Understanding Physical Distancing and Face Mask Use Across High-Risk African American Subgroups During the COVID-19 Pandemic: Application of Health Belief Model.

Physical distancing and face masks remain frontline prevention strategies due to suboptimal vaccine uptake and the highly infectious COVID-19 variants. Communities of color are disproportionately impacted by a chronic disease burden that places them at higher risk of severe COVID-19 disease. Therefore, they can greatly benefit from face mask use and physical distancing, especially if the individual(s) have not received the vaccine. We applied the Health Belief Model to explore barriers and motivators influencing physical distancing and face mask use among high-risk, Black American subgroups during the early COVID-19 pandemic stages. We conducted 62 semi-structured interviews among four Black American subgroups: young adults, individuals with underlying medical conditions, essential workers, and parents. Thematic analysis, guided by the Health Belief Model, yielded six themes: (1) Knowledge on Face Mask Use and Physical Distancing, (2) Perceived Susceptibility and Severity Varies by Subgroup, (3) Experience with and Perceived Self-Efficacy to Engage in Preventive Behavior, (4) Perceived Benefits to engaging in preventive behaviors, (5) Perceived Barriers to engage in preventive behaviors, and (6) Cues to action to increase participation. Each subgroup's unique experience informed multilevel, tailored approaches that can be used by health promotion practitioners to improve face mask use and physical distancing among uniquely vulnerable Black American subgroups in the current and future pandemic.

G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons.

The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.

Psychosocial Stressors and Coping Strategies Among African Americans During Early Stages of the COVID-19 Pandemic: a Qualitative Study.

OBJECTIVES: The disproportionate impact of coronavirus (COVID-19) on African Americans along with associated inequities in social determinants of health (SDOH) and racism increase their vulnerability to the psychosocial impact of COVID-19. This qualitative study applied the socio-ecological model (SEM) to explore psychosocial stressors, coping styles, and needs to improve psychosocial health among unique subgroups of African Americans in early pandemic stages. METHODS: Sixty-two African Americans (16 parents, 15 young adults, 16 essential workers, and 15 individuals with underlying medical conditions) participated in qualitative, semi-structured interviews between May and September 2020. Interview data were analyzed based on the SEM using thematic analysis. RESULTS: The majority (84%) reported being stressed with parents having the highest level. Four themes emerged : (1) our COVID-19 pandemic state of mind, (2) top stressors in the early stages of the COVID-19 pandemic, (3) coping strategies during COVID-19, and (4) needs during the COVID-19 pandemic to reduce stress. While there were similarities, different stressors were experienced among subgroups, which yielded different coping styles and needs from stakeholders across multi-levels to improve their psychosocial health. CONCLUSIONS: Findings suggest current and future pandemic response plans need targeted strategies across multiple levels of influence to address the psychosocial impact of the COVID-19 pandemic on African Americans.

African Americans and the COVID-19 pandemic: A qualitative inquiry of preparedness, challenges, and strategies on how we can move forward.

RATIONALE: The COVID-19 pandemic has disproportionately impacted Black Americans. Inequities in systems and social determinants of health along with racial health disparities impact degree of pandemic preparedness. OBJECTIVE: In early pandemic stages, we aimed to explore: 1) state of pandemic preparedness; 2) effects of socio-ecological factors on preparedness; and 3) multi-level strategies to increase preparedness among uniquely, vulnerable Black American subgroups. METHODS: We conducted 62 in-depth interviews with Black American community members representing parents, individuals with underlying medical conditions, essential workers, and young adults. Based on the McLeroy's Model Ecological for Health Promotion, an inductive-deductive content analysis approach was used to analyze the interview data around the factors influencing preparedness on individual, interpersonal processes and primary groups, community/institutional, and public policy. RESULTS: Majority (56.5%) of the participants stated they were somewhat or very prepared. We identified four themes: 1) Lived Experiences during the COVID-19 Pandemic; 2) Challenges experienced during the COVID-19 Pandemic; 3) I would do this differently they say; 4) Changes Needed to Survive the Pandemic relate to Public Policy, Community/institutional factors, and Interpersonal processes and primary group(s). All participants described their adjustments to live in the new norm. Participants identified perceived challenges and solutions on multi-levels, driven by subgroup. CONCLUSIONS: Pandemic response plans should use targeted strategies across multi-levels to enhance the preparedness of Black Americans, especially those in vulnerable groups. This could reduce the disproportionate COVID-19 disease burden exhibited by Black Americans and better prepare for future pandemics.

ABCA7, a Genetic Risk Factor Associated with Alzheimer's Disease Risk in African Americans.

African American/Black adults are twice as likely to have Alzheimer's disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ɛ4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and 'omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted.

DNA double-strand break repair in cancer: A path to achieving precision medicine.

The assessment of DNA damage can be a significant diagnostic for precision medicine. DNA double strand break (DSBs) pathways in cancer are the primary targets in a majority of anticancer therapies, yet the molecular vulnerabilities that underlie each tumor can vary widely making the application of precision medicine challenging. Identifying and understanding these interindividual vulnerabilities enables the design of targeted DSB inhibitors along with evolving precision medicine approaches to selectively kill cancer cells with minimal side effects. A major challenge however, is defining exactly how to target unique differences in DSB repair pathway mechanisms. This review comprises a brief overview of the DSB repair mechanisms in cancer and includes results obtained with revolutionary advances such as CRISPR/Cas9 and machine learning/artificial intelligence, which are rapidly advancing not only our understanding of determinants of DSB repair choice, but also how it can be used to advance precision medicine. Scientific innovation in the methods used to diagnose and treat cancer is converging with advances in basic science and translational research. This revolution will continue to be a critical driver of precision medicine that will enable precise targeting of unique individual mechanisms. This review aims to lay the foundation for achieving this goal.

Trypanosoma brucei Tim50 Possesses PAP Activity and Plays a Critical Role in Cell Cycle Regulation and Parasite Infectivity.

Trypanosoma brucei, the infective agent for African trypanosomiasis, possesses a homologue of the translocase of the mitochondrial inner membrane 50 (TbTim50). It has a pair of characteristic phosphatase signature motifs, DXDX(T/V). Here, we demonstrated that, besides its protein phosphatase activity, the recombinant TbTim50 binds and hydrolyzes phosphatidic acid in a concentration-dependent manner. Mutations of D242 and D244, but not of D345and D347, to alanine abolished these activities. In silico structural homology models identified the putative binding interfaces that may accommodate different phosphosubstrates. Interestingly, TbTim50 depletion in the bloodstream form (BF) of T. brucei reduced cardiolipin (CL) levels and decreased mitochondrial membrane potential (ΔΨ). TbTim50 knockdown (KD) also reduced the population of G2/M phase and increased that of G1 phase cells; inhibited segregation and caused overreplication of kinetoplast DNA (kDNA), and reduced BF cell growth. Depletion of TbTim50 increased the levels of AMPK phosphorylation, and parasite morphology was changed with upregulation of expression of a few stumpy marker genes. Importantly, we observed that TbTim50-depleted parasites were unable to establish infection in mice. Proteomics analysis showed reductions in levels of the translation factors, flagellar transport proteins, and many proteasomal subunits, including those of the mitochondrial heat shock locus ATPase (HslVU), which is known to play a role in regulation of kinetoplast DNA (kDNA) replication. Reduction of the level of HslV in TbTim50 KD cells was further validated by immunoblot analysis. Together, our results showed that TbTim50 is essential for mitochondrial function, regulation of kDNA replication, and the cell cycle in the BF. Therefore, TbTim50 is an important target for structure-based drug design to combat African trypanosomiasis. IMPORTANCE African trypanosomiasis is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei. During its digenetic life cycle, T. brucei undergoes multiple developmental changes to adapt in different environments. T. brucei BF parasites, dwelling in mammalian blood, produce ATP from glycolysis and hydrolyze ATP in mitochondria for generation of inner membrane potential. We found that TbTim50, a haloacid dehalogenase (HAD) family phosphatase, is critical for T. brucei BF survival in vitro and in vivo. Depletion of TbTim50 in BF reduced levels of CL and mitochondrial ΔΨ and caused a detrimental effect on many cellular functions. Cells accumulated in the G1 phase, and the kinetoplast was overreplicated, likely due to depletion of mitochondrial proteasome (mitochondrial heat shock locus ATPase [HslVU]), a master regulator of kDNA replication. Cell growth inhibition was accompanied by changes in morphology, AMPK phosphorylation, and upregulation of expression of a few stumpy-specific genes. TbTim50 is essential for T. brucei survival and is an important therapeutic target for African trypanosomiasis.

Obesity-associated mutant melanocortin-4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects.

Mutations in the melanocortin-4 receptor (MC4R) are the most common cause of early syndromic obesity known. Most of these mutations result in a loss of protein expression, α-melanocyte-stimulating hormone binding, receptor trafficking or coupling to the stimulatory G-protein, Gαs . However, approximately 26% of the obesity-associated mutations characterised to date exhibit none of these pharmacological defects. In the present study, we investigated seven of these apparently normal mutant MC4R in more detail and found that the majority (five of the seven) exhibit marked defects including defective binding of another endogenous melanocortin ligand, defective glycosylation, and defective recruitment of ß-arrestin. These data provide support for two hypotheses: (i) that the majority of these rare, obesity-associated mutations are likely defective and causative of obesity and (ii) that ß-arrestin recruitment is a valuable marker of normal MC4R function. Recent work has demonstrated a statistical correlation between the efficacy of ß-arrestin recruitment to the MC4R and body mass index; however, the data reported here demonstrate both decreased and increased ß-arrestin signalling in obesity-associated MC4R mutations.

60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH.

The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2-5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.