Digital Commons Network^™

Towards Neuromarkers For Tailored Smoking Cessation Treatments, Francesco Versace, Jason D Robinson, Paul M Cinciripini

Faculty, Staff and Student Publications

Vulnerability to compulsive drug use stems from dysregulated activity within the neural networks that underlie reward and executive functions. Empirical evidence suggests that a) attributing high motivational salience to drug-related stimuli leads to compulsive drug seeking and b) cognitive control deficits lead to compulsive drug taking. Noninvasive neuroimaging techniques enable brain activity monitoring during affective and cognitive processing and are paving the way to precision medicine for substance use disorders. Identifying robust neuromarkers of affective and cognitive dysregulation would allow clinicians to personalize treatments by targeting individual psychophysiological vulnerabilities. However, methodological choices have biased the field toward experimental paradigms that …

Publisher Correction: Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

No abstract provided.

Phase I/Ii Sequencing Study Of Azacitidine, Epacadostat, And Pembrolizumab In Advanced Solid Tumors, Jason J Luke, Marwan Fakih, Charles Schneider, E Gabriela Chiorean, Johanna Bendell, Rebecca Kristeleit, Razelle Kurzrock, Sarah P Blagden, Irene Brana, Laura W Goff, Kevin O'Hayer, Ryan Geschwindt, Michael Smith, Feng Zhou, Aung Naing

Faculty, Staff and Student Publications

Background: Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors.

Methods: ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary …

Adjuvant Therapy With Oncolytic Adenovirus Delta-24-Rgdox After Intratumoral Adoptive T-Cell Therapy Promotes Antigen Spread To Sustain Systemic Antitumor Immunity, Hong Jiang, Dong Ho Shin, Yanhua Yi, Xuejun Fan, Joy Gumin, Jiasen He, Andrew G Gillard, Frederick F Lang, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAA), such as chimeric antigen receptor T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or ovalbumin (OVA)-specific OT-I T cells were injected into the first subcutaneous tumor, followed by three injections of …

Hemorrhagic Herpes Zoster Duplex Unilateralis In A Patient Taking Clopidogrel, Austinn C Miller, Anthony Thompson, Alexzandra Mattia, Laurie A Temiz, Susuana Adjei, Stephen K Tyring

Faculty, Staff and Student Publications

No abstract provided.

Actigraphic Correlates Of Neuropsychiatric Symptoms In Adults With Focal Epilepsy, Mark A Abboud, Jessica L Kamen, John S Bass, Lu Lin, Jay R Gavvala, Sindhu Rao, Stephen F Smagula, Vaishnav Krishnan

Faculty, Staff and Student Publications

Objectives:

Disability in patients with epilepsy (PWEs) is multifactorial: beyond seizure frequency/severity, PWEs are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly affect quality of life. Here, we explored how variations in seizure severity and the burden of self-reported somatic/neuropsychiatric symptoms correlate with disruptions to 24 h activity patterns (rest-activity rhythms [RARs]), determined through wrist accelerometry/actigraphy.

Methods:

Multiday wrist-actigraphy recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18–72), who contemporaneously responded to validated psychometric instruments to measure anxiety, depression, sleepiness, and somatic symptoms. We conducted a similar in silico psychometric-actigraphic correlation …

Changes In Local Tissue Microenvironment In Response To Subcutaneous Long-Acting Delivery Of Tenofovir Alafenamide In Rats And Non-Human Primates, Fernanda P Pons-Faudoa, Nicola Di Trani, Simone Capuani, Nathanael Hernandez, Anthony M Wood, Bharti Nehete, Jean Niles, Kathryn A Shelton, Sarah Kezar, Lane R Bushman, Corrine Ying Xuan Chua, Michael M Ittmann, Peter L Anderson, Pramod N Nehete, Roberto C Arduino, Joan E Nichols, Alessandro Grattoni

Faculty, Staff and Student Publications

Several implantable long-acting (LA) delivery systems have been developed for sustained subcutaneous administration of tenofovir alafenamide (TAF), a potent and effective nucleotide reverse transcriptase inhibitor used for HIV pre-exposure prophylaxis (PrEP). LA platforms aim to address the lack of adherence to oral regimens, which has impaired PrEP efficacy. Despite extensive investigations in this field, tissue response to sustained subcutaneous TAF delivery remains to be elucidated as contrasting preclinical results have been reported in the literature. To this end, here we studied the local foreign body response (FBR) to sustained subdermal delivery of three forms of TAF, namely TAF free base …

Association Of Diet Quality With Metabolic (Dysfunction) Associated Fatty Liver Disease In Veterans In Primary Care, Natalia I Heredia, Aaron P Thrift, David J Ramsey, Rohit Loomba, Hashem B El-Serag

Faculty, Staff and Student Publications

BACKGROUND: Diet is associated with metabolic (dysfunction)-associated fatty liver disease (MAFLD), but the dietary composition associated with MAFLD risk has not been well-examined.

AIM: The purpose of this study was to assess the association of two healthy eating indices with the presence and severity of MAFLD in a sample of Veterans in a primary care setting.

METHODS: This was a single center cross-sectional study using a random stratified sample of Veterans enrolled in primary care. Participants underwent a Fibroscan and completed an interviewer-administered Diet History Questionnaire II from which we calculated the Healthy Eating Index-2015 and Alternate Mediterranean Diet Score. …

Aryl Hydrocarbon Receptor Maintains Hepatic Mitochondrial Homeostasis In Mice, Mi Jeong Heo, Ji Ho Suh, Sung Ho Lee, Kyle L Poulsen, Yu A An, Bhagavatula Moorthy, Sean M Hartig, David D Moore, Kang Ho Kim

Faculty, Staff and Student Publications

OBJECTIVE: Mitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis.

METHODS: In this study, we utilized primary hepatocytes from AhR knockout (KO) mice and AhR knockdown AML12 hepatocytes. An endogenous AhR ligand, kynurenine (Kyn), was used to activate AhR in AML12 hepatocytes. Mitochondrial function and mitophagy process were comprehensively assessed by MitoSOX and mt-Keima fluorescence imaging, Seahorse XF-based …

Evolution Of Cisplatin Resistance Through Coordinated Metabolic Reprogramming Of The Cellular Reductive State, Wangie Yu, Yunyun Chen, Nagireddy Putluri, Abdullah Osman, Cristian Coarfa, Vasanta Putluri, Abu H M Kamal, Jennifer Kay Asmussen, Panagiotis Katsonis, Jeffrey N Myers, Stephen Y Lai, Wuhao Lu, Clifford C Stephan, Reid T Powell, Faye M Johnson, Heath D Skinner, Jawad Kazi, Kazi Mokim Ahmed, Linghao Hu, Addison Threet, Matthew D Meyer, James A Bankson, Tony Wang, Jack Davis, Kirby R Parker, Madison A Harris, Mokryun L Baek, Gloria V Echeverria, Xiaoli Qi, Jin Wang, Andy I Frederick, Alex J Walsh, Olivier Lichtarge, Mitchell J Frederick, Vlad C Sandulache

Faculty, Staff and Student Publications

BACKGROUND: Cisplatin (CDDP) is a mainstay treatment for advanced head and neck squamous cell carcinomas (HNSCC) despite a high frequency of innate and acquired resistance. We hypothesised that tumours acquire CDDP resistance through an enhanced reductive state dependent on metabolic rewiring.

METHODS: To validate this model and understand how an adaptive metabolic programme might be imprinted, we performed an integrated analysis of CDDP-resistant HNSCC clones from multiple genomic backgrounds by whole-exome sequencing, RNA-seq, mass spectrometry, steady state and flux metabolomics.

RESULTS: Inactivating KEAP1 mutations or reductions in KEAP1 RNA correlated with Nrf2 activation in CDDP-resistant cells, which functionally contributed to …

Diverse Murine Vaccinations Reveal Distinct Antibody Classes To Target Fusion Peptide And Variation In Peptide Length To Improve Hiv Neutralization, Mallika Sastry, Anita Changela, Jason Gorman, Kai Xu, Gwo-Yu Chuang, Chen-Hsiang Shen, Cheng Cheng, Hui Geng, Sijy O'Dell, Li Ou, Reda Rawi, Mateo Reveiz, Guillaume B E Stewart-Jones, Shuishu Wang, Baoshan Zhang, Tongqing Zhou, Andrea Biju, Michael Chambers, Xuejun Chen, Angela R Corrigan, Bob C Lin, Mark K Louder, Krisha Mckee, Alexandra F Nazzari, Adam S Olia, Danealle K Parchment, Edward K Sarfo, Tyler Stephens, Jonathan Stuckey, Yaroslav Tsybovsky, Raffaello Verardi, Yiran Wang, Cheng-Yan Zheng, Yuling Chen, Nicole A Doria-Rose, Adrian B Mcdermott, John R Mascola, Peter D Kwong

Faculty, Staff and Student Publications

While neutralizing antibodies that target the HIV-1 fusion peptide have been elicited in mice by vaccination, antibodies reported thus far have been from only a single antibody class that could neutralize ~30% of HIV-1 strains. To explore the ability of the murine immune system to generate cross-clade neutralizing antibodies and to investigate how higher breadth and potency might be achieved, we tested 17 prime-boost regimens that utilized diverse fusion peptide-carrier conjugates and HIV-1 envelope trimers with different fusion peptides. We observed priming in mice with fusion peptide-carrier conjugates of variable peptide length to elicit higher neutralizing responses, a result we …

Dissociation Protocols Used For Sarcoma Tissues Bias The Transcriptome Observed In Single-Cell And Single-Nucleus Rna Sequencing, Danh D Truong, Salah-Eddine Lamhamedi-Cherradi, Robert W Porter, Sandhya Krishnan, Jyothishmathi Swaminathan, Amber Gibson, Alexander J Lazar, J Andrew Livingston, Vidya Gopalakrishnan, Nancy Gordon, Najat C Daw, Nicholas E Navin, Richard Gorlick, Joseph A Ludwig

Faculty, Staff and Student Publications

BACKGROUND: Single-cell RNA-seq has emerged as an innovative technology used to study complex tissues and characterize cell types, states, and lineages at a single-cell level. Classification of bulk tumors by their individual cellular constituents has also created new opportunities to generate single-cell atlases for many organs, cancers, and developmental models. Despite the tremendous promise of this technology, recent evidence studying epithelial tissues and diverse carcinomas suggests the methods used for tissue processing, cell disaggregation, and preservation can significantly bias gene expression and alter the observed cell types. To determine whether sarcomas - tumors of mesenchymal origin - are subject to …

Heritable Aortic Root Aneurysms, Maral Ouzounian, Scott A Lemaire, Dianna M Milewicz

Faculty, Staff and Student Publications

No abstract provided.

Comparison Of Satisfaction With Penile Prosthesis Implantation In Patients With Prostate Cancer Radiation Therapy Versus Radical Prostatectomy, Justin P Mehr, Kyle A Blum, Travis Green, Skyler Howell, Stephen Palasi, Andrew T Sullivan, Benjamin Kim, Christopher Kannady, Run Wang

Faculty, Staff and Student Publications

Background: Penile prosthesis surgery (PPS) is a commonly used treatment for erectile dysfunction (ED), either as first-line therapy or in cases refractory to other treatment options. In patients with a urologic malignancy such as prostate cancer, surgical interventions like radical prostatectomy (RP) as well as non-surgical treatments such as radiation therapy can all induce ED. PPS as a treatment for ED has high satisfaction rates in the general population. Our aim was to compare sexual satisfaction in patients with prosthesis implantation for ED following RP versus ED following radiation therapy for prostate cancer.

Methods: A retrospective chart review from our …

Race-Free Estimated Glomerular Filtration Rate Equation In Kidney Transplant Recipients: Development And Validation Study, Marc Raynaud, Solaf Al-Awadhi, Ivana Juric, Gillian Divard, Yannis Lombardi, Nikolina Basic-Jukic, Olivier Aubert, Laurence Dubourg, Ingrid Masson, Christophe Mariat, Dominique Prié, Vincent Pernin, Moglie Le Quintrec, Timothy S Larson, Mark D Stegall, Boris Bikbov, Piero Ruggenenti, Laurent Mesnard, Hassan N Ibrahim, Marie Bodilsen Nielsen, Arthur J Matas, Brian J Nankivell, Stan Benjamens, Robert A Pol, Stephan J L Bakker, Xavier Jouven, Christophe Legendre, Nassim Kamar, Byron H Smith, Hani M Wadei, Antoine Durrbach, Flavio Vincenti, Giuseppe Remuzzi, Carmen Lefaucheur, Andrew J Bentall, Alexandre Loupy

Faculty, Staff and Student Publications

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.

DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).

PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.

MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. …

Cachexia, Chorea, And Pain In Chronic Nonbacterial Osteitis And Inflammatory Bowel Disease: A Case Report, Ladan Agharokh, Katherine Mamola, Andrew G Yu, Annette L Medina, Bhaskar Gurram, Julie Fuller, Jason Y Park, Weina Chen, Veena Rajaram, Matthew R Hammer, Jeff L Waugh

Faculty, Staff and Student Publications

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014).

CASE PRESENTATION: A 13-year-old Caucasian boy presented …

Hrd Effects On First-Line Adjuvant Chemotherapy And Parpi Maintenance Therapy In Chinese Ovarian Cancer Patients, Lei Li, Yu Gu, Mengpei Zhang, Xiaohua Shi, Zhe Li, Xinyun Xu, Tianqi Sun, Yu Dong, Chao Xue, Xiaoru Zhu, Ran Lv, Kai Jiao, Xuwo Ji, Li-Juan Wang, Yang Zhang, Zhiyong Liang, Ying Jin, Rutie Yin, Ming Wu, Han Liang

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) testing has been approved by FDA for selecting epithelial ovarian cancer (EOC) patients who may benefit from the first-line poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy. However, the effects of HRD on the clinical outcomes of first-line chemotherapy and first-line PARPi maintenance therapy have not been rigorously evaluated in Chinese EOC patients. Here, we developed an HRD assay and applied it to two large retrospectively collected Chinese EOC patient cohorts. In the first-line adjuvant chemotherapy cohort (FACT, N = 380), HRD status significantly improved PFS (median, 15.6 months vs. 9.4 months; HR, 0.688; 95% CI, 0.526-0.899; …

Target Cell-Specific Synaptic Dynamics Of Excitatory To Inhibitory Neuron Connections In Supragranular Layers Of Human Neocortex, Mean-Hwan Kim, Cristina Radaelli, Elliot R Thomsen, Deja Monet, Thomas Chartrand, Nikolas L Jorstad, Joseph T Mahoney, Michael J Taormina, Brian Long, Katherine Baker, Trygve E Bakken, Luke Campagnola, Tamara Casper, Michael Clark, Nick Dee, Florence D'Orazi, Clare Gamlin, Brian E Kalmbach, Sara Kebede, Brian R Lee, Lindsay Ng, Jessica Trinh, Charles Cobbs, Ryder P Gwinn, C Dirk Keene, Andrew L Ko, Jeffrey G Ojemann, Daniel L Silbergeld, Staci A Sorensen, Jim Berg, Kimberly A Smith, Philip R Nicovich, Tim Jarsky, Hongkui Zeng, Jonathan T Ting, Boaz P Levi, Ed Lein

Faculty, Staff and Student Publications

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- …

Enhanced Evasion Of Neutralizing Antibody Response By Omicron Xbb15, Ch11, And Ca31 Variants, Panke Qu, Julia N Faraone, John P Evans, Yi-Min Zheng, Claire Carlin, Mirela Anghelina, Patrick Stevens, Soledad Fernandez, Daniel Jones, Ashish R Panchal, Linda J Saif, Eugene M Oltz, Baoshan Zhang, Tongqing Zhou, Kai Xu, Richard J Gumina, Shan-Lu Liu

Faculty, Staff and Student Publications

Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and …

Optimization Of The Filler-And-Binder Mixing Ratio For Enhanced Mechanical Strength Of Carbon-Carbon Composites, Ji-Hong Kim, Hye-In Hwang, Ji-Sun Im

Faculty, Staff and Student Publications

In this paper, a method for optimizing the mixing ratio of filler coke and binder for high-strength carbon-carbon composites is proposed. Particle size distribution, specific surface area, and true density were analyzed to characterize the filler properties. The optimum binder mixing ratio was experimentally determined based on the filler properties. As the filler particle size was decreased, a higher binder mixing ratio was required to enhance the mechanical strength of the composite. When the d

Therapeutic Potential Of A Small-Molecule Stat3 Inhibitor In A Mouse Model Of Colitis, Prema Robinson, Kelsey Montoya, Emily Magness, Emma Rodriguez, Viviana Villalobos, Nikita Engineer, Peng Yang, Uddalak Bharadwaj, Thomas Kris Eckols, David John Tweardy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms …

Microfibril-Associated Protein 5 And The Regulation Of Skin Scar Formation, Chen Han, Trevor R Leonardo, Bruna Romana-Souza, Junhe Shi, Shalyn Keiser, Heidi Yuan, Mohamad Altakriti, Matthew J Ranzer, Sammy Ferri-Borgogno, Samuel C Mok, Timothy J Koh, Seok Jong Hong, Lin Chen, Luisa A Dipietro

Faculty, Staff and Student Publications

Many factors regulate scar formation, which yields a modified extracellular matrix (ECM). Among ECM components, microfibril-associated proteins have been minimally explored in the context of skin wound repair. Microfibril-associated protein 5 (MFAP5), a small 25 kD serine and threonine rich microfibril-associated protein, influences microfibril function and modulates major extracellular signaling pathways. Though known to be associated with fibrosis and angiogenesis in certain pathologies, MFAP5's role in wound healing is unknown. Using a murine model of skin wound repair, we found that MFAP5 is significantly expressed during the proliferative and remodeling phases of healing. Analysis of existing single-cell RNA-sequencing data from …

Whole-Genome Sequencing Analysis Of Human Metabolome In Multi-Ethnic Populations, Elena V Feofanova, Michael R Brown, Taryn Alkis, Astrid M Manuel, Xihao Li, Usman A Tahir, Zilin Li, Kevin M Mendez, Rachel S Kelly, Qibin Qi, Han Chen, Martin G Larson, Rozenn N Lemaitre, Alanna C Morrison, Charles Grieser, Kari E Wong, Robert E Gerszten, Zhongming Zhao, Jessica Lasky-Su, Bing Yu

Faculty, Staff and Student Publications

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven …

Architecture Of Androgen Receptor Pathways Amplifying Glucagon-Like Peptide-1 Insulinotropic Action In Male Pancreatic Β Cells, Weiwei Xu, M M Fahd Qadir, Daniela Nasteska, Paula Mota De Sa, Caroline M Gorvin, Manuel Blandino-Rosano, Charles R Evans, Thuong Ho, Evgeniy Potapenko, Rajakrishnan Veluthakal, Fiona B Ashford, Stavroula Bitsi, Jia Fan, Manika Bhondeley, Kejing Song, Venkata N Sure, Siva S V P Sakamuri, Lina Schiffer, Wandy Beatty, Rachael Wyatt, Daniel E Frigo, Xiaowen Liu, Prasad V Katakam, Wiebke Arlt, Jochen Buck, Lonny R Levin, Tony Hu, Jay Kolls, Charles F Burant, Alejandra Tomas, Matthew J Merrins, Debbie C Thurmond, Ernesto Bernal-Mizrachi, David J Hodson, Franck Mauvais-Jarvis

Faculty, Staff and Student Publications

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of CO

Progesterone From Ovulatory Menstrual Cycles Is An Important Cause Of Breast Cancer, Herjan J T Coelingh Bennink, Iman J Schultz, Marcus Schmidt, V Craig Jordan, Paula Briggs, Jan F M Egberts, Kristina Gemzell-Danielsson, Ludwig Kiesel, Kirsten Kluivers, Jan Krijgh, Tommaso Simoncini, Frank Z Stanczyk, Robert D Langer

Faculty, Staff and Student Publications

Many factors, including reproductive hormones, have been linked to a woman's risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting …

Challenges In The Clinical Understanding Of Genetic Testing In Birth Defects And Pediatric Diseases, Tina O Findley, Jacqueline G Parchem, Aarti Ramdaney, Sarah U Morton

Faculty, Staff and Student Publications

Advances in prenatal/neonatal genetic screening practices and next generation sequencing (NGS) technologies have made the detection of molecular causes of pediatric diseases increasingly more affordable, accessible, and rapid in return of results. In the past, families searching for answers often required diagnostic journeys leading to delays in targeted care and missed diagnoses. Non-invasive prenatal NGS is now used routinely in pregnancy, significantly altering the obstetric approach to early screening and evaluation of fetal anomalies. Similarly, exome sequencing (ES) and genome sequencing (GS) were once only available for research but are now used in patient care, impacting neonatal care and the …

Circadian Features Of Cluster Headache And Migraine: A Systematic Review, Meta-Analysis, And Genetic Analysis, Barlas Benkli, Sun Young Kim, Nobuya Koike, Chorong Han, Celia K Tran, Emma Silva, Yuanqing Yan, Kazuhiro Yagita, Zheng Chen, Seung-Hee Yoo, Mark J Burish

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies.

METHODS: A librarian created search criteria in MEDLINE Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two physicians independently performed the remainder of the systematic review/meta-analysis using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Separate from the systematic review/meta-analysis, we performed a genetic analysis for genes with a circadian pattern of expression (clock-controlled genes or CCGs) by cross-referencing genome-wide association studies (GWASs) of headache, a nonhuman primate study of CCGs …

Glial Progenitor Heterogeneity And Key Regulators Revealed By Single-Cell Rna Sequencing Provide Insight To Regeneration In Spinal Cord Injury, Haichao Wei, Xizi Wu, Joseph Withrow, Raquel Cuevas-Diaz Duran, Simranjit Singh, Lesley S Chaboub, Jyotirmoy Rakshit, Julio Mejia, Andrew Rolfe, Juan J Herrera, Philip J Horner, Jia Qian Wu

Faculty, Staff and Student Publications

Recent studies have revealed the heterogeneous nature of astrocytes; however, how diverse constituents of astrocyte-lineage cells are regulated in adult spinal cord after injury and contribute to regeneration remains elusive. We perform single-cell RNA sequencing of GFAP-expressing cells from sub-chronic spinal cord injury models and identify and compare with the subpopulations in acute-stage data. We find subpopulations with distinct functional enrichment and their identities defined by subpopulation-specific transcription factors and regulons. Immunohistochemistry, RNAscope experiments, and quantification by stereology verify the molecular signature, location, and morphology of potential resident neural progenitors or neural stem cells in the adult spinal cord before …

The Metabolic Profile Of Young, Watered Chickpea Plants Can Be Used As A Biomarker To Predict Seed Number Under Terminal Drought, Sarah J Purdy, David Fuentes, Purushothaman Ramamoorthy, Christopher Nunn, Brent N Kaiser, Andrew Merchant

Faculty, Staff and Student Publications

Chickpea is the second-most-cultivated legume globally, with India and Australia being the two largest producers. In both of these locations, the crop is sown on residual summer soil moisture and left to grow on progressively depleting water content, finally maturing under terminal drought conditions. The metabolic profile of plants is commonly, correlatively associated with performance or stress responses, e.g., the accumulation of osmoprotective metabolites during cold stress. In animals and humans, metabolites are also prognostically used to predict the likelihood of an event (usually a disease) before it occurs, e.g., blood cholesterol and heart disease. We sought to discover metabolic …

Ca2+ Efflux Facilitated By Co-Transport Of Inorganic Phosphate Anion In The H+/Ca2+ Antiporter Yfke, Wei Niu, Wenchang Zhou, Shuo Lu, Trung Vu, Vasanthi Jayaraman, José D Faraldo-Gómez, Lei Zheng

Faculty, Staff and Student Publications

Ca2+ is an important signaling messenger. In microorganisms, fungi, and plants, H+/Ca2+ antiporters (CAX) are known to play key roles in the homeostasis of intracellular Ca2+ by catalyzing its efflux across the cell membrane. Here, we reveal that the bacterial CAX homolog YfkE transports Ca2+ in two distinct modes: a low-flux H+/Ca2+ exchange mode and a high-flux mode in which Ca2+ and phosphate ions are co-transported (1:1) in exchange for H+. Coupling with phosphate greatly accelerates the Ca2+ efflux activity of YfkE. Our studies reveal that Ca2+ and phosphate bind to adjacent sites in a central translocation pathway and lead …