In vivo base editing extends lifespan of a humanized mouse model of prion disease.

Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain.

Brain-derived tau oligomer polymorphs: distinct aggregations, stability profiles, and biological activities.

Aggregation of microtubule-associated tau protein is a distinct hallmark of several neurodegenerative disorders such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). Tau oligomers are suggested to be the primary neurotoxic species that initiate aggregation and propagate prion-like structures. Furthermore, different diseases are shown to have distinct structural characteristics of aggregated tau, denoted as polymorphs.

Social Vulnerability and Biological Aging in New York City: An Electronic Health Records-Based Study.

Chronological age is not an accurate predictor of morbidity and mortality risk, as individuals' aging processes are diverse. Phenotypic age acceleration (PhenoAgeAccel) is a validated biological age measure incorporating chronological age and biomarkers from blood samples commonly used in clinical practice that can better reflect aging-related morbidity and mortality risk. The heterogeneity of age-related decline is not random, as environmental exposures can promote or impede healthy aging.

Multiplex genome editing eliminates lactate production without impacting growth rate in mammalian cells.

The Warburg effect, which describes the fermentation of glucose to lactate even in the presence of oxygen, is ubiquitous in proliferative mammalian cells, including cancer cells, but poses challenges for biopharmaceutical production as lactate accumulation inhibits cell growth and protein production. Previous efforts to eliminate lactate production in cells for bioprocessing have failed as lactate dehydrogenase is essential for cell growth. Here, we effectively eliminate lactate production in Chinese hamster ovary and in the human embryonic kidney cell line HEK293 by simultaneous knockout of lactate dehydrogenases and pyruvate dehydrogenase kinases, thereby removing a negative feedback loop that typically inhibits pyruvate conversion to acetyl-CoA.

Diabetes in China: epidemiology, pathophysiology and multi-omics.

Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence.

Telehealth Modality Usage by US Physicians in 2022.

Background: The growth of telehealth care delivery during the COVID-19 pandemic highlighted its potential to enhance access to care and improve patient outcomes. As the healthcare landscape moves toward a new equilibrium in care delivery, few studies have examined physician usage of specific telehealth modalities.

Objective: To understand telehealth usage differences among modalities and across subgroups of physicians.

Staffing Up: The Nursing Home Minimum Staffing Rule.

On April 22, 2024, the Centers for Medicare & Medicaid Services (CMS) announced new staffing mandates for long-term care (LTC) facilities in an effort to improve care quality in nursing homes (NHs). The guidelines require a minimum of 3.48 h of daily care per resident, including 0.

Onsite Primary Care to Address Medical Needs Among Permanent Supportive Housing Tenants: A Feasibility Demonstration Project.

Background: There is limited evidence on interventions to address the health needs of vulnerable patients in permanent supportive housing (PSH).

Aim, Setting, Participants: Evaluate the feasibility of Project HOPE, a weekly onsite primary care pilot intervention for tenants of a single-site PSH program.

Program Description: Physicians, nursing, and pharmacy providers work with existing case managers to provide onsite routine and acute care, outreach, and care coordination.

Trends in Co-morbid Dementia and Chronic Kidney Disease.

Background: Little is known about the population of Medicare beneficiaries with both chronic kidney disease (CKD) and Alzheimer's disease and related dementias (ADRD).

Methods: Using data from Medicare fee-for-service (FFS) beneficiaries aged 65 and over identified through 2011-2019 Master Beneficiary Summary File (MBSF), we estimated the size, growth, and racial-ethnic characteristics of the ADRD and CKD populations. Individuals were classified as having ADRD and CKD based on CMS Chronic Conditions Data Warehouse (CCW) indicators in the MBSF Chronic Conditions file.

Robust estimation of the latent trait in graded response models.

Aberrant responses (e.g., careless responses, miskeyed items, etc.

Molecular basis of neurosteroid and anticonvulsant regulation of TRPM3.

Transient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the peripheral sensory system. Recent discoveries of autosomal dominant neurodevelopmental disorders caused by gain-of-function mutations in TRPM3 highlight its role in the central nervous system. Notably, the TRPM3 inhibitor primidone, an anticonvulsant, has proven effective in treating patients with TRPM3-linked neurological disorders and in mouse models of thermal nociception.

Single-molecule analysis of transcription activation: dynamics of SAGA coactivator recruitment.

Transcription activators are said to stimulate gene expression by 'recruiting' coactivators, yet this vague term fits multiple kinetic models. To directly analyze the dynamics of activator-coactivator interactions, single-molecule microscopy was used to image promoter DNA, a transcription activator and the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex within yeast nuclear extract. SAGA readily but transiently binds nucleosome-free DNA without an activator, while chromatin association occurs primarily when an activator is present.

Targeting mitophagy in neurodegenerative diseases.

Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need.

A phase I study of the CDK4/6 inhibitor ribociclib combined with gemcitabine in patients with advanced solid tumors.

Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).

Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of ribociclib plus gemcitabine in patients with advanced solid tumors. Patients received gemcitabine intravenously on days 1 and 8 followed by ribociclib days 8-14, with treatment repeated every 3 weeks.

Optimizing the NGS-based discrimination of multiple lung cancers from the perspective of evolution.

Next-generation sequencing (NGS) offers a promising approach for differentiating multiple primary lung cancers (MPLC) from intrapulmonary metastasis (IPM), though panel selection and clonal interpretation remain challenging. Whole-exome sequencing (WES) data from 80 lung cancer samples were utilized to simulate MPLC and IPM, with various sequenced panels constructed through gene subsampling. Two clonal interpretation approaches primarily applied in clinical practice, MoleA (based on shared mutation comparison) and MoleB (based on probability calculation), were subsequently evaluated.

Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain.

Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.

Effectiveness and safety of hypofractionated gamma knife radiosurgery for large meningiomas and those adjacent to the optic pathway and brainstem: preliminary therapeutic outcomes.

Recent technologic advancements have facilitated the use of hypofractionated Gamma Knife-based radiosurgery (HF-GKRS) to treat large lesions or those in eloquent areas. This study aimed to analyze the preliminary results of HF-GKRS for these meningiomas, and to determine its effectiveness and safety. This single-center retrospective study analyzed data of patients who underwent HF-GKRS for large meningiomas or those in eloquent areas with > 6 months of follow-up.

Evaluating historical changes in a mussel bed community in northern California.

Marine foundation species are increasingly impacted by anthropogenic stressors, driving a loss of diversity within these critical habitats. Prior studies suggest that species diversity within mussel beds has declined precipitously in southern California, USA, but it is unclear whether a similar loss has occurred farther north. Here, we resurvey a mussel bed community in northern California first sampled in 1941 to evaluate changes in diversity after 78 years.

Hepatocellular Carcinoma with Vascular Invasion Treated with Resin Yttrium-90 Transarterial Radioembolization Using Single Compartment Dosimetry.

Purpose: To report outcomes in hepatocellular carcinoma (HCC) patients with lobar and segmental vascular invasion treated with resin Yttrium-90 transarterial radioembolization (Y90-TARE) with single-compartment MIRD (Medical Internal Radiation Dose) model.

Materials And Methods: This was a retrospective IRB approved study of patients with a diagnosis of HCC with vascular invasion undergoing resin Y90-TARE from 2014 to 2022 (n = 61). Patients with Body Surface Area dosimetry (n = 20), main portal vein invasion (n = 6) and patients with an ECOG of > 2 were excluded (n = 1) with a final cohort of 34 patients.

Dynamic switching between brain networks predicts creative ability.

Creativity is hypothesized to arise from a mental state which balances spontaneous thought and cognitive control, corresponding to functional connectivity between the brain's Default Mode (DMN) and Executive Control (ECN) Networks. Here, we conduct a large-scale, multi-center examination of this hypothesis. Employing a meta-analytic network neuroscience approach, we analyze resting-state fMRI and creative task performance across 10 independent samples from Austria, Canada, China, Japan, and the United States (N = 2433)-constituting the largest and most ethnically diverse creativity neuroscience study to date.

Deep learning empowered sensor fusion boosts infant movement classification.

Background: To assess the integrity of the developing nervous system, the Prechtl general movement assessment (GMA) is recognized for its clinical value in diagnosing neurological impairments in early infancy. GMA has been increasingly augmented through machine learning approaches intending to scale-up its application, circumvent costs in the training of human assessors and further standardize classification of spontaneous motor patterns. Available deep learning tools, all of which are based on single sensor modalities, are however still considerably inferior to that of well-trained human assessors.