Nicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling.

Nicotinamide adenine dinucleotide (NAD) is required for a myriad of metabolic, signaling, and post-translational events in cells. Its levels in tissues and organs are closely associated with health conditions. The homeostasis of NAD is regulated by biosynthetic pathways and consuming enzymes.

Oxytocin neurons in the paraventricular and supraoptic hypothalamic nuclei bidirectionally modulate food intake.

Oxytocin (OT) is a neuropeptide produced in the paraventricular (PVH) and supraoptic (SON) nuclei of the hypothalamus. Either peripheral or central administration of OT suppresses food intake through reductions in meal size. However, pharmacological approaches do not differentiate whether observed effects are mediated by OT neurons located in the PVH or in the SON.

Multi-Omic Characterization of Single Cells and Cell-Free Components Detected in the Cerebrospinal Fluid of Patients with Leptomeningeal Disease.

Background/objectives: Up to 30% of patients with breast cancers will develop brain or leptomeningeal metastases, and this risk is especially high with HER2-positive cancers. For patients with central nervous system metastases, cerebrospinal fluid (CSF) liquid biopsies are a promising opportunity to monitor disease, inform treatment, and predict prognosis. This pilot study investigated CSF liquid biopsy analytes from three patients diagnosed with central nervous system metastases based on imaging but not confirmed via clinical cytology.

Discovery of penicillic acid as a chemical probe against tau aggregation in Alzheimer's disease.

Alzheimer's Disease (AD) is a neurodegenerative disorder proven to be caused by the aggregation of protein tau into fibrils, resulting in neuronal death. The irreparable neuronal damage leads to irreversible symptoms with no cure; therefore, disaggregation of these tau fibrils could be targeted as a therapeutic approach to AD. Here we have developed a fungal natural product library to screen for secondary metabolites that have bioactive potential towards AD tau.

Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence.

Discovery of PARP1-Sparing Inhibitors for Protein ADP-Ribosylation.

Poly-ADP-ribose polymerases (PARPs) that catalyze cellular ADP-ribosylation play important roles in human health. PARP inhibitors have found success in the clinic for cancer treatment. However, isoform-specific inhibitors are needed for improved safety.

An NAD with Dually Modified Adenine for Labeling ADP-Ribosylation-Specific Proteins.

Protein adenosine diphosphate (ADP)-ribosylation participates in various pivotal cellular events. Its readers and erasers play key roles in modulating ADP-ribosylation-based signaling pathways. Unambiguous assignments of readers and erasers to individual ADP-ribosylated proteins provide insightful knowledge on ADP-ribosylation biology and require the development of tools and technologies for this goal.

EV-miRNA associated with environmental air pollution exposures in the MADRES cohort.

Air pollution is a hazardous contaminant, exposure to which has substantial consequences for health during critical periods, such as pregnancy. MicroRNA (miRNA) is an epigenetic mechanism that modulates transcriptome responses to the environment and has been found to change in reaction to air pollution exposure. The data are limited regarding extracellular-vesicle (EV) miRNA variation associated with air pollution exposure during pregnancy and in susceptible populations who may be disproportionately exposed.

Determining the efficacy of ExThera Seraph100 blood filtration in patients diagnosed with pancreatic cancer through the liquid biopsy.

Background: Cancer becomes lethal as it spreads from the primary site to the rest of the body. Circulating tumor cells (CTCs) are biomarkers of disease progression and have been associated with decreased overall survival. Blood filtration is a novel concept for removing CTCs from circulation to improve patient prognosis.

Social health, activity behaviors, and quality of life among young adult cancer survivors: Protocol for a prospective observational study.

Approximately 85,000 adolescent and young adults (AYAs; age 15-39) are diagnosed with cancer in the United States annually. Experiencing a cancer diagnosis as an AYA can substantially impact social connections and social health. This paper describes the design and protocol of an observational study to prospectively assess social health and its association with physical activity and quality of life among AYAs after a cancer diagnosis.

Associations between less knee kinematic variability and worse patient-reported outcomes following anterior cruciate ligament reconstruction.

Individuals with anterior cruciate ligament reconstruction (ACLR) exhibit less knee kinematic variability while walking than uninjured controls, associated with deleterious changes in cartilage composition linked to an increased risk for early knee osteoarthritis (KOA). It is unknown whether less knee kinematic variability is also associated with worse knee-related patient-reported outcomes (PROs) consistent with KOA development. This study examined associations between kinematic variability during gait and PROs in individuals post-ACLR.

Is racism like other trauma exposures? Examining the unique mental health effects of racial/ethnic discrimination on posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD).

Although scholars have increasingly drawn attention to the potentially traumatic nature of racial/ethnic discrimination, diagnostic systems continue to omit these exposures from trauma definitions. This study contributes to this discussion by examining the co-occurrence of conventional forms of potentially traumatic experiences (PTEs) with in-person and online forms of racism-based potentially traumatic experiences (rPTEs) like racial/ethnic discrimination. Additionally, we investigated the unique association of rPTEs with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD), accounting for demographics and other PTEs.

Anatomic Interpretability in Neuroimage Deep Learning: Saliency Approaches for Typical Aging and Traumatic Brain Injury.

The black box nature of deep neural networks (DNNs) makes researchers and clinicians hesitant to rely on their findings. Saliency maps can enhance DNN explainability by suggesting the anatomic localization of relevant brain features. This study compares seven popular attribution-based saliency approaches to assign neuroanatomic interpretability to DNNs that estimate biological brain age (BA) from magnetic resonance imaging (MRI).

Exposure to sugar rationing in the first 1000 days of life protected against chronic disease.

We examined the impact of exposure to sugar restrictions within 1000 days after conception on type 2 diabetes and hypertension, leveraging quasi-experimental variation from the end of the United Kingdom's sugar rationing in September 1953. Rationing restricted sugar intake to levels within current dietary guidelines, and consumption nearly doubled immediately after rationing ended. Using an event study design with UK Biobank data comparing adults conceived just before or after rationing ended, we found that early-life rationing reduced type 2 diabetes and hypertension risk by about 35 and 20% and delayed disease onset by 4 and 2 years, respectively.

Multi-ancestry GWAS reveals loci linked to human variation in LINE-1- and Alu-copy numbers.

Long INterspersed Element-1 (LINE-1; L1) and Alu are two families of transposable elements (TEs) occupying ~17% and ~11% of the human genome, respectively. Though only a small fraction of L1 copies is able to produce the machinery to mobilize autonomously, Alu elements and degenerate L1 copies can hijack their functional machinery and mobilize . The expression and subsequent copy number expansion of L1 and Alu can exert pathological effects on their hosts, promoting genome instability, inflammation, and cell cycle alterations.

VISTA: an integrated framework for structural variant discovery.

Structural variation (SV) refers to insertions, deletions, inversions, and duplications in human genomes. SVs are present in approximately 1.5% of the human genome.

SIRT7 remodels the cytoskeleton RAC1 to enhance host resistance to .

Phagocytosis of () followed by its integration into the matured lysosome is critical in the host defense against tuberculosis. How escapes this immune attack remains elusive. In this study, we unveiled a novel regulatory mechanism by which SIRT7 regulates cytoskeletal remodeling by modulating RAC1 activation.

Socioeconomic Inequalities in Frailty Distribution: A Cross-National Comparison of the United States and England.

Objectives: The objective of this study is to examine differences in socioeconomic gradients (i.e., education, income, and wealth) in frailty by gender in the United States and England.

A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner.

We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4× mean depth) and deep whole exome (30-40× mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations.

Dynamics of microRNA secreted via extracellular vesicles during the maturation of embryonic stem cell-derived retinal pigment epithelium.

Retinal pigment epithelial (RPE) cells are exclusive to the retina, critically multifunctional in maintaining the visual functions and health of photoreceptors and the retina. Despite their vital functions throughout lifetime, RPE cells lack regenerative capacity, rendering them vulnerable which can lead to degenerative retinal diseases. With advancements in stem cell technology enabling the differentiation of functional cells from pluripotent stem cells and leveraging the robust autocrine and paracrine functions of RPE cells, extracellular vesicles (EVs) secreted by RPE cells hold significant therapeutic potential in supplementing RPE cell activity.