A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in "pure" models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage.

RIT1 regulation of CNS lipids RIT1 deficiency Alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities.

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a knockout mouse model and high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC).

Early chronic suppression of microglial p38α in a model of Alzheimer's disease does not significantly alter amyloid-associated neuropathology.

The p38 alpha mitogen-activated protein kinase (p38α) is linked to both innate and adaptive immune responses and is under investigation as a target for drug development in the context of Alzheimer's disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38α inhibition can protect against AD-associated neuropathology, the underlying mechanisms are not fully elucidated. Inhibitors of p38α may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to AD pathology.

Complications, Compliance, and 3-Year Outcomes After Endolaserless Vitrectomy With Aflibercept Monotherapy for Proliferative Diabetic Retinopathy-Related Vitreous Hemorrhage.

Background And Objective: To report the 3-year outcomes for endolaserless vitrectomy with intravitreal aflibercept injection (IAI) monotherapy for proliferative diabetic retinopathy (PDR)-related vitreous hemorrhage (VH).

Materials And Method: Eyes underwent endolaserless vitrectomy and received one preoperative and intraoperative IAI followed by randomization to a q8week or q16week IAI group. Additional IAI was administered as needed.

Falling Short: The Contribution of Central Insulin Receptors to Gait Dysregulation in Brain Aging.

Insulin resistance, which manifests as a reduction of insulin receptor signaling, is known to correlate with pathological changes in peripheral tissues as well as in the brain. Central insulin resistance has been associated with impaired cognitive performance, decreased neuronal health, and reduced brain metabolism; however, the mechanisms underlying central insulin resistance and its impact on brain regions outside of those associated with cognition remain unclear. Falls are a leading cause of both fatal and non-fatal injuries in the older population.

Essential Factors for a Healthy Microbiome: A Scoping Review.

Recent discoveries of the purpose and potential of microbial interactions with humans have broad implications for our understanding of metabolism, immunity, the host−microbe genetic interactions. Bioavailability and bioaccessibility of phytonutrients in foods not only enrich microbial diversity in the lower human gastrointestinal tract (GIT) but also direct the functioning of the metagenome of the microbiota. Thus, healthy choices must include foods that contain nutrients that satisfy both the needs of humans and their microbes.

Sensitivity of the S1 neuronal calcium network to insulin and Bay-K 8644 in vivo: Relationship to gait, motivation, and aging processes.

Neuronal hippocampal Ca dysregulation is a critical component of cognitive decline in brain aging and Alzheimer's disease and is suggested to impact communication and excitability through the activation of a larger after hyperpolarization. However, few studies have tested for the presence of Ca dysregulation in vivo, how it manifests, and whether it impacts network function across hundreds of neurons. Here, we tested for neuronal Ca network dysregulation in vivo in the primary somatosensory cortex (S1) of anesthetized young and aged male Fisher 344 rats using single-cell resolution techniques.

Dependence of glucose transport on autophagy and GAPDH activity.

Glucose uptake in the brain is critically important to brain health. Using two widely used cell line model systems, we have found that siramesine, a lysosomotropic agent and ligand for the sigma-2 receptor, inhibits glucose uptake and decreases pools of the GLUT1 glucose transporter at the plasma membrane. Siramesine induces autophagy but also disrupts degradation of autophagy substrates, providing a potential mechanism for its action on glucose uptake.

Diversity and Inclusion on General Surgery, Integrated Thoracic Surgery, and Integrated Vascular Surgery Residency Program Websites.

Background: Increasing diversity in medicine is receiving more attention, yet underrepresented in medicine (UiM) surgeons remain a small fraction of all surgeons. Whether surgical training programs attempt to attract UiM applicants to their programs, and therefore their specialties, through program website information is unclear.

Objective: To analyze the scope of diversity and inclusion (D&I) related information on US allopathic and osteopathic general surgery, integrated thoracic surgery, and integrated vascular surgery residency program websites.

Electrophysiological and Imaging Calcium Biomarkers of Aging in Male and Female 5×FAD Mice.

Background: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer's disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g.

Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.

Background: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer's disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear.

Molecular elevation of insulin receptor signaling improves memory recall in aged Fischer 344 rats.

As demonstrated by increased hippocampal insulin receptor density following learning in animal models and decreased insulin signaling, receptor density, and memory decline in aging and Alzheimer's diseases, numerous studies have emphasized the importance of insulin in learning and memory processes. This has been further supported by work showing that intranasal delivery of insulin can enhance insulin receptor signaling, alter cerebral blood flow, and improve memory recall. Additionally, inhibition of insulin receptor function or expression using molecular techniques has been associated with reduced learning.

Elevating Insulin Signaling Using a Constitutively Active Insulin Receptor Increases Glucose Metabolism and Expression of GLUT3 in Hippocampal Neurons.

Insulin signaling is an integral component of healthy brain function, with evidence of positive insulin-mediated alterations in synaptic integrity, cerebral blood flow, inflammation, and memory. However, the specific pathways targeted by this peptide remain unclear. Previously, our lab used a molecular approach to characterize the impact of insulin signaling on voltage-gated calcium channels and has also shown that acute insulin administration reduces calcium-induced calcium release in hippocampal neurons.

Relationship of Emotional Intelligence to Perceived Stress in Combined Master's of Science and Dietetic Internship Programs.

Background: Emotional intelligence (EI) is often studied with perceived stress in students in health professions fields such as nursing but not dietetics. The purpose of this study was to explore the relationship of EI to perceived stress in graduate dietetic students in Combined Master's of Science (MS) and Dietetic Internship (DI) programs.

Methods: EI and perceived stress were collected using the Schutte EI Scale and Perceived Stress Scale-10, respectively.

Long-Term Intranasal Insulin Aspart: A Profile of Gene Expression, Memory, and Insulin Receptors in Aged F344 Rats.

Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin's efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets.

Broadening the definition of brain insulin resistance in aging and Alzheimer's disease.

It has been >20 years since studies first revealed that the brain is insulin sensitive, highlighted by the expression of insulin receptors in neurons and glia, the presence of circulating brain insulin, and even localized insulin production. Following these discoveries, evidence of decreased brain insulin receptor number and function was reported in both clinical samples and animal models of aging and Alzheimer's disease, setting the stage for the hypothesis that neuronal insulin resistance may underlie memory loss in these conditions. The development of therapeutic insulin delivery to the brain using intranasal insulin administration has been shown to improve aspects of memory or learning in both humans and animal models.

Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines.

Background: Although metastasis is ultimately responsible for about 90% of breast cancer mortality, the vast majority of breast-cancer-related deaths are due to progressive recurrences from non-metastatic disease. Current adjuvant therapies are unable to prevent progressive recurrences for a significant fraction of patients with breast cancer. Autologous tumor cell vaccines (ATCVs) are a safe and potentially useful strategy to prevent breast cancer recurrence, in a personalized and patient-specific manner, following standard-of-care tumor resection.

Insulin Receptor Plasma Membrane Levels Increased by the Progesterone Receptor Membrane Component 1.

The insulin receptor (IR) is a ligand-activated receptor tyrosine kinase that has a key role in metabolism, cellular survival, and proliferation. Progesterone receptor membrane component 1 (PGRMC1) promotes cellular signaling via receptor trafficking and is essential for some elements of tumor growth and metastasis. In the present study, we demonstrate that PGRMC1 coprecipitates with IR.