Medical Specialties Commons^™

The Vitamin D Serum Levels In Pregnant Women Affected By Covid-19: A Systematic Review And Meta-Analysis, Luiza Szarpak, Stepan Feduniw, Michal Pruc, Michal Ciebiera, Basar Cander, Mansur Rahnama-Hezavah, Łukasz Szarpak

Faculty, Staff and Students Publications

Vitamin D can modulate immune responses, and its deficiency is linked to increased autoimmunity and susceptibility to infection. In the general population, it has been observed that serum vitamin D levels are connected with the risk of COVID-19 and its severity. Our study aims to examine reported findings on the effect of vitamin D serum levels on infection of COVID-19 during pregnancy. PubMed, Web of Science, Embase, and Cochrane Library were searched for relevant studies. Serum vitamin D serum levels in COVID-19-positive and COVID-19-negative pregnant women were 24.61 ± 20.86 ng/mL and 24.12 ± 17.33 ng/mL, respectively. In mild vs. …

Gastrulation Morphogenesis In Synthetic Systems, Alyssa A Emig, Margot L K Williams

Faculty, Staff and Students Publications

Recent advances in pluripotent stem cell culture allow researchers to generate not only most embryonic cell types, but also morphologies of many embryonic structures, entirely in vitro. This recreation of embryonic form from naïve cells, known as synthetic morphogenesis, has important implications for both developmental biology and regenerative medicine. However, the capacity of stem cell-based models to recapitulate the morphogenetic cell behaviors that shape natural embryos remains unclear. In this review, we explore several examples of synthetic morphogenesis, with a focus on models of gastrulation and surrounding stages. By varying cell types, source species, and culture conditions, researchers have recreated …

Discovery Of Phosphorylated Lantibiotics With Proimmune Activity That Regulate The Oral Microbiome, Abdelahhad Barbour, Leif Smith, Morvarid Oveisi, Mckinley Williams, Ruo Chen Huang, Cara Marks, Noah Fine, Chunxiang Sun, Fereshteh Younesi, Sina Zargaran, Ravi Orugunty, Thomas D Horvath, Sigmund J Haidacher, Anthony M Haag, Amarpreet Sabharwal, Boris Hinz, Michael Glogauer

Faculty, Staff and Students Publications

Lantibiotics are ribosomally synthesized and posttranslationally modified peptides (RiPPs) that are produced by bacteria. Interest in this group of natural products is increasing rapidly as alternatives to conventional antibiotics. Some human microbiome–derived commensals produce lantibiotics to impair pathogens’ colonization and promote healthy microbiomes. Streptococcus salivarius is one of the first commensal microbes to colonize the human oral cavity and gastrointestinal tract, and its biosynthesis of RiPPs, called salivaricins, has been shown to inhibit the growth of oral pathogens. Herein, we report on a phosphorylated class of three related RiPPs, collectively referred to as salivaricin 10, that exhibit proimmune activity and …

Lateral Septum As A Melanocortin Downstream Site In Obesity Development, Yuanzhong Xu, Zhiying Jiang, Hongli Li, Jing Cai, Yanyan Jiang, Joshua Otiz-Guzman, Yong Xu, Benjamin R Arenkiel, Qingchun Tong

Faculty, Staff and Students Publications

The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that mediate its action are not clear. Here, we found that, among the known paraventricular hypothalamic (PVH) neuron groups, those expressing melanocortin receptors 4 (PVHMc4R) preferably project to the ventral part of the lateral septum (LSv), a brain region known to be involved in emotional behaviors. Photostimulation of PVHMc4R neuron terminals in the LSv reduces feeding and causes aversion, whereas deletion of Mc4Rs or disruption of glutamate release from LSv-projecting PVH neurons …

Symptom Duration And Resolution With Early Outpatient Treatment Of Convalescent Plasma For Coronavirus Disease 2019: A Randomized Trial, Sheriza N Baksh, Sonya L Heath, Yuriko Fukuta, David Shade, Barry Meisenberg, Evan M Bloch, Aaron A R Tobian, Emily S Spivak, Bela Patel, Jonathan Gerber, Jay S Raval, Donald Forthal, James Paxton, Giselle Mosnaim, Shweta Anjan, Janis Blair, Edward Cachay, Judith Currier, Piyali Das, Moises Huaman, Catherine Sutcliffe, Anusha Yarava, Arturo Casadevall, David Sullivan, Daniel Hanley, Kelly A Gebo

Faculty, Staff and Students Publications

BACKGROUND: Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients.

METHODS: We evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm.

RESULTS: Among 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving …

The Metreleptin Effectiveness And Safety Registry (Measure): Concept, Design And Challenges, Morey W Haymond, David Araújo-Vilar, John Balser, James H Lewis, Ruth Louzado, Carla Musso, Julia Von Schnurbein, Martin Wabitsch

Faculty, Staff and Students Publications

BACKGROUND: Metreleptin, a recombinant analog of human leptin, is an approved therapy, adjunct to diet, to treat the metabolic complications of leptin deficiency in patients with lipodystrophy - a group of rare diseases characterized by a paucity of adipose tissue. MEASuRE (Metreleptin Effectiveness And Safety Registry) is a post-authorization, voluntary registry that gathers long-term safety and effectiveness data on metreleptin. Here, we present the aims and evolution of MEASuRE.

METHODS: MEASuRE was established to collect data from patients receiving commercially supplied metreleptin in the United States (US) and European Union (EU). MEASuRE aims to determine the incidence and severity of …

Impact Of The Covid-19 Pandemic On The Education And Procedural Volume Of Fellows In Critical Care Medicine – A Cross-Sectional Survey, Orlando Garner, Kanta Velamuri, Kristen Staggers, Andrea Barbara Braun

Faculty, Staff and Students Publications

BACKGROUND: The COVID-19 pandemic has changed the way medical education is delivered. The purpose of this study was to assess the impact of the COVID-19 pandemic on the education and procedural volume of critical care and pulmonary critical care fellows.

METHODS: We conducted a cross-sectional, internet-based, voluntary, anonymous, national survey of adult critical care fellows and academic attending physicians in critical care and pulmonary critical care fellowship programs in the United States between December 2020 and February 2021. Survey questions covered both didactic and non-didactic aspects of education and procedural volumes. Answers were ranked on a 5-point Likert scale. Survey …

Tau Polarizes An Aging Transcriptional Signature To Excitatory Neurons And Glia, Timothy Wu, Jennifer M Deger, Hui Ye, Caiwei Guo, Justin Dhindsa, Brandon T Pekarek, Rami Al-Ouran, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B …

Connecting Circuits With Networks In Addiction Neuroscience: A Salience Network Perspective, Adriana K Cushnie, Wei Tang, Sarah R Heilbronner

Faculty, Staff and Students Publications

Human neuroimaging has demonstrated the existence of large-scale functional networks in the cerebral cortex consisting of topographically distant brain regions with functionally correlated activity. The salience network (SN), which is involved in detecting salient stimuli and mediating inter-network communication, is a crucial functional network that is disrupted in addiction. Individuals with addiction display dysfunctional structural and functional connectivity of the SN. Furthermore, while there is a growing body of evidence regarding the SN, addiction, and the relationship between the two, there are still many unknowns, and there are fundamental limitations to human neuroimaging studies. At the same time, advances in …

Beclin-1-Dependent Autophagy, But Not Apoptosis, Is Critical For Stem-Cell-Mediated Endometrial Programming And The Establishment Of Pregnancy, Pooja Popli, Suni Tang, Sangappa B Chadchan, Chandni Talwar, Edmund B Rucker, Xiaoming Guan, Diana Monsivais, John P Lydon, Christina L Stallings, Kelle H Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin …

An Ocular Th1 Immune Response Promotes Corneal Nerve Damage Independently Of The Development Of Corneal Epitheliopathy, Alexia Vereertbrugghen, Manuela Pizzano, Florencia Sabbione, Irene Angelica Keitelman, Carolina Maiumi Shiromizu, Douglas Vera Aguilar, Federico Fuentes, Cintia S De Paiva, Mirta Giordano, Analía Trevani, Jeremías G Galletti

Faculty, Staff and Students Publications

Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured …

Management Of Dyspepsia And Helicobacter Pylori Infection: The 2022 Indonesian Consensus Report, Ari Fahrial Syam, Muhammad Miftahussurur, Dadang Makmun, Murdani Abdullah, Abdul Aziz Rani, Gontar Alamsyah Siregar, Marcellus Simadibrata, Nasrul Zubir, I Dewa Nyoman Wibawa, Hery Djagat Purnomo, Chudahman Manan, Dharmika Djojoningrat, Achmad Fauzi, Kaka Renaldi, Hasan Maulahela, Amanda Pitarini Utari, Rabbinu Rangga Pribadi, Virly Nanda Muzellina, Saskia Aziza Nursyirwan, Muhammad Firhat Idrus, Ruswhandi Ruswhandi, Titong Sugihartono, Muhammad Begawan Bestari, Putut Bayupurnama, Triyanta Yuli Pramana, Bogi Pratomo Wibowo, Achmad Fuad Bakry, Fardah Akil, Andi Muhammad Luthfi Parewangi, Haris Widita, I Ketut Mariadi, Ignatia Sinta Murti, Ali Imron Yusuf, Arles Arles, Fauzi Yusuf, Bradley Jimmy Waleleng, Abimanyu Abimanyu, Yustar Mulyadi, Maria Inge Lucida, Yudith Annisa Ayu Rezkhita, Ricky Indra Alfaray, Yoshio Yamaoka

Faculty, Staff and Students Publications

Dyspepsia still becomes a major challenge in upper gastrointestinal disease in Indonesia. This disease often correlated with Helicobacter pylori infection. However, the prevalence of this bacterium is generally low in Indonesia. Therefore, several considerations should be taken into consideration during the management of dyspepsia and H. pylori infection. "Management of dyspepsia and H. pylori infection in Indonesia: The Indonesian consensus report" comprises information gathered from 22 gastroenterology centers across Indonesia. The experts gathered to evolve a consensus, that consists of the statements, grades of recommendations, evidence levels, and rationales for the dyspepsia and H. pylori infection management for daily clinical …

The First Transcriptomic Atlas Of The Adult Lacrimal Gland Reveals Epithelial Complexity And Identifies Novel Progenitor Cells In Mice, Vanessa Delcroix, Olivier Mauduit, Hyun Soo Lee, Anastasiia Ivanova, Takeshi Umazume, Sarah M Knox, Cintia S De Paiva, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

The lacrimal gland (LG) secretes aqueous tears. Previous studies have provided insights into the cell lineage relationships during tissue morphogenesis. However, little is known about the cell types composing the adult LG and their progenitors. Using scRNAseq, we established the first comprehensive cell atlas of the adult mouse LG to investigate the cell hierarchy, its secretory repertoire, and the sex differences. Our analysis uncovered the complexity of the stromal landscape. Epithelium subclustering revealed myoepithelial cells, acinar subsets, and two novel acinar subpopulations: Tfrc^hi and Car6^hi cells. The ductal compartment contained Wfdc2+ multilayered ducts and an Ltf+ cluster formed …

Parent Perspectives Of School/Daycare Experiences In Young Children Newly Diagnosed With Diabetes, Alexa Stern, Brenda Duran, Randi Streisand, Christine H Wang, Carrie Tully, Lauren Clary, Katherine Gallagher, Fran Cogen, Lefkothea Karaviti, Maureen Monaghan, Marisa E Hilliard

Faculty, Staff and Students Publications

OBJECTIVE: A central part of family adjustment to a new diagnosis of type 1 diabetes (T1D) is integrating T1D management into the child's school/daycare. This may be particularly challenging for young children who rely on adults for their diabetes management. This study aimed to describe parent experiences with school/daycare during the first 1.5 years following a young child's T1D diagnosis.

METHODS: As part of a randomized controlled trial of a behavioral intervention, 157 parents of young children with new-onset (<2 >months) T1D reported on their child's school/daycare experience at baseline and at 9- and 15-month post-randomization. We used a mixed-methods …

Mass Spectrometry Imaging Reveals Abnormalities In Cardiolipin Composition And Distribution In Astrocytoma Tumor Tissues, Anna C Krieger, Luis A Macias, J Clay Goodman, Jennifer S Brodbelt, Livia S Eberlin

Faculty, Staff and Students Publications

Cardiolipin (CL) is a mitochondrial lipid with diverse roles in cellular respiration, signaling, and organelle membrane structure. CL content and composition are essential for proper mitochondrial function. Deranged mitochondrial energy production and signaling are key components of glial cell cancers and altered CL molecular species have been observed in mouse brain glial cell xenograft tumors. The objective of this study was to describe CL structural diversity trends in human astrocytoma tumors of varying grades and correlate these trends with histological regions within the heterogeneous astrocytoma microenvironment. To this aim, we applied desorption electrospray ionization coupled with high field asymmetric ion …

Joint Effect Of Human Papillomavirus Exposure, Smoking And Alcohol On Risk Of Oral Squamous Cell Carcinoma, Zheng Yang, Peng Sun, Kristina R Dahlstrom, Neil Gross, Guojun Li

Faculty, Staff and Students Publications

BACKGROUND: Smoking, alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for oral squamous cell carcinoma (OSCC) including SCC of oropharynx (SCCOP) and SCC of oral cavity (SCCOC). Researchers have examined each of these risk factors independently, but few have observed the potential risk of their interaction. This study investigated the interactions among these risk factors and risk of OSCC.

METHODS: Totally 377 patients with newly diagnosed SCCOP and SCCOC and 433 frequency-matched cancer-free controls by age and sex were included. Multivariable logistic regression was performed to calculate ORs and 95% CIs.

RESULTS: We found that overall OSCC …

Whole-Exome Sequencing Study Of Hypospadias, Zhongzhong Chen, Yunping Lei, Richard H Finnell, Yu Ding, Zhixi Su, Yaping Wang, Hua Xie, Fang Chen

Faculty, Staff and Students Publications

Hypospadias results from the impaired urethral development, which is influenced by androgens, but its genetic etiology is still unknown. Through whole exome sequencing analysis, we identified NR5A1, SRD5A2, and AR as mutational hotspots in the etiology of severe hypospadias, as these genes are related to androgen signaling. Additionally, rare damaging variants in cilia-related outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, and DNAH17) (p = 8.5 × 10−47) were significantly enriched in hypospadias cases. The Dnah8 KO mice exhibited significantly decreased testosterone levels, which had an impact on …

Neutralizing Antibody Formation With Onabotulinumtoxina (Botox®) Treatment From Global Registration Studies Across Multiple Indications: A Meta-Analysis, Joseph Jankovic, Jean Carruthers, Markus Naumann, Patricia Ogilvie, Terry Boodhoo, Mayssa Attar, Swati Gupta, Ritu Singh, John Soliman, Irina Yushmanova, Mitchell F Brin, Jie Shen

Faculty, Staff and Students Publications

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and …

Association Of Type 2 Diabetes Subgroups With Cognitive Status Without Modification From Lifestyle Intervention, Michael P Bancks, James Lovato, Ashok Balasubramanyam, Mace Coday, Karen C Johnson, Medha Munshi, Candida Rebello, Lynne E Wagenknecht, Mark A Espeland

Faculty, Staff and Students Publications

CONTEXT: Type 2 diabetes is a risk factor for incident dementia but whether risk and treatment/prevention strategies differ by diabetes subgroup is unknown.

OBJECTIVE: We assessed (1) whether specific type 2 diabetes (T2D) subgroups are associated with mild cognitive impairment (MCI) or probable dementia (PD), and (2) whether T2D subgroups modified the association of the Action for Health in Diabetes (Look AHEAD) multidomain intensive lifestyle intervention (ILI) with MCI/PD.

METHODS: We included 3760 Look AHEAD participants with T2D and overweight or obesity randomly assigned to 10 years of ILI or diabetes support and education. We used k-means clustering techniques with …

Tp53 Germline Pathogenic Variant Frequency In Anaplastic Rhabdomyosarcoma: A Children’S Oncology Group Report, Douglas Fair, Luke Maese, Yueh-Yun Chi, Minjie Li, Douglas S Hawkins, Rajkumar Venkatramani, Erin Rudzinski, David Parham, Lisa Teot, David Malkin, Sharon E Plon, He Li, Aniko Sabo, Philip J Lupo, Joshua D Schiffman

Faculty, Staff and Students Publications

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with …

Expanding Endoscopic Boundaries: Endoscopic Resection Of Large Appendiceal Orifice Polyps With Endoscopic Mucosal Resection And Endoscopic Submucosal Dissection, Ankur P Patel, Mai A Khalaf, Margarita Riojas-Barrett, Tara Keihanian, Mohamed O Othman

Faculty, Staff and Students Publications

BACKGROUND: Large appendiceal orifice polyps are traditionally treated surgically. Recently, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been utilized as alternative resection techniques.

AIM: To evaluate the efficacy and safety of endoscopic resection techniques for the management of large appendiceal orifice polyps.

METHODS: This was a retrospective observational study conducted to assess the feasibility and safety of EMR and ESD for large appendiceal orifice polyps. This project was approved by the Baylor College of Medicine Institutional Review Board. Patients who underwent endoscopic resection of appendiceal orifice polyps ≥ 1 cm from 2015 to 2022 at a tertiary …

Traf4-Mediated Nonproteolytic Ubiquitination Of Androgen Receptor Promotes Castration-Resistant Prostate Cancer, Ramesh Singh, Huan Meng, Tao Shen, Lance Edward V Lumahan, Steven Nguyen, Hong Shen, Subhamoy Dasgupta, Li Qin, Dileep Karri, Bokai Zhu, Feng Yang, Cristian Coarfa, Bert W O'Malley, Ping Yi

Faculty, Staff and Students Publications

Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal …

Traf4-Mediated Nonproteolytic Ubiquitination Of Androgen Receptor Promotes Castration-Resistant Prostate Cancer, Ramesh Singh, Huan Meng, Tao Shen, Lance Edward V Lumahan, Steven Nguyen, Hong Shen, Subhamoy Dasgupta, Li Qin, Dileep Karri, Bokai Zhu, Feng Yang, Cristian Coarfa, Bert W O'Malley, Ping Yi

Faculty, Staff and Students Publications

Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal …

Break The "Hold": The Need To Strengthen The Management Of Hypertension, Obesity, Lipids, And Diabetes (Hold) And Improve Cardiovascular Health In People With Diabetes, Layla A Abushamat, Vijay Nambi

Faculty, Staff and Students Publications

No abstract provided.

Low Educational Attainment Is Associated With Higher All-Cause And Cardiovascular Mortality In The United States Adult Population, Najah Khan, Zulqarnain Javed, Isaac Acquah, Kobina Hagan, Madiha Khan, Javier Valero-Elizondo, Ryan Chang, Umair Javed, Mohamad B Taha, Michael J Blaha, Salim S Virani, Garima Sharma, Ron Blankstein, Martha Gulati, Elias Mossialos, Adnan A Hyder, Miguel Cainzos Achirica, Khurram Nasir

Faculty, Staff and Students Publications

Introduction: Educational attainment is an important social determinant of health (SDOH) for cardiovascular disease (CVD). However, the association between educational attainment and all-cause and CVD mortality has not been longitudinally evaluated on a population-level in the US, especially in individuals with atherosclerotic cardiovascular disease (ASCVD). In this nationally representative study, we assessed the association between educational attainment and the risk of all-cause and cardiovascular (CVD) mortality in the general adult population and in adults with ASCVD in the US.

Methods: We used data from the 2006-2014 National Death Index-linked National Health Interview Survey for adults ≥ 18 years. We generated …

Cardiac Pericytes Mediate The Remodeling Response To Myocardial Infarction, Pearl Quijada, Shuin Park, Peng Zhao, Kamal Ss Kolluri, David Wong, Kevin D Shih, Kai Fang, Arash Pezhouman, Lingjun Wang, Ali Daraei, Matthew D Tran, Elle M Rathbun, Kimberly N Burgos Villar, Maria L Garcia-Hernandez, Thanh Td Pham, Charles J Lowenstein, M Luisa Iruela-Arispe, S Thomas Carmichael, Eric M Small, Reza Ardehali

Faculty, Staff and Students Publications

Despite the prevalence of pericytes in the microvasculature of the heart, their role during ischemia-induced remodeling remains unclear. We used multiple lineage-tracing mouse models and found that pericytes migrated to the injury site and expressed profibrotic genes, coinciding with increased vessel leakage after myocardial infarction (MI). Single-cell RNA-Seq of cardiac pericytes at various time points after MI revealed the temporally regulated induction of genes related to vascular permeability, extracellular matrix production, basement membrane degradation, and TGF-β signaling. Deleting TGF-β receptor 1 in chondroitin sulfate proteoglycan 4-expressing (Cspg4-expressing) cells reduced fibrosis following MI, leading to a transient improvement in the cardiac …

Kras Hijacks The Mirna Regulatory Pathway In Cancer, Angelina S Bortoletto, Ronald J Parchem

Faculty, Staff and Students Publications

Extensive studies have focused on the misregulation of individual miRNAs in cancer. More recently, mutations in the miRNA biogenesis and processing machinery have been implicated in several malignancies. Such mutations can lead to global miRNA misregulation, which may promote many of the well-known hallmarks of cancer. Interestingly, recent evidence also suggests that oncogenic Kristen rat sarcoma viral oncogene homolog (KRAS) mutations act in part by modulating the activity of members of the miRNA regulatory pathway. Here, we highlight the vital role mutations in the miRNA core machinery play in promoting malignant transformation. Furthermore, we discuss how mutant KRAS can simultaneously …

Functional Variants Identify Sex-Specific Genes And Pathways In Alzheimer’S Disease, Thomas Bourquard, Kwanghyuk Lee, Ismael Al-Ramahi, Minh Pham, Dillon Shapiro, Yashwanth Lagisetty, Shirin Soleimani, Samantha Mota, Kevin Wilhelm, Maryam Samieinasab, Young Won Kim, Eunna Huh, Jennifer Asmussen, Panagiotis Katsonis, Juan Botas, Olivier Lichtarge

Faculty, Staff and Students Publications

The incidence of Alzheimer's Disease in females is almost double that of males. To search for sex-specific gene associations, we build a machine learning approach focused on functionally impactful coding variants. This method can detect differences between sequenced cases and controls in small cohorts. In the Alzheimer's Disease Sequencing Project with mixed sexes, this approach identified genes enriched for immune response pathways. After sex-separation, genes become specifically enriched for stress-response pathways in male and cell-cycle pathways in female. These genes improve disease risk prediction in silico and modulate Drosophila neurodegeneration in vivo. Thus, a general approach for machine learning on …

Structure Of A Eukaryotic Cholinephosphotransferase-1 Reveals Mechanisms Of Substrate Recognition And Catalysis, Lie Wang, Ming Zhou

Faculty, Staff and Students Publications

Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic cell membranes. In eukaryotes, two highly homologous enzymes, cholinephosphotransferase-1 (CHPT1) and choline/ethanolamine phosphotransferase-1 (CEPT1) catalyze the final step of de novo PC synthesis. CHPT1/CEPT1 joins two substrates, cytidine diphosphate-choline (CDP-choline) and diacylglycerol (DAG), to produce PC, and Mg2+ is required for the reaction. However, mechanisms of substrate recognition and catalysis remain unresolved. Here we report structures of a CHPT1 from Xenopus laevis (xlCHPT1) determined by cryo-electron microscopy to an overall resolution of ~3.2 Å. xlCHPT1 forms a homodimer, and each protomer has 10 transmembrane helices (TMs). The first 6 TMs carve …

Topical Administration Of An Apoptosis Inducer Mitigates Bleomycin-Induced Skin Fibrosis, Md Nurul Huda, Edgar A Borrego, Cristina D Guerena, Armando Varela-Ramirez, Renato J Aguilera, Christine M Hamadani, Eden E L Tanner, Abu Zayed Md Badruddoza, Sandeep K Agarwal, Md Nurunnabi

Faculty, Staff and Students Publications

Pathological fibrosis is distinguished from physiological wound healing by persistent myofibroblast activation, suggesting that therapies that induce myofibroblast apoptosis selectively could prevent progression and potentially reverse the established fibrosis, such as for scleroderma (a heterogeneous autoimmune disease characterized by multiorgan fibrosis). Navitoclax (NAVI) is a BCL-2/BCL-xL inhibitor with antifibrotic properties and has been investigated as a potential therapeutic for fibrosis. NAVI makes myofibroblasts particularly vulnerable to apoptosis. However, despite NAVI's significant potency, clinical translation of BCL-2 inhibitors, NAVI in this case, is hindered due to the risk of thrombocytopenia. Therefore, in this work, we utilized a newly developed ionic liquid …