Digital Commons Network^™

Glutamine Produces Ammonium To Tune Lysosomal Ph And Regulate Lysosomal Function, Jian Xiong, Thi Thu Trang Luu, Kartik Venkatachalam, Guangwei Du, Michael X Zhu

Faculty, Staff and Student Publications

Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino …

Association Of Gulf War Illness With Characteristics In Deployed Vs Non-Deployed Gulf War Era Veterans In The Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis, Linh M Duong, Alice B S Nono Djotsa, Jacqueline Vahey, Lea Steele, Rachel Quaden, Kelly M Harrington, Sarah T Ahmed, Renato Polimanti, Elani Streja, John Michael Gaziano, John Concato, Hongyu Zhao, Krishnan Radhakrishnan, Elizabeth R Hauser, Drew A Helmer, Mihaela Aslan, Elizabeth J Gifford

Center for Medical Ethics and Health Policy Staff Publications

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 …

Trem2 Dependent And Independent Functions Of Microglia In Alzheimer's Disease, Jinchao Hou, Yun Chen, Gary Grajales-Reyes, Marco Colonna

2020-Current year OA Pubs

Microglia are central players in brain innate immunity and have been the subject of extensive research in Alzheimer's disease (AD). In this review, we aim to summarize the genetic and functional discoveries that have advanced our understanding of microglia reactivity to AD pathology. Given the heightened AD risk posed by rare variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2), we will focus on the studies addressing the impact of this receptor on microglia responses to amyloid plaques, tauopathy and demyelination pathologies in mouse and human. Finally, we will discuss the implications of recent discoveries on microglia …

In Silico Activity And Admet Profiling Of Phytochemicals From Ethiopian Indigenous Aloes Using Pharmacophore Models, Lemessa Etana Bultum, Gemechu Bekele Tolossa, Gwangmin Kim, Ohhyeon Kwon, Doheon Lee

2020-Current year OA Pubs

In silico profiling is used in identification of active compounds and guide rational use of traditional medicines. Previous studies on Ethiopian indigenous aloes focused on documentation of phytochemical compositions and traditional uses. In this study, ADMET and drug-likeness properties of phytochemicals from Ethiopian indigenous aloes were evaluated, and pharmacophore-based profiling was done using Discovery Studio to predict therapeutic targets. The targets were examined using KEGG pathway, gene ontology and network analysis. Using random-walk with restart algorithm, network propagation was performed in CODA network to find diseases associated with the targets. As a result, 82 human targets were predicted and found …

Risk Factors For Sars-Cov-2 Transmission In Close Contacts Of Adults At High Risk Of Infection Due To Occupation: Results From The Contact Tracing Strategy Of The Covida Epidemiological Surveillance Study In Bogotá, Colombia, In 2020-2021, Andrea Ramírez Varela, Sandra Contreras-Arrieta, Guillermo Tamayo-Cabeza, Leonardo Salas Zapata, Yuldor Caballero-Díaz, Luis Jorge Hernández Florez, Andrés Patiño Benavidez, Rachid Laajaj, Fernando De La Hoz, Giancarlo Buitrago Gutierrez, Silvia Restrepo, Eduardo Behrentz

Faculty, Staff and Student Publications

OBJECTIVES: To estimate the risk factors for SARS-CoV-2 transmission in close contacts of adults at high risk of infection due to occupation, participants of the CoVIDA study, in Bogotá D.C., Colombia.

SETTING: The CoVIDA study was the largest COVID-19 intensified sentinel epidemiological surveillance study in Colombia thus far, performing over 60 000 RT-PCR tests for SARS-CoV-2 infection. The study implemented a contact tracing strategy (via telephone call) to support traditional surveillance actions performed by the local health authority.

PARTICIPANTS: Close contacts of participants from the CoVIDA study.

PRIMARY AND SECONDARY OUTCOME MEASURES: SARS-CoV-2 testing results were obtained (RT-PCR with CoVIDA …

Multiomics Characterization Of Methicillin-Resistant Staphylococcus Aureus (Mrsa) Isolates With Heterogeneous Intermediate Resistance To Vancomycin (Hvisa) In Latin America, Betsy E Castro, Rafael Rios, Lina P Carvajal, Mónica L Vargas, Mónica P Cala, Lizeth León, Blake Hanson, An Q Dinh, Oscar Ortega-Recalde, Carlos Seas, Jose M Munita, Cesar A Arias, Sandra Rincon, Jinnethe Reyes, Lorena Diaz

Faculty, Staff and Student Publications

BACKGROUND: Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms.

OBJECTIVE: To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches.

METHODS: 39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and …

Control Of Sars-Cov-2 Infection By Mt1-Mmp-Mediated Shedding Of Ace2, Xuanming Guo, Jianli Cao, Jian-Piao Cai, Jiayan Wu, Jiangang Huang, Pallavi Asthana, Sheung Kin Ken Wong, Zi-Wei Ye, Susma Gurung, Yijing Zhang, Sheng Wang, Zening Wang, Xin Ge, Hiu Yee Kwan, Aiping Lyu, Kui Ming Chan, Nathalie Wong, Jiandong Huang, Zhongjun Zhou, Zhao-Xiang Bian, Shuofeng Yuan, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung …

Hif1a-Dependent Induction Of Alveolar Epithelial Pfkfb3 Dampens Acute Lung Injury, Christine U Vohwinkel, Nana Burns, Ethan Coit, Xiaoyi Yuan, Eszter K Vladar, Christina Sul, Eric P Schmidt, Peter Carmeliet, Kurt Stenmark, Eva S Nozik, Rubin M Tuder, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during …

Human Health During Space Travel: State-Of-The-Art Review, Chayakrit Krittanawong, Nitin Kumar Singh, Richard A Scheuring, Emmanuel Urquieta, Eric M Bershad, Timothy R Macaulay, Scott Kaplin, Carly Dunn, Stephen F Kry, Thais Russomano, Marc Shepanek, Raymond P Stowe, Andrew W Kirkpatrick, Timothy J Broderick, Jean D Sibonga, Andrew G Lee, Brian E Crucian

Faculty, Staff and Student Publications

The field of human space travel is in the midst of a dramatic revolution. Upcoming missions are looking to push the boundaries of space travel, with plans to travel for longer distances and durations than ever before. Both the National Aeronautics and Space Administration (NASA) and several commercial space companies (e.g., Blue Origin, SpaceX, Virgin Galactic) have already started the process of preparing for long-distance, long-duration space exploration and currently plan to explore inner solar planets (e.g., Mars) by the 2030s. With the emergence of space tourism, space travel has materialized as a potential new, exciting frontier of business, hospitality, …

Aptamer Proteomics Of Serum Exosomes From Patients With Primary Raynaud's And Patients With Raynaud's At Risk Of Evolving Into Systemic Sclerosis, Sonsoles Piera-Velazquez, Simon T. Dillon, Xuesong Gu, Towia A. Libermann, Sergio A. Jimenez

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc.

OBJECTIVE: To identify proteins contained within serum exosomes employing an aptamer proteomic analysis that may serve to reveal patients with Raynaud's Phenomenon at risk of developing SSc.

METHODS: Exosomes were isolated from serum samples from patients with Primary Raynaud's Phenomenon and from patients with Raynaud's Phenomenon harbouring serum antinuclear antibodies (ANA) who may be at high risk of evolving into SSc. The expression of 1,305 proteins was quantified …

Rare Diseases And Space Health: Optimizing Synergies From Scientific Questions To Care, Maria Puscas, Gabrielle Martineau, Gurjot Bhella, Penelope E Bonnen, Phil Carr, Robyn Lim, John Mitchell, Matthew Osmond, Emmanuel Urquieta, Jaime Flamenbaum, Giuseppe Iaria, Yann Joly, Étienne Richer, Joan Saary, David Saint-Jacques, Nicole Buckley, Etienne Low-Decarie

Faculty, Staff and Students Publications

Knowledge transfer among research disciplines can lead to substantial research progress. At first glance, astronaut health and rare diseases may be seen as having little common ground for such an exchange. However, deleterious health conditions linked to human space exploration may well be considered as a narrow sub-category of rare diseases. Here, we compare and contrast research and healthcare in the contexts of rare diseases and space health and identify common barriers and avenues of improvement. The prevalent genetic basis of most rare disorders contrasts sharply with the occupational considerations required to sustain human health in space. Nevertheless small sample …

Engineering Naturally Occurring Cd7- T Cells For The Immunotherapy Of Hematological Malignancies, Abdullah Freiwan, Jaquelyn T Zoine, Jeremy Chase Crawford, Abishek Vaidya, Stefan A Schattgen, Jacquelyn A Myers, Sagar L Patil, Mahsa Khanlari, Hiroto Inaba, Jeffery M Klco, Charles G Mullighan, Giedre Krenciute, Peter J Chockley, Swati Naik, Deanna M Langfitt, Maksim Mamonkin, Esther A Obeng, Paul G Thomas, Stephen Gottschalk, M Paulina Velasquez

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- …

Expanded Proteomic Survey Of The Human Parasite Leishmania Major Focusing On Changes In Null Mutants Of The Golgi Gdp-Mannose/Fucose/Arabinopyranose Transporter, Gloria Polanco, Nichollas E Scott, Lon F Lye, Stephen M Beverley

2020-Current year OA Pubs

The trypanosomatid protozoan parasite

A Genome-Wide Association Study Of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants, Harold Bae, Ping An, Mary Feitosa, Et Al.

2020-Current year OA Pubs

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609,

Antibodies Targeting The Neuraminidase Active Site Inhibit Influenza H3n2 Viruses With An S245n Glycosylation Site, Daniel Stadlbauer, Ali H Ellebedy, Et Al.

2020-Current year OA Pubs

Contemporary influenza A H3N2 viruses circulating since 2016 have acquired a glycosylation site in the neuraminidase in close proximity to the enzymatic active site. Here, we investigate if this S245N glycosylation site, as a result of antigenic evolution, can impact binding and function of human monoclonal antibodies that target the conserved active site. While we find that a reduction in the inhibitory ability of neuraminidase active site binders is measurable, this class of broadly reactive monoclonal antibodies maintains protective efficacy in vivo.

Molecular Markers In Maternal Blood Exosomes Allow Early Detection Of Fetal Alcohol Spectrum Disorders, Nune Darbinian, Armine Darbinyan, John Sinard, Gabriel Tatevosian, Nana Merabova, Faith D'Amico, Tarek Khader, Ahsun Bajwa, Diana Martirosyan, Alina K Gawlinski, Richa Pursnani, Huaqing Zhao, Shohreh Amini, Mary Morrison, Laura Goetzl, Michael E Selzer

Faculty, Staff and Student Publications

Prenatal alcohol exposure can cause developmental abnormalities (fetal alcohol spectrum disorders; FASD), including small eyes, face and brain, and neurobehavioral deficits. These cannot be detected early in pregnancy with available imaging techniques. Early diagnosis could facilitate development of therapeutic interventions. Banked human fetal brains and eyes at 9−22 weeks’ gestation were paired with maternal blood samples, analyzed for morphometry, protein, and RNA expression, and apoptotic signaling. Alcohol (EtOH)-exposed (maternal self-report) fetuses were compared with unexposed controls matched for fetal age, sex, and maternal race. Fetal brain-derived exosomes (FB-E) were isolated from maternal blood and analyzed for protein, RNA, and apoptotic …

Large-Scale Crispri And Transcriptomics Of Staphylococcus Epidermidis Identify Genetic Factors Implicated In Lifestyle Versatility., Michelle Spoto, Johanna P. Riera Puma, Elizabeth Fleming, Changhui Guan, Yvette Ondouah Nzutchi, Dean Kim, Julia Oh

Faculty Research 2022

Staphylococcus epidermidis is a ubiquitous human commensal skin bacterium that is also one of the most prevalent nosocomial pathogens. The genetic factors underlying this remarkable lifestyle plasticity are incompletely understood, mainly due to the difficulties of genetic manipulation, precluding high-throughput functional profiling of this species. To probe the versatility of S. epidermidis to survive across a diversity of environmental conditions, we developed a large-scale CRISPR interference (CRISPRi) screen complemented by transcriptional profiling (RNA sequencing) across 24 diverse conditions and piloted a droplet-based CRISPRi approach to enhance throughput and sensitivity. We identified putative essential genes, importantly revealing amino acid metabolism as …

Progressive Acceleration Of Insulin Exposure Over 7 Days Of Infusion Set Wear, Jasmin R. Kastner, Timothy S. Bailey, Poul Strange, Leon Shi, Keith A. Oberg, Paul J. Strasma, Jeffrey I. Joseph, Douglas B. Muchmore

Department of Anesthesiology Faculty Papers

Insulin exposure varies over 3 days of insulin infusion set (IIS) wear making day-to-day insulin dosing challenging for people with diabetes (PWD). Here we report insulin pharmacodynamic (PD) and pharmacokinetic (PK) data extending these observations to 7 days of IIS wear. PWD (A1C ≤8.5%, C-peptide tmax (P < 0.001), Cmax (P < 0.05), and mean residence time (P < 0.0001). Area under the insulin concentration curve (AUC0–300) declined by ∼24% from days 0 to 7 (P < 0.05). These results confirm/extend previous observations showing progressive acceleration of insulin exposure over IIS wear time. This may have implications for PWD and designers of closed-loop algorithms, although larger studies are necessary to confirm this. The study was registered in clinicaltrials.gov (NCT04398030).

Menstrual Health Among Adolescents And Young Adults In Rural Haiti., Emily R. Rupe, Jonathan Rodean, Emily A. Hurley, Melissa K. Miller, Marie Daphnee Boncoeur, Abbey R. Masonbrink

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Adolescent and young adult (AYA) females in low- and middle-income countries often face disparities in menstrual health (MH). Poor MH and lack of sexual and reproductive health education leads to school absenteeism, increasing risk for adverse psychosocial and educational outcomes. Further, disasters (e.g., earthquakes) are linked with unsafe living environments and sanitation facilities for women. We sought to describe MH perspectives and practices among AYAs in rural Haiti.

METHODS: We conducted a cross-sectional survey in two rural communities in Haiti. AYA females aged 14-24 years completed questions on demographics, the Menstrual Practice Needs Scale (36 items; MPNS-36) and the …

A Unique High-Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance In Cantu Syndrome, Gautam K Singh, Conor Mcclenaghan, Manish Aggarwal, Hongjie Gu, Maria S Remedi, Dorothy K Grange, Colin G Nichols

2020-Current year OA Pubs

Background Cardiomegaly caused by left ventricular hypertrophy is a risk factor for development of congestive heart failure, classically associated with decreased systolic and/or diastolic ventricular function. Less attention has been given to the phenotype of left ventricular hypertrophy with enhanced ventricular function and increased cardiac output, which is potentially associated with high-output heart failure. Lack of recognition may pose diagnostic ambiguity and management complexities. Methods and Results We sought to systematically characterize high-output cardiac hypertrophy in subjects with Cantu syndrome (CS), caused by gain-of-function variants in

Does Receiving A Sars-Cov-2 Antibody Test Result Change Covid-19 Protective Behaviors? Testing Risk Compensation In Undergraduate Students With A Randomized Controlled Trial, Christina Ludema, Molly S Rosenberg, Jonathan T Macy, Sina Kianersi, Maya Luetke, Chen Chen, Lilian Golzarri-Arroyo, Erin Ables, Kevin Maki, David B Allison

Children’s Nutrition Research Center Staff Publications

Background: Risk compensation, or matching behavior to a perceived level of acceptable risk, can blunt the effectiveness of public health interventions. One area of possible risk compensation during the SARS-CoV-2 pandemic is antibody testing. While antibody tests are imperfect measures of immunity, results may influence risk perception and individual preventive actions. We conducted a randomized control trial to assess whether receiving antibody test results changed SARS-CoV-2 protective behaviors.

Purpose: Assess whether objective information about antibody status, particularly for those who are antibody negative and likely still susceptible to SARS-CoV-2 infection, increases protective behaviors. Secondarily, assess whether a positive antibody test …

A Flexible-Hazards Cure Model With Application To Patients With Soft Tissue Sarcoma, Can Xie, Xuelin Huang, Ruosha Li, Peter W T Pisters

Faculty, Staff and Student Publications

In medical research, it is often of great interest to have an accurate estimation of cure rates by different treatment options and for different patient groups. If the follow-up time is sufficiently long and the sample size is large, the proportion of cured patients will make the Kaplan-Meier estimator of survival function have a flat plateau at its tail, whose value indicates the overall cure rate. However, it may be difficult to estimate and compare the cure rates for all the subsets of interest in this way, due to the limit of sample sizes and curse of dimensionality. In the …

Correlations Between Complex Human Phenotypes Vary By Genetic Background, Gender, And Environment, Michael Elgart, Matthew O Goodman, Carmen Isasi, Han Chen, Alanna C Morrison, Paul S De Vries, Huichun Xu, Ani W Manichaikul, Xiuqing Guo, Nora Franceschini, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Donald M Lloyd-Jones, Myriam Fornage, Adolfo Correa, Nancy L Heard-Costa, Ramachandran S Vasan, Ryan Hernandez, Robert C Kaplan, Susan Redline, Tamar Sofer

Faculty, Staff and Student Publications

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we …

Spatial Heterogeneity Of Infiltrating T Cells In High-Grade Serous Ovarian Cancer Revealed By Multi-Omics Analysis, Bin Yang, Xiong Li, Wei Zhang, Junpeng Fan, Yong Zhou, Wenting Li, Jingjing Yin, Xiaohang Yang, Ensong Guo, Xi Li, Yu Fu, Si Liu, Dianxing Hu, Xu Qin, Yingyu Dou, Rourou Xiao, Funian Lu, Zizhuo Wang, Tianyu Qin, Wei Wang, Qinghua Zhang, Shuaicheng Li, Ding Ma, Gordon B Mills, Gang Chen, Chaoyang Sun

Faculty, Staff and Student Publications

Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites. Two immune "cold" patterns in ovarian cancer are identified: (1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells and (2) omental lesions infiltrated with non-tumor-specific bystander cells. Exhausted CD8 T …

In-Depth Analysis Of Alternative Splicing Landscape In Multiple Myeloma And Potential Role Of Dysregulated Splicing Factors, Anil Aktas Samur, Mariateresa Fulciniti, Herve Avet-Loiseau, Michael A Lopez, Sanika Derebail, Jill Corre, Stephane Minvielle, Florence Magrangeas, Philippe Moreau, Kenneth C Anderson, Giovanni Parmigiani, Mehmet K Samur, Nikhil C Munshi

Faculty, Staff and Student Publications

Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we …

The Role Of Lncrnas In The Tumor Microenvironment And Immunotherapy Of Melanoma, Wencheng Zhou, Xuewen Xu, Ying Cen, Junjie Chen

Faculty, Staff and Student Publications

Melanoma is one of the most lethal tumors with highly aggressive and metastatic properties. Although immunotherapy and targeted therapy have certain therapeutic effects in melanoma, a significant proportion of patients still have drug resistance after treatment. Recent studies have shown that long noncoding RNAs (lncRNAs) are widely recognized as regulatory factors in cancer. They can regulate numerous cellular processes, including cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) progression and the immune microenvironment. The role of lncRNAs in malignant tumors has received much attention, whereas the relationship between lncRNAs and melanoma requires further investigation. Our review summarizes tumor suppressive and oncogenic lncRNAs …

Stabilization Of Mcl-1 By E3 Ligase Traf4 Confers Radioresistance, Ming Li, Feng Gao, Xiaoying Li, Yu Gan, Shuangze Han, Xinfang Yu, Haidan Liu, Wei Li

Faculty, Staff and Students Publications

The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of …

Covid-19 Induces Cns Cytokine Expression And Loss Of Hippocampal Neurogenesis, Allison L Soung, Abigail Vanderheiden, Xiaoping Jiang, Traci Bricker, Adrianus C M Boon, Robyn S Klein, Et Al.

2020-Current year OA Pubs

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied. Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood-brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the …

Research Infrastructure Core Facilities At Research Centers In Minority Institutions: Part I-Research Resources Management, Operation, And Best Practices, Paul B Tchounwou, Mohamad Malouhi, Elizabeth O Ofili, Emma Fernández-Repollet, Daniel F Sarpong, Richard Yanagihara, Renato J Aguilera, Cecilia Ayón, Xiaoxin Chen, Asok Dasmahapatra, Song Gao, Cimona V Hinton, Robert Holt, Vladimir Kolesnichenko, Michael D Powell, Fatima Merchant, Kinfe K Redda, Abiel Roche-Lima, Cecilia M Shikuma, Jacqueline J Stevens, Jose A Torres, Robert T Trotter, James Wachira, Paul Wang, Kristen J Wells, Jason White, Yanyuan Wu

Faculty, Staff and Student Publications

Funded by the National Institutes of Health (NIH), the Research Centers in Minority Institutions (RCMI) Program fosters the development and implementation of innovative research aimed at improving minority health and reducing or eliminating health disparities. Currently, there are 21 RCMI Specialized (U54) Centers that share the same framework, comprising four required core components, namely the Administrative, Research Infrastructure, Investigator Development, and Community Engagement Cores. The Research Infrastructure Core (RIC) is fundamentally important for biomedical and health disparities research as a critical function domain. This paper aims to assess the research resources and services provided and evaluate the best practices in …

Multiplex Immunofluorescence-Guided Laser Capture Microdissection For Spatial Transcriptomics Of Metastatic Melanoma Tissues., Jan Martinek, Te-Chia Wu, Lili Sun, Jianan Lin, Kyung In Kim, Florentina Marches, Paul Robson, Joshy George, Karolina Palucka

Faculty Research 2022

We describe a pipeline for optimized and streamlined multiplexed immunofluorescence-guided laser capture microdissection allowing the harvest of individual cells based on their phenotype and tissue localization for transcriptomic analysis with next-generation RNA sequencing. Here, we analyze transcriptomes of CD3+ T cells, CD14+ monocytes/macrophages, and melanoma cells in non-dissociated metastatic melanoma tissue. While this protocol is described for melanoma tissues, we successfully applied it to human tonsil, skin, and breast cancer tissues as well as mouse lung tissues. For complete details on the use and execution of this protocol, please refer to Martinek et al. (2022).