul 2025 00:00:00 +0000

Abstract

OBJECTIVE

To assess within a multi-center trial the safety of H3.3K27M specific peptide vaccine in combination with poly-ICLC in HLA-A02.01+ patients diagnosed with H3.3K27M+ diffuse midline gliomas.

METHODS

Subjects 3–21 years of age with CLIA confirmed H3.3K27 mutation status were eligible. Patients were enrolled after completion of focal radiation therapy. The trial enrolled two strata: Stratum A included newly diagnosed patients with diffuse intrinsic pontine glioma (DIPG) (n=19); Stratum B included non-DIPG midline glioma patients including spinal cord tumors as an exploratory strata (n=10). The H3.3K27M vaccine was administered in combination with poly-ICLC every 3 weeks for a total of 8 doses followed by every 6 weeks for a maximum of 96 weeks of therapy. Immuno-monitoring and imaging occurred every 3 months. Modified iRANO criteria are used for ongoing assessment of disease status. Patients’ peripheral blood mononuclear cell (PBMC) samples were...

EPCO-14. MULTIFACETED TRANSCRIPTOMIC AND PROTEOMIC ANALYSES IDENTIFIED PUTATIVE ALTERNATIVE SPLICING-DERIVED CELL SURFACE ANTIGENS IN GLIOMA

Fri, 18 Jul 2025 00:00:00 +0000

Abstract

BACKGROUND

To develop effective immunotherapy for gliomas, it is crucial to expand the repertoire of targetable antigens. Recent studies have suggested that alternative splicing (AS), or its deriving tumor-specific junctions (“neojunctions”), could generate cryptic amino acid sequences that can be a source of neoantigens. In this study, we investigated neojunctions based on multifaceted transcriptomic and proteomic analyses, seeking the potential cell surface antigens that may be targeted by CAR.

METHODS

For screening, we analyzed bulk RNA-sequencing data of TCGA-GBM/LGG with high tumor purity (n = 429) and GTEx normal tissues (n = 9,166). Cohorts of spatially mapped intratumoral samples and longitudinally collected tumors were used to determine clonality and stability of the candidate neojunctions. Nanopore long-read amplicon sequencing was deployed to confirm the full-length transcript sequence. Their protein-level expression was explored by analyzing...

Diet Patterns Are Associated with Circulating Metabolites and Lipid Profiles of South Asians in the United States.

Fri, 18 Jul 2025 00:00:00 +0000

Background

South Asians are at higher risk for cardiometabolic disease than many other racial/ethnic minority groups. Diet patterns in US South Asians have unique components associated with cardiometabolic disease.

Objectives

We aimed to characterize the metabolites associated with 3 representative diet patterns.

Methods

We included 722 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort study aged 40-84 y without known cardiovascular disease. Fasting serum specimens and diet and demographic questionnaires were collected at baseline and diet patterns previously generated through principal components analysis. LC-MS-based untargeted metabolomic and lipidomic analysis was conducted with targeted integration of known metabolite and lipid signals. Linear regression models of diet pattern factor score and log-transformed metabolites adjusted for age, sex, caloric intake, and BMI and adjusted for multiple comparisons...

Clinical impact of pharmacogenetic risk variants in a large chinese cohort.

Fri, 18 Jul 2025 00:00:00 +0000

Incorporating pharmacogenetics into clinical practice promises to improve therapeutic outcomes by optimizing drug selection and dosage based on genetic factors affecting drug response. A key advantage of PGx-guided therapy is to decrease the likelihood of adverse events. To evaluate the clinical impact of PGx risk variants, we performed a retrospective study using genetic and clinical data from the largest Han Chinese cohort, comprising 486,956 individuals, assembled by the Taiwan Precision Medicine Initiative. We found that nearly all participants carried at least one genetic variant that could affect drug response, with many carrying multiple risk variants. Here we show the detailed analyses of four gene-drug pairs, azathioprine (NUDT15/TPMT), clopidogrel (CYP2C19), statins (ABCG2/CYP2C9/SLCO1B1), and NSAIDs (CYP2C9), for which sufficient data exists for statistical power. While the results validate previous findings that PGx risk variants are significantly associated with drug-related...

IMMU-33. NEOANTIGEN-SPECIFIC T CELLS CAN INFILTRATE IDH-MUTANT LOWER GRADE GLIOMAS AND PERSIST IN THE PERIPHERAL BLOOD

Fri, 18 Jul 2025 00:00:00 +0000

Abstract The prospect of using immunotherapy for IDH-mutant LGGs has been daunting given the immune-poor microenvironment and low mutational burden. We hypothesized that LGG-targeting T cells might still be present at low frequency and with limited regional infiltration into the tumor. To improve sensitivity, we combined high-density multi-region tumor sampling with high-throughput neoantigen-T cell screening for a patient with WHO Grade II diffuse astrocytoma who eventually progressed, at second recurrence, to anaplastic astrocytoma. We performed maximal-anatomic sampling from 10 distinct regions of the tumor at the initial resection, as well as single sampling at first recurrence, for exome-based prediction of clonal and subclonal expressed neoantigens, RNAseq-based estimation of regional immune cell composition, and T cell receptor (TCR) beta deep sequencing. Based on our predictions, we then generated a barcoded library of patient-specific peptide-HLA multimers loaded with...

EPCO-10. CHANGES IN ALTERNATIVE SPLICING AND ASSOCIATED NEOANTIGENS DUE TO THERAPY

Fri, 18 Jul 2025 00:00:00 +0000

Abstract Recent studies have identified alternative splicing (AS) as a novel source of neoantigens for immunotherapy. Surprisingly little is known about the AS milieu in recurrent glioblastoma (GBM), despite this being the venue for most clinical trials. We profiled 29 primary-recurrent paired human GBM specimens via RNA sequencing and re-analyzed RNA-sequencing data from non-malignant human brain tissues. From these data, we reconstructed the landscape of AS in GBM through recurrence and contrasted that to isoforms observed in non-malignant brain. The AS events we identified were cross-referenced with single-cell GBM atlases to determine cell-type specific splicing patterns. From this we identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies. We found recurrent-specific isoforms of mitogen-activated kinase pathway genes which are expressed exclusively by GBM stem-like cells that enhance invasiveness. These studies shed...

DDRE-10. IMMUNE PROFILES ASSOCIATE WITH OUTCOMES IN HLA-A*02:01+, H3.3K27M+ PATIENTS WITH DIFFUSE MIDLINE GLIOMAS TREATED WITH H3.3K27M PEPTIDE VACCINE COMBINED WITH POLY-ICLC: A PNOC REPORT

Fri, 18 Jul 2025 00:00:00 +0000

Abstract

BACKGROUND

Patients with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have dismal outcomes. We previously described the H3.3K27M mutation as a shared neoantigen in HLA-A*02.01+ H3.3K27M+ DMGs. Within the Pacific Pediatric Neuro-Oncology Consortium, we assessed the safety and efficacy of an H3.3K27M-targeted peptide vaccine.

PATIENTS AND METHODS

Newly diagnosed patients aged 3–21 years with positive HLA-A*02.01+ and H3.3K27M+ status were enrolled into two strata after completion of radiation therapy: Stratum A for DIPG (n=19); Stratum B for non-pontine DMG (n=10). Vaccine was administered in combination with poly-ICLC every three weeks for eight cycles, followed by once every six weeks. Immunological responses were assessed in peripheral blood mononuclear cells using mass cytometry.

RESULTS

19 patients enrolled in Stratum A (median age=11 years) and 10 in Stratum B (median age=13 years). There were no grade...

IMMU-31. PNOC007: H3.3K27M SPECIFIC PEPTIDE VACCINE COMBINED WITH POLY-ICLC FOR THE TREATMENT OF NEWLY DIAGNOSED HLA-A2+ H3.3K27M DIFFUSE MIDLINE GLIOMAS (DMG)

Fri, 18 Jul 2025 00:00:00 +0000

Abstract

OBJECTIVE

To assess safety and efficacy within a multi-center trial the H3.3K27M specific peptide vaccine with poly-ICLC in HLA-A02.01+ patients diagnosed with H3.3K27M+ DMGs.

METHODS

After focal radiation therapy, participants 3–21 years of age were enrolled into two strata. Stratum A: newly diagnosed diffuse intrinsic pontine glioma (DIPG); Stratum B: other DMGs. H3.3K27M vaccine was administered with poly-ICLC IM every 3 weeks for 8 doses followed by every 6 weeks for a total of 96 weeks. Immuno-monitoring of peripheral blood mononuclear cell (PBMC) and imaging occurred every 3 months. Modified iRANO criteria were applied. PBMC samples were evaluated by mass cytometry.

RESULTS

From November 2016 until March 2019, 19 eligible patients (median age 11, range 5–17 yrs; 53 % female) were enrolled in Stratum A and 10 eligible patients (median age 13, range 7–18 yrs; 60 % female) in Stratum B. Treatment was well tolerated (7 grade 3; 0 grade 4 related...

IMMU-31. TUMOR-SPECIFIC ALTERNATIVE SPLICING GENERATES SPATIALLY-CONSERVED HLA-BINDING NEOANTIGEN TARGETS DETECTED THROUGH INTEGRATIVE TRANSCRIPTOMIC AND PROTEOMIC ANALYSES

Fri, 18 Jul 2025 00:00:00 +0000

Abstract

BACKGROUND

While immunotherapy is profoundly efficacious in certain cancers, its success is limited in cancers with lower mutational burden, such as gliomas. Therefore, investigating neoantigens beyond those from somatic mutations can expand the repertoire of immunotherapy targets. Recent studies detected alternative-splicing (AS) events in various cancer types that could potentially translate into tumor-specific proteins. Our study investigates AS within glioma to identify novel MHC-I-presented neoantigen targets through an integrative transcriptomic and proteomic computational pipeline, complemented by an extensive spatiotemporal analysis of the AS candidates.

METHODS

Bulk RNA-seq of high tumor purity TCGA-GBM/LGG (n=429) were analyzed through a novel systematic pipeline, and tumor-specific splicing junctions (neojunctions) were identified in silico by cross-referencing with bulk RNA-seq of GTEx normal tissue (n=9,166). Two HLA-binding prediction algorithms...

IMMU-30. UTILIZING A NOVEL MASS CYTOMETRY-BASED IMMUNOMONITORING PLATFORM FOR THE CHARACTERIZATION OF VACCINE-REACTIVE, EPITOPE-SPECIFIC CD8+ T-CELLS IN HLA-A*0201+ PATIENTS WITH K27M+ DIFFUSE MIDLINE GLIOMAS

Fri, 18 Jul 2025 00:00:00 +0000

Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. We have identified a novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation and implemented a pilot clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC007). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine and tetanus toxoid (TT) peptide emulsified in Montanide in combination with poly-ICLC every 3 weeks for a total of 24 weeks. Our objective is to characterize vaccine-induced H3.3K27M-specific T-cell subpopulations in peripheral blood mononuclear cells through the evaluation of surface markers correlated with activation, memory, and exhaustion phenotypes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. Through this approach, the temporal...

Effective coverage measurements and cascade for maternal, newborn, child and adolescent health in high-income countries: systematic review

Thu, 17 Jul 2025 00:00:00 +0000

Background

The concept of 'effective coverage' (EC) aims to combine the concept of coverage with the quality of care delivered and, ultimately, the health benefits received by the population in need. To date, systematic reviews of EC of maternal, newborn, child and adolescent health (MNCAH) have focused on low- and middle-income countries (LMICs). No review has examined whether and how the concept has been applied in high-income countries (HICs). To address this gap, this systematic review investigated the application of EC measures in MNCAH care in HICs.

Methods

This was a systematic review that followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. The search strategy was developed from previous EC reviews conducted in LMICs and further adapted to the HIC setting. Additional search terms were identified through discussion with experts from the Life Stage Quality of Care Metrics Technical Working Group subgroup...

Sex Differences in Management of Hypertension in US Ambulatory Practice

Thu, 17 Jul 2025 00:00:00 +0000

Sex Differences in Management of Hypertension in US Ambulatory Practice

Timeliness of Injury Care and Housing Status

Thu, 17 Jul 2025 00:00:00 +0000

Background

Unhoused people have longer hospital lengths of stays than housed. This study examined if unhoused people have less timely injury care than housed.

Methods

We conducted a retrospective cohort study of adult injury encounters from January 2015 - December 2022 at the only level 1 trauma center in an urban county. We merged the trauma registry with a county-wide integrated dataset to reliably identify our primary exposure: housing status in the fiscal year of injury. The primary outcome was time to the operating room in hours. Secondary outcomes were emergency department (ED) length of stay in minutes and additional timeliness measures. Multivariable linear regression models with clustered standard errors estimated the association of housing status with each log-transformed outcome, adjusting for clinical and demographic covariates.

Results

Among 21,264 trauma encounters, 18.8 % (N = 4003) were in unhoused people. Unhoused and housed people had similar...

Comparing the Accuracy of Different Wearable Activity Monitors in Patients With Lung Cancer and Providing Initial Recommendations: Protocol for a Pilot Validation Study.

Thu, 17 Jul 2025 00:00:00 +0000

Background

Wearable activity monitors (WAMs) provide insights into physical activity (PA) and are widely used in behavioral interventions and cancer survivorship research. However, validation studies of wearable devices in populations with cancer are scarce, and existing studies using activity monitors in patients with cancer lack standardization. This gap is particularly significant in patients with lung cancer (LC), who often experience unique mobility challenges and gait impairments that may affect device accuracy. This study addresses this gap by validating the Fitbit Charge 6, ActiGraph LEAP, and activPAL3 micro in patients with LC in both laboratory and free-living conditions and developing a standardized framework for assessing wearable devices in populations with cancer and impaired mobility.

Objective

This study aims to validate and compare the accuracy of consumer-grade (Fitbit Charge 6) and research-grade (activPAL3 micro and ActiGraph LEAP) WAMs in patients...

Neuromuscular disease: 2023 update.

Thu, 17 Jul 2025 00:00:00 +0000

This review highlights ten important advances in the neuromuscular disease field that were reported in 2022. As with prior updates in this article series, the overarching topics include (i) advances in understanding of fundamental neuromuscular biology; (ii) new / emerging diseases; (iii) advances in understanding of disease etiology and pathogenesis; (iv) diagnostic advances; and (v) therapeutic advances. Within this general framework, the individual disease entities that are discussed in more detail include neuromuscular complications of COVID-19 (another look at the topic first covered in the 2021 and 2022 reviews), DNAJB4-associated myopathy, NMNAT2-deficient hereditary axonal neuropathy, Guillain-Barré syndrome, sporadic inclusion body myositis, and amyotrophic lateral sclerosis. In addition, the review highlights a few other advances (including new insights into mechanisms of fiber maturation during muscle regeneration and fiber rebuilding following reinnervation, improved...

Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy

Thu, 17 Jul 2025 00:00:00 +0000

Background

Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer's disease (AD), including a subset characterized neuropathologically at autopsy.

Methods

Proximity extension assay (Olink Explore®) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N = 16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE + (N = 7) and CTE- (N = 9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene...

Ultrafine‐Grained Materials With Antibacterial Properties: A Novel Approach to Reducing Spinal Implant‐Associated Infections

Thu, 17 Jul 2025 00:00:00 +0000

Background

Implant-associated infection remains a serious complication of instrumented spinal surgery. Since biofilm formation on the implant surface is a key factor in the pathogenesis of such infections, current preventive strategies include the use of implants with antibiotic coatings. However, these approaches raise concerns related to antibiotic resistance and cytotoxicity. Ultrafine-grained (UFG) stainless steel, characterized by nanoscale grain sizes, has demonstrated superior mechanical properties and potential antimicrobial effects. This study aimed to evaluate the antibacterial properties of UFG stainless steel implants against Staphylococcus aureus biofilm formation in both in vitro and in vivo models.

Methods

UFG and conventional SUS316L stainless steel wires were incubated with bioluminescent Staphylococcus aureus Xen36 for up to 7 days in vitro. Biofilm formation was assessed using crystal violet (CV) staining, colony-forming...

Reduction of neuronal activity mediated by blood-vessel regression in the adult brain

Thu, 17 Jul 2025 00:00:00 +0000

The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we report that a substantial proportion of blood vessels in the adult mouse brain sporadically occlude and regress. Their regression proceeds through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels are found to be widespread in mouse, monkey and human brains. We further reveal that blood vessel regression cause a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain.

Fine-mapping genomic loci refines bipolar disorder risk genes

Thu, 17 Jul 2025 00:00:00 +0000

Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms...

Ocular Microbiota of Severe Meibomian Gland Dysfunction (Chronic Dry Eyes) after Intense Pulsed Light (IPL)

Thu, 17 Jul 2025 00:00:00 +0000

Ocular IPL therapy has recently been widely used for MGD, especially for patients not showing improvement with traditional therapies (warm compresses and lid scrubs) to clean debris and reduce bacterial overgrowth. Insights on the ocular microbiome and quantitative microbiome in MGD after a course of IPL could provide useful data on bacterial community monitoring and associated mechanisms linked with IPL. Ocular swabs were obtained from a severe MGD patient and age-sex matched healthy for metagenomics, followed by 16S rRNA gene sequencing and qPCR. Of 10 samples, including left and right eyes (el, er) of severe MGD females before (Db) and after 2-4 IPLs (Da2, Da3, and Da4) and the matched non-MGD females (H), both of ~40 years Using 16S rRNA gene sequencing as microbiota and combined 16S rRNA gene qPCR as quantitative microbiota revealed significant disperse in the microbiome structures of Db compared with Da and H (HOMOVA, p<0.001). Bacterial Propionibacterium acnes and unclassified...

Collagen Biosynthesis and Its Molecular Ensemble: What Remains Unexplored.

Thu, 17 Jul 2025 00:00:00 +0000

Collagen embodies an intriguing paradox in protein biology. Despite being one of the most abundant protein superfamilies in vertebrates and having a seemingly simple structural organization, its biosynthesis is anything but straightforward. This apparent simplicity masks a complex and often contradictory biosynthetic landscape that poses significant challenges, particularly for newcomers to the field. Rather than following a linear or uniform pathway, collagen biosynthesis involves a coordinated series of tightly regulated steps, cotranslational post-translational modifications (PTMs), chain selection and registration, triple helix formation, and secretion, orchestrated by a specialized machinery, collectively termed the collagen molecular ensemble. This ensemble must overcome unconventional paradigms in protein biogenesis, rife with exceptions and unresolved questions. In this perspective, I examine underexplored aspects of the collagen biosynthetic machinery, spotlighting challenges...

E-cigarette and cannabis use among current and recently quit smokers: Co-use and Co-cessation

Thu, 17 Jul 2025 00:00:00 +0000

Background

Concurrent use of cigarettes with e-cigarette or cannabis (co-use) is common. It is unclear whether people who want to quit smoking cigarettes would also be interested in quitting using e-cigarettes/cannabis (co-cessation).

Methods

In a survey of 391 Californian adults, participants reported past 30-day use of and intentions to quit cigarettes, e-cigarettes, and cannabis, and reasons for using e-cigarettes and/or cannabis. Using cross-tabulation tables, we examined the relationship between cigarette, e-cigarette, and cannabis cessation intentions. We subsequently examined how the reasons for using e-cigarettes and cannabis related to e-cigarette and cannabis use frequency, while controlling for cigarette use and demographic characteristics.

Results

Of those who used both cigarettes and e-cigarettes and planned to quit smoking within the next 30 days, 68.9 % also planned to quit using e-cigarettes. Of those who used both cigarettes and...

Correction to: SYK negatively regulates ITAM-mediated human NK cell signaling and CD19-CAR NK cell efficacy.

Thu, 17 Jul 2025 00:00:00 +0000

Correction to: SYK negatively regulates ITAM-mediated human NK cell signaling and CD19-CAR NK cell efficacy.

Housing Status and Longitudinal Care Patterns After Injury

Thu, 17 Jul 2025 00:00:00 +0000

Study objective

Injury is a leading cause of hospitalization in people experiencing homelessness, yet post-injury care use is unknown. We sought to understand care use patterns in the 12 months after injury in people experiencing homelessness versus housed low-income Medicaid beneficiaries.

Methods

We conducted a retrospective cohort study examining injured Medicaid beneficiaries in San Francisco from 2015 to 2022. Our primary exposure was housing status at the time of injury, obtained from linking the county's only Level 1 Trauma Center's Trauma Registry to the county-wide Coordinated Care Management System integrated data system. The primary outcome was emergency department (ED) visits in the 12 months after injury. Secondary outcomes were hospital admissions, outpatient visits, and mental health encounters. We adjusted for demographic, clinical, and injury variables as well as preinjury care use.

Results

Among 5,998 people, 32.9% (N=1,926) were experiencing...

Transcriptional profiling of Chlamydia trachomatis and its host in an ex vivo endocervical primary cell culture system using dual RNA sequencing

Thu, 17 Jul 2025 00:00:00 +0000

Chlamydia trachomatis (Ct) is an obligate intracellular bacterium that causes significant ocular and urogenital morbidity worldwide. Understanding host-pathogen interactions is challenging but dual RNA sequencing offers simultaneous transcriptome data for comprehensive interrogations into these interactions. While transcriptional profiling of both Ct and host-derived immortalized cells has been performed, this study used dual RNA sequencing to examine host-pathogen interactions in ex vivo human primary endocervical stromal cells infected with Ct strain E/Bour. At 1-hour post-infection (1hpi), 168 differentially expressed host genes (DEGs) were identified, 40% of which were non-coding RNAs, novel proteins, or pseudogenes. Pathway analysis revealed no significant enrichment at this stage, indicating a quiescent host response. At 24hpi, 212 DEGs were identified, with strong upregulation of interferon-stimulated genes and activation of the cGAS-STING and RLR pathways, despite the...

Continued Homelessness and Depressive Symptoms in Older Adults

Thu, 17 Jul 2025 00:00:00 +0000

Importance

Depression is common in adults experiencing homelessness. It is unclear whether continued homelessness is associated with more depressive symptoms.

Objective

To examine the association between residential status and depressive symptoms in adults aged 50 years or older experiencing homelessness at study entry.

Design, setting, and participants

This cohort study analyzed results from the Health Outcomes of People Experiencing Homelessness in Older Middle Age (HOPE HOME) project, which in 2013 began enrolling adults aged 50 years or older experiencing homelessness in Oakland, California, and conducted structured interviews every 6 months for a mean duration of 5.5 years through 2023 (for this cohort study). Eligible participants included those aged 50 years or older, able to speak English, and experiencing homelessness at enrollment. We analyzed data collected from 2013 to 2023.

Exposures

The exposure of interest was residential status. At...

Factors Associated with Military Sexual Trauma (MST) Disclosure During VA Screening Among Women Veterans

Thu, 17 Jul 2025 00:00:00 +0000

Background

Capturing military sexual trauma (MST) exposure is critical for Veterans' health equity. For many, it improves access to VA services and allows for appropriate care.

Objective

Identify factors associated with nondisclosure of MST in VA screening among women.

Design

Cross-sectional telephone survey linked with VA electronic health record (EHR) data.

Participants

Women Veterans using primary care or women's health services at 12 VA facilities in nine states.

Main measures

Survey self-reported MST (sexual assault and/or harassment during military service), socio-demographics and experiences with VA care, as well as EHR MST results. Responses were categorized as "no MST" (no survey or EHR MST), "MST captured by EHR and survey," and "MST not captured by EHR" (survey MST but no EHR MST). We used stepped multivariable logistic regression to examine "MST not captured by EHR" as a function of socio-demographics, patient experiences, and screening...

Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial

Thu, 17 Jul 2025 00:00:00 +0000

Background

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated.

Methods

Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis...

Vaping nicotine and cannabis on the same occasion is linked to increased vaping consumption among young adults: A smartphone-based daily diary study

Thu, 17 Jul 2025 00:00:00 +0000

Significance

Vaping both nicotine and cannabis in the past 30 days (co-vaping) is common among young adults. It is unclear which co-vaping patterns may increase substance use and dependence. We examined day-level associations between vaping patterns with vaping quantity.

Method

Daily assessments of vaping behaviors were collected via smartphone for 30 consecutive days among 111 young adults (aged 18-29, vaping nicotine/cannabis at least 20 days during the past month) in California, US, in 2023-2024. Participants reported daily use of nicotine/tobacco (e.g., e-cigarettes, cigarettes) and cannabis products (e.g., vaporized/combustible cannabis). Vaping intensities were the number of times a participant vaped nicotine/cannabis in an entire day. Vaping patterns on a given day were categorized into non-vaping, single-substance vaping, same-day different-occasion co-vaping, and same-occasion co-vaping. Generalized linear mixed-effect models examined day-level associations...

Syndemic theory and Its Use in developing health interventions and programming: A scoping review.

Wed, 16 Jul 2025 00:00:00 +0000

Syndemic theory and Its Use in developing health interventions and programming: A scoping review.

Dynamics of Th1/Th17 responses and antimicrobial pathways in leprosy skin lesions

Wed, 16 Jul 2025 00:00:00 +0000

Background

Reversal reactions (RR) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RR.

Methods

We performed RNA sequencing on paired skin biopsy specimens from nine leprosy patients collected before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae-infected macrophages and axenic cultures.

Results

In the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators...

Perceptual and technical barriers in sharing and formatting metadata accompanying omics studies

Wed, 16 Jul 2025 00:00:00 +0000

Metadata, or "data about data," is essential for organizing, understanding, and managing large-scale omics datasets. It enhances data discovery, integration, and interpretation, enabling reproducibility, reusability, and secondary analysis. However, metadata sharing remains hindered by perceptual and technical barriers, including the lack of uniform standards, privacy concerns, study design limitations, insufficient incentives, inadequate infrastructure, and a shortage of trained personnel. These challenges compromise data reliability and obstruct integrative meta-analyses. Addressing these issues requires standardization, education, stronger roles for journals and funding agencies, and improved incentives and infrastructure. Looking ahead, emerging technologies such as artificial intelligence and machine learning may offer promising solutions to automate metadata processes, increasing accuracy and scalability. Fostering a collaborative culture of metadata sharing will maximize...

‘It's not discrete, it's not going to be easy’: A qualitative analysis of the practical application of syndemic theory in healthcare

Wed, 16 Jul 2025 00:00:00 +0000

‘It's not discrete, it's not going to be easy’: A qualitative analysis of the practical application of syndemic theory in healthcare

Association of a major tobacco tax increase in California with increased smoking cessation

Wed, 16 Jul 2025 00:00:00 +0000

Background

In November 2016, California voters approved Proposition 56, increasing the cigarette tax by $2.00 per pack and nearly tripling spending on tobacco prevention. This study examined whether the initiative was associated with increased smoking cessation.

Methods

States in the United States were categorized into 3 groups: California, 18 other states (including the District of Columbia) that raised taxes, and 32 states that did not raise taxes. Tax and price increases, tobacco prevention spending per capita, 3-month smoking cessation rates using data from the Behavioral Risk Factor Surveillance System (N = 443 054), and the proportion of daily smoking were compared for 2014-2016 and 2017-2019 for these groups.

Results

California had the largest increases in cigarette price (30.8%) and tobacco prevention spending (271.9%), both adjusted for inflation. Other states that raised taxes experienced price increases of 6.3% on average. The 3-month smoking...

Massively parallel reporter assays and mouse transgenic assays provide correlated and complementary information about neuronal enhancer activity

Tue, 15 Jul 2025 00:00:00 +0000

High-throughput massively parallel reporter assays (MPRAs) and phenotype-rich in vivo transgenic mouse assays are two potentially complementary ways to study the impact of noncoding variants associated with psychiatric diseases. Here, we investigate the utility of combining these assays. Specifically, we carry out an MPRA in induced human neurons on over 50,000 sequences derived from fetal neuronal ATAC-seq datasets and enhancers validated in mouse assays. We also test the impact of over 20,000 variants, including synthetic mutations and 167 common variants associated with psychiatric disorders. We find a strong and specific correlation between MPRA and mouse neuronal enhancer activity. Four out of five tested variants with significant MPRA effects affected neuronal enhancer activity in mouse embryos. Mouse assays also reveal pleiotropic variant effects that could not be observed in MPRA. Our work provides a catalog of functional neuronal enhancers and variant effects and highlights...

"Am I going to have to run to get out of this place? A qualitative study exploring HIV clinical and service provider experiences from California regions heavily impacted by climate disaster

Tue, 15 Jul 2025 00:00:00 +0000

"Am I going to have to run to get out of this place? A qualitative study exploring HIV clinical and service provider experiences from California regions heavily impacted by climate disaster

Matrix-based DNA Extraction for Targeted Next-Generation Sequencing on Decontaminated Sputum Samples

Tue, 15 Jul 2025 00:00:00 +0000

Matrix-based DNA Extraction for Targeted Next-Generation Sequencing on Decontaminated Sputum Samples

Cartridge-based sequencing for bedaquiline resistance detection from sputum

Tue, 15 Jul 2025 00:00:00 +0000

Cartridge-based sequencing for bedaquiline resistance detection from sputum

"Everyone says 'safe sex' but no one ever says 'safe drugs', you know?": Perspectives on the intersection of drug checking services, drug policy and the overdose crisis.

Tue, 15 Jul 2025 00:00:00 +0000

Two separate samples of drug checking stakeholders, 'providers' and 'clients' were recruited. Providers participated in in-depth semi-structured qualitative interviews over Zoom on their experiences advocating for and operating drug checking services in the US and Canada. Clients were people who used drugs and lived in or commuted to the San Francisco Bay Area and participated in semi-structured interviews in November 2022. Interviews were transcribed...

Engineering synthetic signaling receptors to enable erythropoietin-free erythropoiesis

Mon, 14 Jul 2025 00:00:00 +0000

Abstract

Blood transfusion plays a vital role in modern medicine. However, availability is contingent on donated blood, and frequent shortages pose a significant healthcare challenge. Ex vivo manufacturing of red blood cells (RBCs) derived from universal donor O-negative pluripotent stem cells emerges as a solution, yet the high cost of recombinant cytokines required for ex vivo erythroid differentiation remains a major barrier. Erythropoietin (EPO) signaling through the EPO receptor is indispensable to RBC development, and EPO is one of the most expensive components in erythroid-promoting media. Here, we used design-build-test cycles to develop highly optimized small molecule-inducible synthetic EPO receptors (synEPORs) which were integrated at a variety of genomic loci using homology-directed repair genome editing. We found that integration of synEPOR at the endogenous EPOR locus in an induced pluripotent stem cell producer line enabled culture with small molecule...

In utero lipid nanoparticle delivery achieves robust editing in hematopoietic stem cells

Mon, 14 Jul 2025 00:00:00 +0000

In vivo genome editing for hematologic malignancies is limited by inefficient delivery of genome editors to hematopoietic stem cells (HSC) in the bone marrow. To overcome this limitation, we capitalized on the inherent liver tropism of lipid nanoparticles (LNPs) and the liver niche of fetal HSCs. We demonstrate that in utero delivery of LNPs without active targeting ligands to the fetal liver results in potentially therapeutic levels of HSC editing.

UNCOVERseq Enables Sensitive and Controlled Gene Editing Off-Target Nomination Across CRISPR-Cas Modalities and Systems

Mon, 14 Jul 2025 00:00:00 +0000

Abstract: The rapid development of CRISPR-Cas gene editing technologies has revolutionized genetic medicine, offering unprecedented precision and potential for treating a wide array of genetic disorders. However, assessing the risks of unintended gene editing effects remains critical, and is complicated by new editing modalities and unclear analytical guidelines. We present UNCOVERseq (Unbiased Nomination of CRISPR Off-target Variants using Enhanced RhPCR), an improvedin cellulooff-target nomination workflow designed to sensitively nominate off-target sites (<0.01% editing) with defined input requirements and analytical process controls to provide empirical performance evidence across diverse circumstances. Using this workflow, we nominated off-targets across 192 guide RNAs (gRNAs) and demonstrated superior performance compared to existing methodologies. We identified a subset of six gRNAs with a dynamic range of specificity and confirmed the relevance and high true positive...

Dual α-globin and truncated EPO receptor knockin restores hemoglobin production in α-thalassemia-derived red blood cells

Mon, 14 Jul 2025 00:00:00 +0000

Alpha-thalassemia is an autosomal recessive disease with increasing worldwide prevalence. The molecular basis is due to mutation or deletion of one or more duplicated α-globin genes, and disease severity is directly related to the number of allelic copies compromised. The most severe form, α-thalassemia major (αTM), results from loss of all four copies of α-globin and has historically resulted in fatality in utero . However, in utero transfusions now enable survival to birth. Postnatally, patients face challenges similar to β-thalassemia, including severe anemia and erythrotoxicity due to imbalance of β-globin and α-globin chains. While curative, hematopoietic stem cell transplantation (HSCT) is limited by donor availability and potential transplant-related complications. Despite progress in genome editing treatments for β-thalassemia, there is no analogous curative option for patients suffering from α-thalassemia. To address this, we designed a novel Cas9/AAV6-mediated genome...

Predictors of parent self-monitoring patterns in a family-based behavioral weight loss treatment program

Fri, 11 Jul 2025 00:00:00 +0000

Objective

Self-monitoring dietary intake is a critical component of family-based intensive health behavior and lifestyle treatment for pediatric obesity, but adherence rates are often low. This study identifies predictors of parent self-monitoring rates during treatment.

Methods

A secondary analysis of parent self-monitoring data from a randomized controlled trial involving 150 parent-child dyads. Patterns of self-monitoring were identified using a latent class mixed model approach. Logistic regression analyses evaluated predictors of self-monitoring patterns.

Results

Latent class models identified two trajectory groups: a high consistent self-monitoring group and a low-decreasing self-monitoring group. When compared to parents in the low group, parents in the high group lost more weight throughout treatment. Children in the high group had a similar trajectory for weight loss; however, the groups were not statistically different. Higher levels of family chaos...

Suppression of NRAS-mutant melanoma growth with NRAS-targeting Antisense Oligonucleotide treatment reveals therapeutically relevant kinase co-dependencies

Wed, 9 Jul 2025 00:00:00 +0000

Background

Melanoma is an aggressive form of skin cancer, and patients with NRAS-mutant melanoma face limited treatment options due to the lack of direct NRAS inhibitors. This study explores the utilization of antisense oligonucleotides (ASOs) to directly target NRAS-mRNA for therapeutic approaches.

Methods

We designed and tested NRAS-mRNA-targeting ASOs. Experiments in melanoma cell lines and mouse models assessed effects on cell survival, apoptosis, and tumor growth. A kinase activity profiling platform identified therapeutically exploitable pathways influenced by NRAS suppression.

Results

Our research suggests that ASOs do not need to target the mutated NRAS segment to be effective. ASOs designed for the non-mutated NRAS sequence eliminate NRAS-dependent melanoma cells while sparing NRAS wild-type cells. They act independently of subcellular target localization, reduce NRAS-mRNA levels, inhibit MAPK signaling, induce apoptosis, and suppress melanoma growth...

Clinical melanoma characteristics and survival—a single-center retrospective study between 2000 and 2010

Wed, 9 Jul 2025 00:00:00 +0000

The aim of this study was to characterize clinical, histological, and outcome features of primary melanoma in 1329 patients managed at a single-center institution between 2000 and 2010. Parameters included age at diagnosis, sex, tumor location, histology, stage, Breslow thickness, and sentinel lymph node status among others. The mean age at diagnosis was 59.1 ± 16.7 years. Women were significantly younger than men when diagnosed (57.2 vs. 61.0 years; p < 0.001). Most melanomas (83%) were diagnosed on typically sun-exposed skin areas. Superficial spreading melanoma (39.5%) was the most frequent histological subtype. The median Breslow thickness was significantly higher for men compared to women (1.10 mm vs. 0.90 mm; p = 0.018). 38.3% of patients with positive and 12.9% of patients with negative sentinel biopsies progressed. Five-year survival analysis for a sub-cohort of 577 patients showed better 5‑year overall survival for woman compared to men (75.8% vs....

Recommended measurement protocols for sickle cell disease in the PhenX toolkit: psychosocial factors and social determinants of health

Tue, 8 Jul 2025 00:00:00 +0000

Objectives

Consensus Measures for Phenotypes and eXposures (PhenX) Toolkit (https://www.phenxtoolkit.org/) is a web-based catalog of recommended measurement protocols and associated bioinformatics tools to assist with study design and facilitate cross-study data integration and analyses. Before February 2023 (v.44), protocols specific to sickle cell disease did not address key psychosocial factors or social determinants of health that impact care and outcomes. This paper describes the protocol selection process and final recommendations to address this limitation.

Methods

To identify protocols for the new collection, the PhenX Sickle Cell Disease Research and Scientific Panel provided a list of scope elements for consideration and assembled a panel with relevant expertise in psychology, behavioral science, hematology, and nursing to form a Psychosocial and Social Determinants of Health Working Group. A consensus process prioritized and identified the scope elements...

Antenatal corticosteroids for pregnant women at risk of preterm labour in low- and middle-income countries: utilisation and facility readiness.

Tue, 8 Jul 2025 00:00:00 +0000

Background

Administering antenatal corticosteroids (ACS) to pregnant women at risk of imminent preterm labour improves newborn survival. However, ACS remains substantially underused in low- and middle-income countries (LMICs), where most preterm births occur globally. Providing ACS in inadequately equipped settings can be harmful. Health facilities must demonstrate readiness to ensure safe and effective ACS use. We aimed to assess ACS utilisation and facility readiness to administer ACS based on the World Health Organization (WHO) recommendations.

Methods

We used data from Service Provision Assessments in nine LMICs. The primary outcome was ACS utilisation, which was defined as having ever provided ACS in a health facility. We assessed the availability of injectable corticosteroids (dexamethasone or betamethasone) and facility readiness to administer ACS appropriately. To measure readiness, we developed an overall readiness index based on 35 indicators, grouped...

Development of chronic pain and high‐impact chronic pain across the US rural–urban continuum, 2019–2020

Mon, 7 Jul 2025 00:00:00 +0000

Purpose

Rural health disadvantages are well documented in previous literature; however, research on rural-urban disparities in chronic pain outcomes is scarce. This paper fills this gap by examining pain prevalences and longitudinal transitions across the rural-urban continuum (i.e., large central metro, large fringe metro, medium and small metro, and nonmetropolitan).

Methods

Based on the 2019-2020 National Health Interview Survey Longitudinal Cohort (NHIS-LC) data, we examined the disparities in pain prevalences and transitions among different pain statuses, including no pain, nonchronic pain, chronic pain, and high-impact chronic pain (HICP), across the rural-urban continuum and by age, sex, race/ethnicity, and region. A test for linear trend was conducted to examine the significance of linear changes across the rural-urban continuum.

Findings

The findings reveal significant linear increases in the prevalence of chronic pain and HICP, as well as transitions...

Adult child educational attainment and older parents’ psychosocial outcomes during the COVID-19 pandemic

Mon, 7 Jul 2025 00:00:00 +0000

Background

Older adults' psychosocial outcomes during the COVID-19 pandemic have been inequitable by socio-economic status (SES). However, studies have focused solely on own SES, ignoring emerging evidence of the relationship between adult child SES and late-life health. We evaluated whether adult child educational attainment - a core marker of SES - is associated with older parents' psychosocial outcomes during the pandemic.

Methods

We used data from the Survey of Health, Aging, and Retirement in Europe (SHARE) 2004-2018 and the SHARE Corona Surveys (SCS) 2020 and 2021. We included 40,392 respondents ≥ 65 years who had pre-pandemic information on adult child educational attainment and self-reported psychosocial outcomes during the pandemic, including self-assessments of worsened psychosocial outcomes compared to the pre-pandemic period. We used generalized estimating equations with a Poisson distribution and a log link, adjusted for respondent and family-level...

Placement

Sun, 6 Jul 2025 00:00:00 +0000

Placement

Insights Into Recovery From Acute Fulminant Myocarditis Following Successful Treatment With Ruxolitinib by Comprehensive Single-Cell Profiling

Sun, 6 Jul 2025 00:00:00 +0000

Insights Into Recovery From Acute Fulminant Myocarditis Following Successful Treatment With Ruxolitinib by Comprehensive Single-Cell Profiling

Immune checkpoint inhibitor-associated myocarditis: a novel risk score

Sun, 6 Jul 2025 00:00:00 +0000

Background and aims

Immune checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this 'cardiomyotoxicity' are lacking. The main aim of this study was to determine predictors and construct a risk score associated with negative outcomes in patients admitted for ICI myocarditis.

Methods

A multicentre registry collected data retrospectively from 17 countries between 2014 and 2023. A multivariable Cox regression model was used to determine risk factors for the primary composite outcome: time to severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardiomuscular symptoms, diagnostics, and treatments. Time-dependent covariates...

Length of Neuromuscular Re-education Therapy and Growth Parameters in Premature Infants

Sun, 6 Jul 2025 00:00:00 +0000

Objective

Neuromuscular re-education (NMRE) therapy including bracing, containment, facilitation techniques, joint compression, weight (WT) bearing, and myofascial release has been shown to improve neurodevelopmental maturation in premature infants. This study aimed to examine the association of NMRE with growth parameters including WT and length (L) at 36 weeks postmenstrual age (PMA) and at discharge.

Study design

We analyzed data of infants <34 weeks gestational age (GA) or <1,800 g birth weight (BW) to examine the association of NMRE with growth parameters using correlation coefficient analysis. The effect of potential confounders was examined using multilinear regression models.

Results

Study includes 253 premature infants. Average GA was 30^0/7 weeks (±2^3/7) and BW was 1,315 g (±416), 49.8% were females and 65% were African Americans. NMRE has inverse correlation with WT at birth and at 36 weeks PMA, -0.66 (<0.001) and...

Preclinical mouse models of immune checkpoint inhibitor-associated myocarditis

Sun, 6 Jul 2025 00:00:00 +0000

In this Review, we present a comprehensive analysis of preclinical models used to study immune checkpoint inhibitor-associated myocarditis (hereafter ICI-myocarditis), a potentially lethal immune-related adverse event. We begin by providing an overview of immune checkpoint inhibitors, highlighting how their efficacy in cancer treatment is counterbalanced by their predisposition to cause immune-related adverse events. Next, we draw from human data to identify disease features that an effective mouse model should ideally mimic. After that, we present a critical evaluation of a wide variety of existing mouse models including genetic, pharmacological and humanized models. We summarize insights gathered about the underlying mechanisms of ICI-myocarditis and the role of mouse models in these discoveries. We conclude with a perspective on the future of preclinical models, highlighting potential model improvements and research directions that could strengthen our understanding of ICI-myocarditis,...

The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5

Fri, 4 Jul 2025 00:00:00 +0000

Glutamine reprogramming plays a crucial role in the growth and survival of clear cell renal cell carcinoma (ccRCC), although the mechanisms governing its regulation are still not fully understood. We demonstrate that the RNA demethylase fat mass and obesity-associated gene (FTO) drives glutamine reprogramming to support ccRCC growth and survival. Genetic and pharmacologic inhibition of FTO in ccRCC cells impaired glutamine-derived reductive carboxylation, depleted pyrimidines, and increased reactive oxygen species. This led to increased DNA damage and reduced survival, which could be rescued by pyrimidine nucleobases or the antioxidant N-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter solute carrier family 1 member 5 (SLC1A5) messenger RNA to promote its expression. Restoration of SLC1A5 expression in FTO-knockdown cells rescued metabolic and survival defects. FTO inhibition reduced ccRCC tumor xenograft and PDX growth under the renal capsule....

Solute-Vehicle-Skin Interactions and Their Contribution to Pharmacokinetics of Skin Delivery.

Fri, 4 Jul 2025 00:00:00 +0000

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients is a delicate balance between the molecular properties of the drug, the skin properties of the patients, and the formulation properties. Understanding this interplay can aid in the development of products applied to the skin. The kinetics of percutaneous absorption and an understanding of the rate-limiting steps involved can facilitate the optimization of these systems and enhance the degree to which skin drug delivery can be achieved. Solute-vehicle, vehicle-skin, and solute-skin interactions contribute notably to product release as well as the rate of absorption and diffusion across skin layers. These interactions alter the degree of permeation by interfering with the skin barrier or solubility...

Total Syntheses of Stereoisomeric Congeners of Rufomycin Natural Products Having Anti-Mycobacterial Activity

Thu, 3 Jul 2025 00:00:00 +0000

Syntheses of bioactive rufomycin natural product congeners that differ in stereochemistry at a conserved methyl-substituted amino-hydroxy-piperidone (Ahp) moiety have been achieved for the first time. In addition to gaining new insights into the formation and conformation of the Ahp stereoisomers, we were intrigued to find that theirs reduction improves rufomycin bioactivity significantly.

BDNF Val66Met polymorphism moderates associations between physical activity and neurocognitive outcomes in older adults

Thu, 3 Jul 2025 00:00:00 +0000

Introduction

Increased brain-derived neurotrophic factor (BDNF) release through physical activity (PA) is thought to underlie protective effects of PA on brain aging. The BDNF Val66Met single-nucleotide polymorphism (rs6265) reduces activity-dependent BDNF release and has been linked to early Alzheimer's disease (AD) pathology and cognition. We examined whether BDNF genotype influences the association of PA with plasma markers of AD, axonal degeneration, and neuroinflammation, along with consequences for cognition, in older adults without dementia.

Methods

One hundred eighty older adults (M_age = 73.1; SD_age = 9.1; 61% female; 42% BDNF Met allele carriers) from the University of California San Francisco (UCSF) Memory and Aging Center completed 30 days of actigraphy monitoring, plasma assays of phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and BDNF Val66Met...

Frequency of Attendance to a Behavioral Intervention on Health-related Outcomes in a Multicomponent Food as Medicine Intervention

Thu, 3 Jul 2025 00:00:00 +0000

Objective

Determine whether the frequency of attendance to Recipe4Health was associated with improvements in health-related outcomes.

Design

Secondary analysis of the Recipe4Health quasi-experimental study.

Setting

Federally Qualified Health Centers in Alameda County, California.

Participants

Patients with nutrition-related chronic conditions and/or food insecurity.

Intervention

Sixteen weekly produce deliveries and behavioral intervention sessions.

Main outcome measures

Attendance was categorized by percentage: low (< 50%), moderate (50% to < 75%), and high (≥ 75%), and outcomes included vegetable/fruit intake, physical activity (PA), mental health, and clinical biomarkers.

Analysis

Prepost changes were assessed using repeated measures linear mixed-effects models, adjusting for baseline values.

Results

Of the 199 patients, approximately one-third had low (36%), moderate (30%), and high (34%) attendance. Patients with...

Increased CSF drainage by non-invasive manipulation of cervical lymphatics

Thu, 3 Jul 2025 00:00:00 +0000

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain drains to lymph nodes in the neck, but the connections and regulation have been challenging to identify^1-24. Here we used fluorescent tracers in Prox1-GFP lymphatic reporter mice to map the pathway of CSF outflow through lymphatics to superficial cervical lymph nodes. CSF entered initial lymphatics in the meninges at the skull base and continued through extracranial periorbital, olfactory, nasopharyngeal and hard palate lymphatics, and then through smooth muscle-covered superficial cervical lymphatics to submandibular lymph nodes. Tracer studies in adult mice revealed that a substantial amount of total CSF outflow to the neck drained to superficial cervical lymph nodes. However, aged mice had fewer lymphatics in the nasal mucosa and hard palate and reduced CSF outflow to cervical lymph nodes. Superficial cervical lymphatics in aged mice had increased endothelial cell expression of Nos3, encoding...

Is it safe to use class 1C antiarrhythmic drugs in patients with coronary artery disease and/or cardiomyopathy?

Thu, 3 Jul 2025 00:00:00 +0000

Class 1C antiarrhythmic drugs (AADs) are a key treatment option for effective rhythm control in several common arrhythmias. Here, we review the relevant background on Class 1C AADs, these drugs' indications and contraindications, and potential safe ways to use them. The safety profile of 1C AADs, and related restrictions on their use, has been largely based on the decades-old CAST trial, but more recent evidence may favor re-evaluating previously excluded populations. This review examines opportunities to reconsider certain patient populations that have previously been excluded from the use of 1C AADs. This reconsideration is made feasible due to advances in cardiac reperfusion, medical therapies for heart failure, and cardiac imaging.

The application of Kirchhoff's Laws to saturable, michaelis-menten, pharmacokinetics

Thu, 3 Jul 2025 00:00:00 +0000

The application of Kirchhoff's Laws to saturable, michaelis-menten, pharmacokinetics

Single Tri-Epitopic Antibodies (TeAbs) to Botulinum Neurotoxin Serotypes B, E, and F Recapitulate the Full Potency of a Combination of Three Monoclonal Antibodies in Toxin Neutralization

Thu, 3 Jul 2025 00:00:00 +0000

Recombinant monoclonal antibody (mAb) botulinum neurotoxin (BoNT) antitoxins, consisting of three mAbs that bind non-overlapping epitopes, are highly potent. However, the three-mAb mixtures pose unique development and manufacturing challenges. Combining even more mAbs to create multivalent antitoxin drugs multiplies those challenges. We previously reported that a single tri-epitopic IgG1-based mAb (TeAb) containing the variable domains of the three parental BoNT/A mAbs and an Fc was as potent as the combination of three IgGs in the mouse neutralization assay (MNA). Here, we extended the tri-epitopic strategy to three other BoNT serotypes. Each TeAb (TeAb-B for BoNT/B, TeAb-E for BoNT/E, and TeAb-F for BoNT/F) binding was measured using fluorescence-activated cell sorting and flow fluorimetry, and the potency was tested in the MNA. The three TeAbs displayed binding affinities that were the same within error of the parental IgGs for each epitope, and all had higher avidity to each...

Response to the commentary on “are all measures of liver Kpuu a function of FH, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance?”

Thu, 3 Jul 2025 00:00:00 +0000

Recently, Sugano commented on our above-titled publication stating that he was a reviewer for the paper. In the Acknowledgements, Sugano indicated that we "kindly suggested publishing the reviewer report as an article". What we had actually written was: "prior to accepting the [unidentified] reviewer's approach, however, we believe he/she would have to publish a paper justifying the methodology and proposing how in vivo clinical data could be analyzed with such methodology". We further explained the fallacy of the accepted mechanistic models of hepatic elimination in a subsequent manuscript titled "Pharmacokinetic theory must consider published experimental data", published online a month after the Sugano commentary became available -not in time for the author to review the full explanation before his commentary was published. Our above-titled publication makes no assumptions or discussions regarding how Kp_uu should be measured, the major topic of the Sugano paper....

Impact of Hoarding and Obsessive–Compulsive Disorder Symptomatology on Quality of Life and Their Interaction With Depression Symptomatology

Thu, 3 Jul 2025 00:00:00 +0000

Hoarding disorder (HD) is a psychiatric condition characterized by difficulty discarding items and accumulation of clutter. Although studies have established the negative impact of HD and compulsive hoarding behavior, fewer have examined the impact on quality of life (QoL) of hoarding behavior independent of obsessive-compulsive disorder (OCD). Moreover, specific aspects of QoL such as success in work/academics or satisfaction with interpersonal relationships have not been well-investigated. In this study, we examined, in a sample of 2100 adult participants obtained from Amazon Mechanical Turk, the relationships between hoarding, OCD, and depression symptomatology and four QoL domains (success, enrichment, environment, and family) derived from a factor analysis of the Quality of Life Inventory (QoLI). We performed linear regressions to examine associations between psychiatric symptomatology and QoL domains and then conducted mediation analyses to investigate the role of depressive...

The effects of traumatic brain Injury, post-traumatic stress disorder on Amyloid-β associated network hyperconnectivity and progression of gray matter atrophy

Thu, 3 Jul 2025 00:00:00 +0000

Background

Amyloid-β associated network hypersynchrony is an early manifestation of pre-clinical Alzheimer's Disease (AD). The overall goal was to investigate a. how TBI and PTSD influence hypersynchrony expression and b. how progressing gray matter atrophy affects hypersynchrony expression.

Methods

T1-weighted images, resting-state fMRIs and amyloid-β SUVRs were obtained from 234 DoD-ADNI subjects with or without TBI and/or PTSD. The denoised BOLD signal from 382 rois was extracted with CONN and dynamic resting state analysis was used to identify 8 states including one corresponding to a hypersynchrony state (HSS). SuStaIn with gray matter volumes and amyloid-β SUVR as inputs was used to identify 2 subtypes with progressive gray matter loss.

Results

HSS dwell-time correlated positively with amyloid-β (Kendall tau = 0.125,p = 0.047) and tau Braak stage 5&6 SUVR (Kendall tau = 0.200,p = 0.035). TBI increased the...

Development and validation of a risk nomogram predicting pneumothorax requiring chest tube placement post-percutaneous CT-guided lung biopsy.

Thu, 3 Jul 2025 00:00:00 +0000

BACKGROUND: Pneumothorax requiring chest tube after CT-guided transthoracic lung biopsy presents added clinical risk and costs to the healthcare system. Identifying high-risk patients can prompt alternative biopsy modes and/or better preparation for more focused post-procedural care. We aimed to develop and externally validate a risk nomogram for pneumothorax requiring chest tube placement following CT-guided lung biopsy, leveraging quantitative emphysema algorithm. METHODS: This two-center retrospective study included patients who underwent CT-guided lung biopsy from between 1994 and 2023. Data from one hospital was set aside for validation (n = 613). Emphysema severity was quantified and categorized to 3-point scale using a previously published algorithm based on 3×3×3 kernels and Hounsfield thresholding, and a risk calculator was developed using forward variable selection and logistic regression. The model was validated using bootstrapping and Harrell's C-index. RESULTS: 2,512...

Abstract 296: Synergistic actions of oncolytic vaccinia virus and sunitinib on pancreatic neuroendocrine tumors in RIP-Tag2 mice

Thu, 3 Jul 2025 00:00:00 +0000

Abstract: Pexa-Vec (JX-594) is an engineered oncolytic vaccinia virus that lacks thymidine kinase and expresses human granulocyte-macrophage colony stimulating factor. In addition to having oncolytic effects on tumor cells and promoting an immune response, Pexa-Vec has been found to cause rapid reduction of tumor blood flow in preclinical models and in clinical trials. The angiogenesis inhibitor sunitinib reduces tumor vascularity and can augment the activity of vesicular stomatitis virus by suppressing two interferon-induced anti-viral host proteins, RNA-dependent protein kinase and ribonuclease L. We explored the interaction of mpJX-594, a mouse-adapted version of Pexa-Vec, and sunitinib. The mouse-adapted version, mpJX-594, was engineered from Western Reserve strain vaccinia virus by deletion of thymidine kinase and addition of human GM-CSF, yellow fluorescent protein, and luciferase genes. The effects of mpJX-594 or sunitinib given individually...

Keratinocyte–TRPV1 sensory neuron interactions in a genetically controllable mouse model of chronic neuropathic itch

Thu, 3 Jul 2025 00:00:00 +0000

Our understanding of neural circuits that respond to skin dysfunction, triggering itch, and pathophysiological scratching remains incomplete. Here, we describe a profound chronic itch phenotype in transgenic mice expressing the tetracycline transactivator (tTA) gene within the Phox2a lineage. Phox2a; tTA mice exhibit intense, localized scratching and regional skin lesions, controllable by the tTA inhibitor, doxycycline. As gabapentin and the kappa opioid receptor agonist, nalfurafine, but not morphine, significantly reduce scratching, this phenotype has a pharmacological profile of neuropathic pruritus. Importantly, the Phox2a; tTA expression occurs in a spatially restricted population of skin keratinocytes that overlaps precisely with the skin area that is scratched. Localized G_i-DREADD-mediated inactivation of these Phox2a-keratinocytes completely reverses the skin lesions, while inducible tTA activation of keratinocytes initiates the condition. Notably, ablation...