Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

Despite the prevalence and well-recognized adverse effects of prenatal alcohol exposure and alcohol use disorder in the causation of numerous diseases, their potential roles in the etiology of neurodegenerative diseases remain poorly characterized. This is especially true of the rare neurodegenerative diseases, for which small population sizes make it difficult to conduct broad studies of specific etiological factors. Nonetheless, alcohol has potent and long-lasting effects on neurodegenerative substrates, at both the cellular and systems levels. This review highlights the general effects of alcohol in the brain that contribute to neurodegeneration across diseases, and then focuses on specific diseases in which alcohol exposure is likely to play a major role. These specific diseases include dementias (alcohol-induced, frontotemporal, and Korsakoff syndrome), ataxias (cerebellar and frontal), and Niemann-Pick disease (primarily a Type B variant and Type C). We conclude that there is ample evidence to support a role of alcohol abuse in the etiology of these diseases, but more work is needed to identify the primary mechanisms of alcohol’s effects

Student-Produced Guides alongside First-Year Medical Curriculum: How Peer-Produced Textbooks Change Student Success within Neurology, Cardiopulmonary, and Mixed Systems Courses.

OBJECTIVES: In the United States, medical schools do not have a unified curricular plan that integrates basic sciences and organ-based systems in undergraduate medical education. Instead, institutions rely on independently created lecture material during the first-year medical school curriculum. The drawback to this approach is that no commercial or organizational resources cater to this individualized study plan. This study explored whether students who use student-produced course guides experience increased first-year success and improved skills. METHODS: First-year students at an allopathic medical school completed anonymous surveys about their reference guide usage, time management, organization, stress level, and examination scores. Statistical analysis was performed using Spearman\u27s coefficient of correlation and χ RESULTS: In total, 186 total students received the survey three times immediately after completing each organ system-based course. A total of n = 49 viable responses were received. One-fourth of the respondents used the guides for ≥3 hours/week. Respondents who used the reference guides reported improved time management, organization, self-confidence, and reduced student stress levels during the first year of medical school, but examination scores were unaffected. CONCLUSIONS: Access to student-produced guides increased confidence in self-rated measures of time management skills, organizational ability, and ability to balance medical course expectations. Because of the small sample size, future work will expand the survey population to increase the power to detect differences in these factors

Hsp90 Heterocomplexes Regulate Steroid Hormone Receptors: From Stress Response to Psychiatric Disease

The hypothalamus-pituitary-adrenal (HPA) axis directly controls the stress response. Dysregulation of this neuroendocrine system is a common feature among psychiatric disorders. Steroid hormone receptors, like glucocorticoid receptor (GR), function as transcription factors of a diverse set of genes upon activation. This activity is regulated by molecular chaperone heterocomplexes. Much is known about the structure and function of these GR/heterocomplexes. There is strong evidence suggesting altered regulation of steroid receptor hormones by chaperones, particularly the 51 kDa FK506-binding protein (FKBP51), may work with environmental factors to increase susceptibility to various psychiatric illnesses including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), and anxiety. This review highlights the regulation of steroid receptor dynamics by the 90kDa heat shock protein (Hsp90)/cochaperone heterocomplexes with an in depth look at how the structural regulation and imbalances in cochaperones can cause functional effects on GR activity. Links between the stress response and circadian systems and the development of novel chaperone-targeting therapeutics are also discussed

Morphometric analysis of the second through fifth metacarpal through posteroanterior X-Rays.

Over the past 10 years, metacarpal fractures have had an annual incidence of 13.6 per 10,000 individuals. Literature has not reviewed anatomical variations through radiographic imaging, which may play a role in reducing postoperative complications. The purpose of this study was to use radiographic imaging to provide a detailed anatomy of the second through fifth metacarpals. This retrospective study measured length, neck width, narrowest body width, and narrowest medullary canal width of the second through fifth metacarpals through the use of posteroanterior X-rays. Patients who were ≥18 years and received hand radiographs from January 2015 to July 2019 were included in this study. Those with acute injury or fracture of the metacarpal were excluded. Five hundred and seventy-two metacarpals were included in this study, with 143 metacarpals measured each for the second through fifth metacarpal. The second metacarpal had the largest measured length, neck width, and narrowest body width at 68.72, 12.34, and 8.74 mm, respectively. The fifth metacarpal had the greatest average medullary canal width at 4.15 mm. This is the largest study in literature to comprehensively examine the anatomical variation of the second through fifth metacarpals. The second metacarpal had greatest dimensions except for canal width, which was the fifth metacarpal. Men almost consistently had greater metacarpal size when compared to women, and age was associated with second and third metacarpal canal width. The increased knowledge of metacarpal anatomy may potentially lay the foundation of further improvement of metacarpal implants and potentially reduce postoperative complications. Clin. Anat., 33:1014-1018, 2020. © 2019 Wiley Periodicals, Inc

Crystal Structure of Firefly Luciferase in a Second Catalytic Conformation Supports a Domain Alternation Mechanism

Beetle luciferases catalyze a two-step reaction that includes the initial adenylation of the luciferin substrate, followed by an oxidative decarboxylation that ultimately produces light. Evidence for homologous acyl-CoA synthetases supports a domain alternation catalytic mechanism in which these enzymes’ C-terminal domain rotates by ∼140° to adopt two conformations that are used to catalyze the two partial reactions. While many structures exist of acyl-CoA synthetases in both conformations, to date only biochemical evidence supports domain alternation with luciferase. We have determined the structure of a cross-linked luciferase enzyme that is trapped in the second conformation. This new structure supports the role of the second catalytic conformation and provides insights into the biochemical mechanism of the luciferase oxidative step

FKBP5 and early life stress affect the hippocampus by an age-dependent mechanism

Early life stress (ELS) adversely affects the brain and is commonly associated with the etiology of mental health disorders, like depression. In addition to the mood-related symptoms, patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased peripheral inflammation, and structural brain alterations. Although the underlying causes are unknown, polymorphisms in the FK506-binding protein 5 (FKBP5) gene, a regulator of glucocorticoid receptor (GR) activity, interact with childhood adversities to increase vulnerability to depressive disorders. We hypothesized that high FKBP5 protein levels combined with early life stress (ELS) would alter the HPA axis and brain, promoting depressive-like behaviors. To test this, we exposed males and females of a mouse model overexpressing FKBP5 in the brain (rTgFKBP5 mice), or littermate controls, to maternal separation for 14 days after birth. Then, we evaluated neuroendocrine, behavioral, and brain changes in young adult and aged mice. We observed lower basal corticosterone (CORT) levels in rTgFKBP5 mice, which was exacerbated in females. Aged, but not young, rTgFKBP5 mice showed increased depressive-like behaviors. Moreover, FKBP5 overexpression reduced hippocampal neuron density in aged mice, while promoting markers of microglia expression, but these effects were reversed by ELS. Together, these results demonstrate that high FKBP5 affects basal CORT levels, depressive-like symptoms, and numbers of neurons and microglia in the hippocampus in an age-dependent manner