Triclosan disrupts immune cell function by depressing Ca influx following acidification of the cytoplasm.

Triclosan (TCS) is an antimicrobial agent that was effectively banned by the FDA from hand soaps in 2016, hospital soaps in 2017, and hand sanitizers in 2019; however, TCS can still be found in a few products. At consumer-relevant, non-cytotoxic doses, TCS inhibits the functions of both mitochondria and mast cells, a ubiquitous cell type. Via the store-operated Ca entry mechanism utilized by many immune cells, mast cells undergo antigen-stimulated Ca influx into the cytosol, for proper function.

Identifying the molecular systems that influence cognitive resilience to Alzheimer's disease in genetically diverse mice.

Individual differences in cognitive decline during normal aging and Alzheimer's disease (AD) are common, but the molecular mechanisms underlying these distinct outcomes are not fully understood. We utilized a combination of genetic, molecular, and behavioral data from a mouse population designed to model human variation in cognitive outcomes to search for the molecular mechanisms behind this population-wide variation. Specifically, we used a systems genetics approach to relate gene expression to cognitive outcomes during AD and normal aging.

The Intrinsic Activity of Thyroxine Is Critical for Survival and Growth and Regulates Gene Expression in Neonatal Liver.

Thyroxine (T4) is generally considered to be a prohormone that requires conversion to triiodothyronine (T3) to exert biological activity. Although evidence suggests that T4 has intrinsic activity, it is questionable if this activity has any physiological relevance. To answer this question, triple knockout (KO) mice (Triples) that cannot express the types 1 (D1) and 2 (D2) deiodinase and the genes were generated.

miRNA Mechanisms Underlying the Association of Beta Blocker Use and Bone Mineral Density.

Osteoporosis is a debilitating and costly disease that causes fractures in 33% of women and 20% of men over the age of 50 years. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture compared with non-users. The mechanism underlying this association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however, the mechanism in humans is unknown.

Redundant Trojan horse and endothelial-circulatory mechanisms for host-mediated spread of Candida albicans yeast.

The host innate immune system has developed elegant processes for the detection and clearance of invasive fungal pathogens. These strategies may also aid in the spread of pathogens in vivo, although technical limitations have previously hindered our ability to view the host innate immune and endothelial cells to probe their roles in spreading disease. Here, we have leveraged zebrafish larvae as a model to view the interactions of these host processes with the fungal pathogen Candida albicans in vivo.

Chronic cortisol exposure in early development leads to neuroendocrine dysregulation in adulthood.

Objective: Chronic early life stress can affect development of the neuroendocrine stress system, leading to its persistent dysregulation and consequently increased disease risk in adulthood. One contributing factor is thought to be epigenetic programming in response to chronic cortisol exposure during early development. We have previously shown that zebrafish embryos treated chronically with cortisol develop into adults with constitutively elevated whole-body cortisol and aberrant immune gene expression.

Targeting metabolism to reverse T-cell exhaustion in chronic viral infections.

CD8 T-cells are an essential component of the adaptive immune response accountable for the clearance of virus-infected cells via cytotoxic effector functions. Maintaining a specific metabolic profile is necessary for these T-cells to sustain their effector functions and clear pathogens. When CD8 T-cells are activated via T-cell receptor recognition of viral antigen, they transition from a naïve to an effector state and eventually to a memory phenotype, and their metabolic profiles shift as the cells differentiate to accomidate different metabolic demands.

Klf9 is a key feedforward regulator of the transcriptomic response to glucocorticoid receptor activity.

The zebrafish has recently emerged as a model system for investigating the developmental roles of glucocorticoid signaling and the mechanisms underlying glucocorticoid-induced developmental programming. To assess the role of the Glucocorticoid Receptor (GR) in such programming, we used CRISPR-Cas9 to produce a new frameshift mutation, GR, which eliminates all potential in-frame initiation codons upstream of the DNA binding domain. Using RNA-seq to ask how this mutation affects the larval transcriptome under both normal conditions and with chronic cortisol treatment, we find that GR mediates most of the effects of the treatment, and paradoxically, that the transcriptome of cortisol-treated larvae is more like that of larvae lacking a GR than that of larvae with a GR, suggesting that the cortisol-treated larvae develop GR resistance.

Effects of HIV gp120 on Neuroinflammation in Immunodeficient vs. Immunocompetent States.

HIV affects 37 million people worldwide, 25-69% of which develop HIV-associated neurocognitive disorders (HAND) regardless of antiviral treatment. HIV infection of the brain decreases cognitive function, disrupts/impairs learning and memory, and reduces quality of life for those affected. HIV-induced neuroinflammation has been associated with viral proteins such as gp120 and Tat, which remain elevated in the CNS even in patients with low peripheral viremia counts.

Noninvasive Electrocardiography in the Perinatal Mouse.

Electrocardiography (ECG) has long been relied upon as an effective and reliable method of assessing cardiovascular (and cardiopulmonary) function in both human and animal models of disease. Individual heart rate, rhythm, and regularity, combined with quantitative parameters collected from ECG, serve to assess the integrity of the cardiac conduction system as well as the integrated physiology of the cardiac cycle. This article provides a comprehensive description of the methods and techniques used to perform a noninvasive ECG on perinatal and neonatal mouse pups as early as the first postnatal day, without requiring the use of anesthetics.

A Drosophila Model to Study Wound-induced Polyploidization.

Polyploidy is a frequent phenomenon whose impact on organismal health and disease is still poorly understood. A cell is defined as polyploid if it contains more than the diploid copy of its chromosomes, which is a result of endoreplication or cell fusion. In tissue repair, wound-induced polyploidization (WIP) has been found to be a conserved healing strategy from fruit flies to vertebrates.

GDNF promotes hair formation and cutaneous wound healing by targeting bulge stem cells.

Glial-cell-derived neurotrophic factor (GDNF) is a well-studied neuroregenerative factor; however, the degree to which it supports hair formation and skin wound repair is not known. By using a (GDNF family receptor alpha 1) knock-in reporter mouse line, GDNF signaling was found to occur within hair bulge stem cells (BSCs) during the initiation of the hair cycle and early stages of hair formation after depilation. Both recombinant and transgene overexpression of GDNF promoted BSC colony growth, hair formation, and skin repair after wounding through enhanced self-renewal of BSCs and commitment of BSC-derived progenitors into becoming epidermal cells at the injury site.

Learning and generalization of within-category representations in a rule-based category structure.

The task requirements during the course of category learning are critical for promoting within-category representations (e.g., correlational structure of the categories).

Vascularized Polymers Spatially Control Bacterial Cells on Surfaces.

Nature uses vascular systems to permit large-area control over the functionality of surfaces that lie above them. In this work, the application of this concept to the control of a hybrid living-nonliving system is demonstrated. Defined arrangements of vascular channels are created in agar using a fugitive ink printing method.

Deficiency of Complement Component C1Q Prevents Cerebrovascular Damage and White Matter Loss in a Mouse Model of Chronic Obesity.

Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity.

Efficient Construction of Atomic-Resolution Models of Non-Sulfated Chondroitin Glycosaminoglycan Using Molecular Dynamics Data.

Glycosaminoglycans (GAGs) are linear, structurally diverse, conformationally complex carbohydrate polymers that may contain up to 200 monosaccharides. These characteristics present a challenge for studying GAG conformational thermodynamics at atomic resolution using existing experimental methods. Molecular dynamics (MD) simulations can overcome this challenge but are only feasible for short GAG polymers.

Critical Assessment of In Vitro and In Vivo Models to Study Marrow Adipose Tissue.

Purpose Of The Review: The purpose of this review is to describe the in vitro and in vivo methods that researchers use to model and investigate bone marrow adipocytes (BMAds).

Recent Findings: The bone marrow (BM) niche is one of the most interesting and dynamic tissues of the human body. Relatively little is understood about BMAds, perhaps in part because these cells do not easily survive flow cytometry and histology processing and hence have been overlooked.

Cardiac injury modulates critical components of prostaglandin E signaling during zebrafish heart regeneration.

The inability to effectively stimulate cardiomyocyte proliferation remains a principle barrier to regeneration in the adult human heart. A tightly regulated, acute inflammatory response mediated by a range of cell types is required to initiate regenerative processes. Prostaglandin E (PGE), a potent lipid signaling molecule induced by inflammation, has been shown to promote regeneration and cell proliferation; however, the dynamics of PGE signaling in the context of heart regeneration remain underexplored.

Aging-associated decrease in the histone acetyltransferase KAT6B is linked to altered hematopoietic stem cell differentiation.

Aged hematopoietic stem cells (HSCs) undergo biased lineage priming and differentiation toward production of myeloid cells. A comprehensive understanding of gene regulatory mechanisms causing HSC aging is needed to devise new strategies to sustainably improve immune function in aged individuals. Here, a focused short hairpin RNA screen of epigenetic factors reveals that the histone acetyltransferase Kat6b regulates myeloid cell production from hematopoietic progenitor cells.

Gene therapies for axonal neuropathies: Available strategies, successes to date, and what to target next.

Nearly one-hundred loci in the human genome have been associated with different forms of Charcot-Marie-Tooth disease (CMT) and related inherited neuropathies. Despite this wealth of gene targets, treatment options are still extremely limited, and clear "druggable" pathways are not obvious for many of these mutations. However, recent advances in gene therapies are beginning to circumvent this challenge.

Who is willing to participate in research? A screening model for an anxiety and depression trial in the epilepsy clinic.

Objective: Anxiety and depression in epilepsy are prevalent, associated with poor outcomes, underrecognized, undertreated, and thus a key area of need for treatment research. The objective of this study was to assess factors associated with research participation among epilepsy clinic patients who screened positive for anxiety or depression. This was accomplished by characterizing clinical and psychiatric factors among patients seen in an epilepsy clinic and evaluating which factors were associated with consent for potential research participation, via a combined clinical and research screening model.