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Role of SMAD2 and SMAD3 on Adipose Tissue Development and Function
Get PDFIntroduction: Obesity and its associated metabolic syndrome are major medical problems worldwide including United States. Adipose tissue is the primary site of energy storage, playing important roles in health. Adipose tissue also has other critical functions, producing adipocytokines and contributing to normal nutrient metabolism, which in turn play important roles in satiety, inflammation, and total energy homeostasis. Activin A and activin B play important roles in maintaining body composition and energy homeostasis. This dissertation highlights the role of activin/SMADs signaling in adipose tissue development, function, and maintenance.
SMAD2/3 proteins are downstream mediators of transforming growth factor-β (TGFβ) family signaling, including activins, which regulate critical preadipocyte and mature adipocyte functions. Previous studies have demonstrated that Smad2 global knockout mice exhibit embryonic lethality, whereas global loss of Smad3 protects mice against diet-induced obesity and the direct contributions of Smad2 and Smad3 in adipose tissues individually or in combination and the responses of these tissues to activin signaling are unknown. Additionally, our lab demonstrated that the combined loss of activin A and activin B have reduced adiposity in mice and appearance of brown-like cells in visceral white adipose tissue. However, the cell-autonomous role of activins on cell proliferation and differentiation remained unknown in vitro. My hypothesis was that activin signaling regulate adipocyte differentiation and functions via SMAD2/3-mediated mechanism(s) and that the individual or combined adipose-specific deletion of SMAD2/SMAD3 would result in reduced adiposity similar to activin deficient mice.
Objective: Here, we sought to determine the primary effects of adipocyte-selective reduction of Smad2 or Smad3 individually and in combination, on diet-induced adiposity and to establish whether preadipocytes isolated from subcutaneous and visceral white adipose tissues differ in their differentiation capacity. We also assessed the role of activins on cell proliferation and differentiation using an in vitro model.
Research Design: To assess the adipose-selective requirements of Smad2, Smad3 and Smad2/3, we generated three lines of adipose-selective conditional knockout (cKO) mice including Smad2cKO, Smad3cKO, and Smad2/3 double cKO mice using Smad2 and/or Smad3 “floxed” mice intercrossed with Adiponectin-Cre mice. Additionally, we isolated preadipocytes and examined adipogenic activity of visceral and subcutaneous preadipocyte and the effects of activin on preadipocyte proliferation and differentiation in vitro. Furthermore, we used mouse embryonic fibroblasts (MEFs) from wild type mice and activin double knockout mice to study the cell autonomous role of activin on differentiation and cell fate.
Results: Our results demonstrated that subcutaneous preadipocytes differentiate uniformly and almost all wildtype subcutaneous preadipocytes differentiated into mature adipocytes. In contrast, visceral preadipocytes differentiated poorly. Exogenous activin A promoted proliferation and suppressed differentiation of subcutaneous preadipocytes more robustly given that visceral adipocytes differentiate poorly at baseline. Additionally, global knockout of activin A and B promoted differentiation and browning in differentiated MEFs in vitro consistent with in vivo studies. Furthermore, we showed that Smad2cKO mice did not exhibit significant effects on weight gain, irrespective of diet, whereas Smad3cKO male mice displayed a trend of reduced body weight on high fat diet. On both (LFD and HFD) diets, Smad3cKO male mice displayed an adipose depot-selective phenotype, with significant reduction in subcutaneous fat mass but not visceral fat mass. Smad2/3cKO male mice did not show any difference in body weight or fat mass compared to control mice. Female mice with adipose-selective combined deletion of Smad2/3, displayed reduced body weight and reduction of fat mass in both visceral and subcutaneous depot with higher metabolic rate on HFD compared to control littermates.
Conclusions: Our study demonstrated that Smad3 is an important contributor to the development and/or maintenance of subcutaneous white adipose tissue in a sex-selective fashion. Combined reduction of Smad2/3 protects female mice from diet induced obesity and is important for visceral and subcutaneous depots in a sex-selective fashion. These findings have implications for understanding SMAD-mediated, depot selective regulation of adipocyte growth and differentiation. Activin treatment promoted proliferation of preadipocytes, while activin deficiency promoted differentiation and altered the phenotypic characteristics of White adipocytes to brown-like cells in vitro consistent with in vivo
Preventing Pneumonia Through Early Mobilization of Critically Ill Adults
Get PDFThe purpose of this critically appraised topic (CAT) is to investigate early mobilization and its effect on preventing pneumonia in adults in the intensive care unit (ICU). The final portfolio contains four research articles from both national and international journals. Study designs included two meta-analyses, one case series, and one retrospective study. All four of the articles specifically described the effects of early mobilization on individuals in the hospital and ICU and showed positive results in reducing the likelihood of developing pneumonia. This CAT will be used to draft new practice guidelines for mentoring new managers in both occupational therapy and physical therapy
Effects of Social Determinants of Health in Progression to Type 2 Diabetes
Get PDFThe prevalence of prediabetes and diabetes in the United States and around the world has increased faster than expected in the last 30 years. The economic burden this costs a nation can be astronomic both in terms of expense and loss in productivity. One-third of U.S. adults, 86 million people, have prediabetes. Effective management is needed that can reach these 86 million, and others at high risk, to reduce their progression to diagnosed Type 2 diabetes. After the literature review, there was not enough literature to support how these led to the progression to diabetes. The abundant literature is centered on how to prevent complications and improve the quality of life of those living with type 2 diabetes. This paper will focus on the longitudinal association between these social determinants and how they may predispose to the progression to Type 2 diabetes
Creating a Medical Library Terms Taxonomy for Citation Analysis
Get PDFObjective: To create a medical library terms taxonomy in order to find trends in the medical library literature.
In order to explore trends in scholarly publishing by health sciences librarians in the last five years, we endeavored to examine keywords used in articles published in four health sciences library journals during this time. From our initial review we determined that: author-created keywords are not always based on a controlled vocabulary; MeSH subheadings do not include terms unique to the library field; and Library of Congress taxonomy is too broad. Thus, it was necessary to create a taxonomy by grouping similar keywords into categories in order to accurately identify trends.
Methods: Citations from four health sciences library journals from 2016-2020 were exported from PubMed and EBSCO Academic Search Premier into EndNote X9. Keywords from all citations were exported from EndNote as a text file and then imported into Microsoft Excel. Pivot tables were used to determine the number of times each keyword was used and to aggregate identical keywords. A team of six librarians with a variety of skill sets and backgrounds reviewed each keyword to determine how to categorize and group terms to create a taxonomy.
Results: 8,806 keywords from the journals were downloaded into spreadsheets and aggregated. Pivot tables were used to combine identical terms resulting in 2,801 unique keywords which are currently being categorized to complete the taxonomy.
Conclusion: While choosing keywords without use of a controlled vocabulary when submitting a manuscript allows for flexibility and customization, and might result in better retrieval during natural language searching, what we discovered through this project is that choosing keywords without the use of a controlled vocabulary makes it difficult to see trends and to conduct a bibliometric analysis
How the Morehouse School of Medicine (MSM) Archives Reflect the School’s Mission
Get PDFOBJECTIVE: To demonstrate how our archives embody the school’s mission.
METHODS: The importance of the artifacts will be revealed through relating the stories behind and significance of artifacts to the school’s history and mission. Included will be paintings, statuary, Mace, logo, bowls, symbols of presidency, publications, and special print collection. The story will be told through interviews with long term members of the school’s faculty and staff.
RESULTS: 1. From our beginning, key people (oval portraits) envisioned graduates (round pictures) being committed to working with patients in underserved areas, confronting disparity, and later pursuing equity in treatment. 2. President Valerie Montgomery Rice exemplifies the mission for equity. Former President and Surgeon General David Satcher led us to fight health disparities. Former Surgeon General guided the efforts to serve the underserved. 3. Statuary reflects the journey of medicine into the rural, urban, and other underserved areas, balancing professional demands while supporting others, locally, nationally, and internationally. 4. The diversion of the pipeline from school to prison to from school to MSM to serve, heal, and discover.
CONCLUSIONS: This archival collection positively reflects the MSM mission. Different pictures, portraits, artifacts, and statues examined are indicative of the MSM mission to enlarge the number of physicians, biomedical scientists, and public health professionals, especially minorities, and to help alleviate health disparities and bring about health equity to the un- and underserved around the world
Advancing RNA Virus Discovery and Biology with Whole Genome Sequencing
Get PDFTwo RNA virus families that pose a threat to human and animal health are Hantaviridae and Coronaviridae. These RNA viruses which originate in wildlife continue and will continue to cause disease, and hence, it is critical that scientific research define the mechanisms as to how these viruses spillover and adapt to new hosts to become endemic. One gap in our ability to define these mechanisms is the lack of whole genome sequences for many of these viruses. To address this specific gap, I developed a versatile amplicon-based whole-genome sequencing (WGS) approach to identify viral genomes of hantaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within reservoir and spillover hosts.
In my research studies, I used the amplicon-based WGS approach to define the genetic plasticity of viral RNA within pathogenic and nonpathogenic hantavirus species. The standing genetic variation of Andes orthohantavirus and Prospect Hill orthohantavirus was mapped out and amino acid changes occurring outside of functional domains were identified within the nucleocapsid and glycoprotein. I observed several amino acid changes in functional domains of the RNA-dependent RNA polymerase, as well as single nucleotide polymorphisms (SNPs) within the 3’ non-coding region (NCR) of the S-segment. To identify whether virus adaptation would occur within the S- and L-segments we attempted to adapt hantaviruses in vitro in a spillover host model through passaging experiments. In early passages we identified few mutations in the M-segment with the majority being identified in the S-segment 3’ NCR and the L-segment. This work suggests that hantavirus adaptation occurs in the S- and L-segments although the effect of these mutants on pathology is yet to be determined. While sequencing laboratory isolates is easily accomplished, sequencing low concentrations of virus within the reservoir is a formidable task. I further translated our amplicon-based WGS approach into a pan-oligonucleotide amplicon-based WGS approach to sequence hantavirus vRNA and mRNA from reservoir and spillover hosts in Ukraine. This approach successfully identified a novel Puumala orthohantavirus (PUUV) strain in Ukraine and using Bayesian phylogenetics we found this strain to be associated with the PUUV Latvian lineage.
Early during the SARS-CoV-2 pandemic, I applied the knowledge gained in the hantavirus WGS efforts to sequencing of SARS-CoV-2 from nasopharyngeal swabs collected in April 2020. The genetic diversity of 45 SARS-CoV-2 isolates was evaluated with the methods I developed. We identified D614G, a notable mutation known for increasing transmission, in over 90% of our isolates. Two major lineages distinguish SARS-CoV-2 variants worldwide, lineages A and B. While most of our isolates were found within B lineage, we also identified one isolate within lineage A. We performed in vitro work which confirmed A lineage isolates as having poor replication in the trachea as compared to the nasal cavity. Five of these isolates presented a unique array of mutations which were assessed in the keratin 18 human angiotensin-converting enzyme 2 (K18-hACE2) mouse model for its response immunologically and pathogenically. We identified a distinction of pathogenesis between the A and B lineages with emphysema being common amongst A lineage isolates. Additionally, we discovered a small cohort of likely SNPs that defined the late induction of eosinophils during infection. In summary, this work will further define the dynamics of genetic variation and plasticity within virus populations that cause disease outbreaks and will allow a deeper understanding of the virus-host relationship
Identifying the Molecular Cause of Extreme Endoplasmic Reticulum Dilation in Pediatric Osteosarcoma and Its Relationship to the Disease
Get PDFPediatric osteosarcoma tumors are characterized by an unusual abundance of grossly dilated endoplasmic reticulum and an immense genomic instability that has complicated identifying new effective molecular therapeutic targets. Here we report a novel molecular signature that encompasses the majority of 108 patient tumor samples, PDXs and osteosarcoma cell lines. These tumors exhibit reduced expression of four critical COPII vesicle proteins that has resulted in the accumulation of procollagen-I protein within ‘hallmark’ dilated ER. Using CRISPR activation technology, increased expression of only SAR1A and SEC24D to physiologically normal levels was sufficient to restore both collagen-I secretion and resolve dilated ER morphology to normal
Responding to the Pandemic: A Multicountry Study on Social-Political Factors and Health Outcomes of COVID-19
Get PDFIntroduction. Coronavirus Disease 2019 (COVID-19) poses a major global threat to human beings, which has caused devastating consequences of population health, political, and economic crises in many countries. This dissertation was composed of three research activities to study the following aims: (1) review the existing literature focusing on political factors and health outcomes of COVID-19; (2) assess the relationship between democracy and case fatality rate of COVID-19 by controlling for the effect of age, comorbidity, health expenditure, healthcare workforce, and population density; and (3) identify the trajectory pattern cases peak days, deaths peak days, and peak periods.
Methods. We accessed data from the World Health Organization (WHO), World Bank, Johns Hopkins University, and the Democracy Index 2019 database. First, we conducted a systematic review that searched three databases and synthesized the articles about democracy and health outcomes of COVID-19. Second, we analyzed data from 148 countries with at least 2,000 confirmed cases of COVID-19 by October 25, 2020. Multiple linear regression was used to examine the association between the Democracy Index and case fatality rate of COVID-19 while controlling for other variables, most notably the age distribution of the population. Lastly, we used the patterns of data at the early onset of COVID-19 from seven countries to estimate the time lag between peak days of cases and deaths.
Results. Our first research found that of 170 publications in the databases search, 12 publications were screened for systematic review. Among them, one study reported no association between democracy and health outcomes of COVID-19. Eleven articles claimed there was a relationship between democracy level and outcomes of COVID-19. Two papers reported negative associations between democracy and adverse outcomes of the population, while the other nine articles claimed there were positive associations between democracy and the poor health status of populations. When examining the relationship between democracy and health outcomes of COVID-19, the second research demonstrated that the number of hospital beds, the proportion of population above age 65, and current health expenditure as a percentage of the gross domestic product (GDP) are significantly related to the case fatality rates of COVID-19 across 148 countries (p \u3c 0.05). The Democracy Index was not statistically related to the case fatality rates of COVID-19 when considering all 148 countries analyzed but was negatively associated with case fatality rates among 47 high-income countries. In addition, the healthcare workforce, population density, and comorbidity were not statistically significant among the 148 countries. Finally, the findings in the last research suggested that comparative analyses of data from different regions and countries reveal the differences between peaks of cases and deaths caused by COVID-19 and the incomplete and underestimated cases in Wuhan. Different countries may show different patterns of cases peak days, deaths peak days, and peak periods. Error in the early COVID-19 statistics in Brazil was identified.
Conclusions. This research is the first to our knowledge to study the relationship between democracy and health outcomes of COVID-19 across countries with large sample sizes. According to the multicountry data, the cross-sectional study suggests that enhancing healthcare system facilities is vital to improving clinical outcomes. Protecting the population older than 65 and adjusting the health expenditure budget may need to be considered. The findings suggest that in high-income countries the higher democracy index is associated with more deaths from COVID-19, perhaps due to the decreased ability of the government to control the movement and behavior of its citizens. Besides, the simulated graphical trajectory method identifies statistical biases in surveillance data. This approach incorporates all sources of available data and provides a robust method to characterize the time course of an infectious disease. Regions and countries beginning with high mortality rates from the COVID-19 epidemic will suffer a long, painful period of the disease epidemic. Where the mortality rate is relatively high, healthcare professionals should prepare for a longer period of fighting this pandemic. Data quality is key to case fatality rate estimation which is needed by policymakers to make correct and timely critical decisions
Delineating the Upc2A Regulon in Candida glabrata
Get PDFCandida glabrata is the second most common cause of invasive candidiasis. Intrinsic resistance has greatly limited the utility of the triazole antifungal, fluconazole, in the treatment of invasive fungal infection. The transcription factor Upc2 regulates the expression of sterol biosynthesis genes in yeast. Disrupting UPC2A in C. glabrata greatly increases its susceptibility to fluconazole (FLU) in both FLU-susceptible and -resistant clinical isolates. Therefore, the Upc2A and its target genes represent a potential pathway for overcoming FLU resistance in C. glabrata. We aimed to delineate the Upc2A regulon to determine its target genes involved in FLU resistance. Transcriptome sequencing (RNA-seq) analysis was used to compare gene expression profiles of: a) wild-type (WT) strains with and without UPC2A under non-stressed conditions; b) those same strains treated with three sterol biosynthesis inhibitors (SBIs; FLU, terbinafine, fenpropimorph); and c) strains with an activating mutation (GOF) in UPC2A. Global chromatin Immunoprecipitation (ChIP-seq) was used to identify genes whose promoters were bound by Upc2A in strains carrying WT and GOF alleles of Upc2A with and without fluconazole exposure. Only three genes (UPC2A, ERG25, and ERG3) were found to be downregulated in the absence of UPC2A. Sixteen genes were commonly upregulated in response to SBIs’ treatment in a Upc2A-dependent way, including ERG2, ERG3, and ERG11, the promoters of 10 of which were bound by Upc2A. A total of 15 genes were upregulated, including ERG2, ERG3, ERG25, and ERG11 in the strain containing GOF mutation and the promoters of 6 of these genes were bound by Upc2A. Based on our data, ERG3, ERG11, HEM13, and CAGL0H09592g (ScTIR1) could be potential targets of Upc2A in C. glabrata. This more comprehensive understanding of the Upc2A regulon in C. glabrata may eventually lead to strategies to overcome FLU resistance and enhance fluconazole activity against this important fungal pathogen
Magnetic vector potential manipulation of Majorana fermions in DNA quantum logic
Get PDFIn the quantum logic of the DNA molecule, electrons are held and conducted coherently as spinless Cooper pairs and are shielded from electromagnetic energy by a Faraday cage effect of the double lipid bilayer of the nuclear membrane. The magnetic vector potential generated by cellular depolarization can synchronize logical activity in portions of the DNA molecule by affecting spin directions of appropriately oriented spinless electrons via the Aharonov-Bohm effect, but is not blocked by that Faraday cage effect. Within the logically and thermodynamically reversible chiral enantiomeric symmetry of the deoxyribose moieties the decoherent transition of Cooper pair to Dirac pair in a p-orbital of the C2-C3 covalent bond effects chiral selection between the C2-endo and C3-endo conformations. Such a spin-1/2 chiral collective movement of particles can be considered as a quasiparticle excitation that is its own antiparticle (C2-endo vs. C3-endo), meeting the definition of a Majorana fermion