Digital Commons Network^™

Sars-Cov-2 Omicron Virus Causes Attenuated Disease In Mice And Hamsters, Peter J Halfmann, Shun Iida, Kiyoko Iwatsuki-Horimoto, Tadashi Maemura, Maki Kiso, Suzanne M Scheaffer, Tamarand L Darling, Astha Joshi, Baoling Ying, James Brett Case, Zhenlu Chong, Bradley Whitener, Zhenlu Chong, Larissa B Thackray, Adrianus C M Boon, Michael S Diamond, Et Al

Open Access Publications

The recent emergence of B.1.1.529, the Omicron variant

Metabolic Stress Induces Gd2+ Cancer Stem Cell-Like Phenotype In Triple-Negative Breast Cancer, Appalaraju Jaggupilli, Stanley Ly, Khoa Nguyen, Vivek Anand, Bin Yuan, Fouad El-Dana, Yuanqing Yan, Zoe Arvanitis, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Helen Piwnica-Worms, Henry Charles Manning, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

Background: Metabolic stress resulting from nutrient deficiency is one of the hallmarks of a growing tumour. Here, we tested the hypothesis that metabolic stress induces breast cancer stem-like cell (BCSC) phenotype in triple-negative breast cancer (TNBC).

Methods: Flow cytometry for GD2 expression, mass spectrometry and Ingenuity Pathway Analysis for metabolomics, bioinformatics, in vitro tumorigenesis and in vivo models were used.

Results: Serum/glucose deprivation not only increased stress markers but also enhanced GD2+ BCSC phenotype and function in TNBC cells. Global metabolomics profiling identified upregulation of glutathione biosynthesis in GD2high cells, suggesting a role of glutamine in the BCSC phenotype. Cueing …

Chronic Estrus Disrupts Uterine Gland Development And Homeostasis, C Allison Stewart, M David Stewart, Ying Wang, Rachel D Mullen, Bonnie K Kircher, Rui Liang, Yu Liu, Richard R Behringer

Faculty, Staff and Student Publications

Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By age 20 weeks, uterine gland development was comparable to controls, …

Naked (N) Mutant Mice Carry A Nonsense Mutation In The Homeobox Of Hoxc13, Carlos J Perez, Lars Mecklenburg, Almudena Fernandez, Marta Cantero, Tiago Antonio De Souza, Kevin Lin, Sharon Y R Dent, Lluis Montoliu, Alexander Awgulewitsch, Fernando Benavides

Faculty, Staff and Student Publications

Loss of function mutations in HOXC13 have been associated with Ectodermal Dysplasia-9, Hair/Nail Type (ECTD9) in consanguineous families, characterized by sparse to complete absence of hair and nail dystrophy. Here we characterize the spontaneous mouse mutation Naked (N) as a terminal truncation in the Hoxc13 (homeobox C13) gene. Similar to previous reports for homozygous Hoxc13 knock-out (KO) mice, homozygous N/N mice exhibit generalized alopecia with abnormal nails and a short lifespan. However, in contrast to Hoxc13 heterozygous KO mice, N/+ mice show generalized or partial alopecia, associated with loss of hair fibres, along with normal lifespan and fertility. Our data …

Of Vascular Defense, Hemostasis, Cancer, And Platelet Biology: An Evolutionary Perspective, David G Menter, Vahid Afshar-Kharghan, John Paul Shen, Stephanie L Martch, Anirban Maitra, Scott Kopetz, Kenneth V Honn, Anil K Sood

Faculty, Staff and Student Publications

We have established considerable expertise in studying the role of platelets in cancer biology. From this expertise, we were keen to recognize the numerous venous-, arterial-, microvascular-, and macrovascular thrombotic events and immunologic disorders are caused by severe, acute-respiratory-syndrome coronavirus 2 (SARS-CoV-2) infections. With this offering, we explore the evolutionary connections that place platelets at the center of hemostasis, immunity, and adaptive phylogeny. Coevolutionary changes have also occurred in vertebrate viruses and their vertebrate hosts that reflect their respective evolutionary interactions. As mammals adapted from aquatic to terrestrial life and the heavy blood loss associated with placentalization-based live birth, platelets …

Inhibition Of Calcium-Triggered Secretion By Hydrocarbon-Stapled Peptides, Ying Lai, Giorgio Fois, Jose R Flores, Michael J Tuvim, Qiangjun Zhou, Kailu Yang, Jeremy Leitz, John Peters, Yunxiang Zhang, Richard A Pfuetzner, Luis Esquivies, Philip Jones, Manfred Frick, Burton F Dickey, Axel T Brunger

Faculty, Staff and Student Publications

Membrane fusion triggered by Ca2+ is orchestrated by a conserved set of proteins to mediate synaptic neurotransmitter release, mucin secretion and other regulated exocytic processes1-4. For neurotransmitter release, the Ca2+ sensitivity is introduced by interactions between the Ca2+ sensor synaptotagmin and the SNARE complex5, and sequence conservation and functional studies suggest that this mechanism is also conserved for mucin secretion6. Disruption of Ca2+-triggered membrane fusion by a pharmacological agent would have therapeutic value for mucus hypersecretion as it is the major cause of airway obstruction in the pathophysiology of respiratory viral infection, asthma, chronic obstructive pulmonary disease and cystic fibrosis7-11. …

Clinical Exome Sequencing Data Reveal High Diagnostic Yields For Congenital Diaphragmatic Hernia Plus (Cdh+) And New Phenotypic Expansions Involving Cdh, Tiana M Scott, Ian M Campbell, Andres Hernandez-Garcia, Seema R Lalani, Pengfei Liu, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.

Results: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other …

Visual Pigment-Deficient Cones Survive And Mediate Visual Signaling Despite The Lack Of Outer Segments, Hui Xu, Nange Jin, Jen-Zen Chuang, Zhao Zhang, Xiaoyue Zhong, Zhijing Zhang, Ching-Hwa Sung, Christophe P Ribelayga, Yingbin Fu

Faculty, Staff and Students Publications

Rhodopsin and cone opsins are essential for light detection in vertebrate rods and cones, respectively. It is well established that rhodopsin is required for rod phototransduction, outer segment disk morphogenesis, and rod viability. However, the roles of cone opsins are less well understood. In this study, we adopted a loss-of-function approach to investigate the physiological roles of cone opsins in mice. We showed that cones lacking cone opsins do not form normal outer segments due to the lack of disk morphogenesis. Surprisingly, cone opsin-deficient cones survive for at least 12 mo, which is in stark contrast to the rapid rod …

Enhanced Immunoprecipitation Techniques For The Identification Of Rna-Binding Protein Partners: Igf2bp1 Interactions In Mammary Epithelial Cells, Saja A Fakhraldeen, Scott M Berry, David J Beebe, Avtar Roopra, Celia M Bisbach, Vladimir S Spiegelman, Natalie M Niemi, Caroline M Alexander

2020-Current year OA Pubs

RNA-binding proteins (RBPs) regulate the expression of large cohorts of RNA species to produce programmatic changes in cellular phenotypes. To describe the function of RBPs within a cell, it is key to identify their mRNA-binding partners. This is often done by crosslinking nucleic acids to RBPs, followed by chemical release of the nucleic acid fragments for analysis. However, this methodology is lengthy, which involves complex processing with attendant sample losses, thus large amounts of starting materials and prone to artifacts. To evaluate potential alternative technologies, we tested "exclusion-based" purification of immunoprecipitates (IFAST or SLIDE) and report here that these methods …

Isoform-Specific Functions Of Pparγ In Gene Regulation And Metabolism, Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J Richter, Dongyin Guan, Kun Zhu, Brianna M Krusen, Arielle N Roberts, Jessica Miller, David J Steger, Mitchell A Lazar

Faculty, Staff and Students Publications

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, …

Tissue-Targeted Crispr-Cas9-Mediated Genome Editing Of Multiple Homeologs In F0 Generation Xenopus Laevis Embryos, Mark E Corkins, Bridget D Delay, Rachel K Miller

Faculty, Staff and Student Publications

Xenopus laevis frogs are a powerful developmental model that enables studies combining classical embryology and molecular manipulation. Because of the large embryo size, ease of microinjection, and ability to target tissues through established fate maps, X. laevis have become the predominant amphibian research model. Given that their allotetraploid genome has complicated the generation of gene knockouts, strategies need to be established for efficient mutagenesis of multiple homeologs to evaluate gene function. Here we describe a protocol to utilize CRISPR-Cas9-mediated genome editing to target either single alleles or multiple alloalleles in F0 X. laevis embryos. A single guide (sg) RNA is …

Non-Autophagy Role Of Atg5 And Nbr1 In Unconventional Secretion Of Il-12 Prevents Gut Dysbiosis And Inflammation, Seth D. Merkley, Samuel M. Goodfellow, Yan Guo, Zoe E R Wilton, Janie R. Byrum, Kurt C. Schwalm, Darrell L. Dinwiddie, Rama R. Gullapalli, Vojo Deretic, Anthony Jimenez Hernandez, Steven B. Bradfute, Julie G. In, Eliseo F. Castillo

Pediatrics Research and Scholarship

Intestinal myeloid cells play a critical role in balancing intestinal homeostasis and inflammation. Here, we report that expression of the autophagy-related 5 [Atg5] protein in myeloid cells prevents dysbiosis and excessive intestinal inflammation by limiting IL-12 production. Mice with a selective genetic deletion of Atg5 in myeloid cells [Atg5ΔMye] showed signs of dysbiosis preceding colitis, and exhibited severe intestinal inflammation upon colitis induction that was characterised by increased IFNγ production. The exacerbated colitis was linked to excess IL-12 secretion from Atg5-deficient myeloid cells and gut dysbiosis. Restoration of the intestinal microbiota or genetic deletion of IL-12 in Atg5ΔMye mice attenuated …

Stat6 Blockade Abrogates Aspergillus-Induced Eosinophilic Chronic Rhinosinusitis And Asthma, A Model Of Unified Airway Disease, Hua Sun, Ashish Damania, Megan L Mair, Eniola Otukoya, Yi-Dong Li, Katherine Polsky, Yuying Zeng, Jeremiah A Alt, Martin J Citardi, David B Corry, Amber U Luong, John Morgan Knight

Faculty, Staff and Student Publications

Unified airway disease, including concurrent asthma and chronic rhinosinusitis (CRS), is a common, but poorly understood disorder with no curative treatment options. To establish a murine model of chronic unified eosinophilic airway inflammation, mice were challenged with Aspergillus niger, and sinonasal mucosa and lung tissue were evaluated by immunohistochemistry, flow cytometry, and gene expression. Inhalation of A niger conidia resulted in a Th2-biased lung and sinus inflammation that typifies allergic asthma and CRS. Gene network and pathway analysis correlated with human disease with upregulation of not only the JAK-STAT and helper T-cell pathways, but also less expected pathways governing …

The Europdx Data Portal: An Open Platform For Patient-Derived Cancer Xenograft Data Sharing And Visualization., Zdenka Dudová, Nathalie Conte, Jeremy Mason, Dalibor Stuchlík, Radim Peša, Csaba Halmagyi, Zinaida Perova, Abayomi Mosaku, Ross Thorne, Alex Follette, Ľuboslav Pivarč, Radim Šašinka, Muhammad Usman, Steven Neuhauser, Dale A. Begley, Debra M Krupke, Massimiliano Frassà, Alessandro Fiori, Riccardo Corsi, Luca Vezzadini, Claudio Isella, Andrea Bertotti, Carol J Bult, Helen Parkinson, Enzo Medico, Terrence Meehan, Aleš Křenek

Faculty Research 2022

BACKGROUND: Patient-derived xenografts (PDX) mice models play an important role in preclinical trials and personalized medicine. Sharing data on the models is highly valuable for numerous reasons - ethical, economical, research cross validation etc. The EurOPDX Consortium was established 8 years ago to share such information and avoid duplicating efforts in developing new PDX mice models and unify approaches to support preclinical research. EurOPDX Data Portal is the unified data sharing platform adopted by the Consortium.

MAIN BODY: In this paper we describe the main features of the EurOPDX Data Portal ( https://dataportal.europdx.eu/ ), its architecture and possible utilization by …

Acquired Hydrocephalus Is Associated With Neuroinflammation, Progenitor Loss, And Cellular Changes In The Subventricular Zone And Periventricular White Matter, Maria Garcia-Bonilla, Leandro Castaneyra-Ruiz, Sarah Zwick, Michael Talcott, Ayodamola Otun, Albert M Isaacs, Diego M Morales, David D Limbrick, James P Mcallister

2020-Current year OA Pubs

BACKGROUND: Hydrocephalus is a neurological disease with an incidence of 80-125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants.

METHODS: Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19-40 days, MRI scanning was performed to measure the …

Syndecan-2 Regulates Pad2 To Exert Antifibrotic Effects On Ra-Ild Fibroblasts, Konstantin Tsoyi, Anthony J Esposito, Bo Sun, Ryan G Bowen, Kevin Xiong, Fernando Poli, Rafael Cardenas, Sarah G Chu, Xiaoliang Liang, Stefan W Ryter, Christine Beeton, Tracy J Doyle, Matthew J Robertson, Lindsay J Celada, Freddy Romero, Souheil Y El-Chemaly, Mark A Perrella, I-Cheng Ho, Ivan O Rosas

Faculty, Staff and Students Publications

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix …

Repeated Endo-Tracheal Tube Disconnection Generates Pulmonary Edema In A Model Of Volume Overload: An Experimental Study, Bhushan H Katira, Doreen Engelberts, Sheena Bouch, Jordan Fliss, Luca Bastia, Kohei Osada, Kim A Connelly, Marcelo B P Amato, Niall D Ferguson, Wolfgang M Kuebler, Brian P Kavanagh, Laurent J Brochard, Martin Post

2020-Current year OA Pubs

BACKGROUND: An abrupt lung deflation in rodents results in lung injury through vascular mechanisms. Ventilator disconnections during endo-tracheal suctioning in humans often cause cardio-respiratory instability. Whether repeated disconnections or lung deflations cause lung injury or oedema is not known and was tested here in a porcine large animal model.

METHODS: Yorkshire pigs (~ 12 weeks) were studied in three series. First, we compared PEEP abruptly deflated from 26 cmH

RESULTS: As compared to PEEP 5 cmH

CONCLUSION: Single abrupt deflation from high PEEP, and repeated short deflations from moderate PEEP cause pulmonary oedema, impaired oxygenation, and increased PVR, in this …

Blood–Brain Barrier Disruption Mediated By Ffa1 Receptor—Evidence Using Miniscope, Kristen L Lindenau, Jeffrey L Barr, Christopher R Higgins, Kevin T Sporici, Eugen Brailoiu, Gabriela C Brailoiu

Faculty, Staff and Student Publications

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), obtained from diet and dietary supplements, have been tested in clinical trials for the prevention or treatment of several diseases. n-3 PUFAs exert their effects by activation of free fatty acid (FFA) receptors. FFA1 receptor, expressed in the pancreas and brain, is activated by medium- to long-chain fatty acids. Despite some beneficial effects on cognition, the effects of n-3 PUFAs on the blood-brain barrier (BBB) are not clearly understood. We examined the effects of FFA1 activation on BBB permeability in vitro, using rat brain microvascular endothelial cells (RBMVEC), and in vivo, by assessing Evans …

Novel Role Of Ghrelin Receptor In Gut Dysbiosis And Experimental Colitis In Aging, Ji Yeon Noh, Chia-Shan Wu, Jennifer A A Deluca, Sridevi Devaraj, Arul Jayaraman, Robert C Alaniz, Xiao-Di Tan, Clinton D Allred, Yuxiang Sun

Faculty, Staff and Students Publications

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout …

Similarly Efficacious Anti-Malarial Drugs Sj733 And Pyronaridine Differ In Their Ability To Remove Circulating Parasites In Mice, Arya Sheelanair, Aleksandra S. Romanczuk, Rosemary A. Aogo, Rohit Nemai Haldar, Lianne I. M. Lansink, Deborah Cromer, Yandira G. Salinas, R. Kiplin Guy, James S. Mccarthy, Miles P. Davenport, Ashraful Haque, David S. Khoury

Pharmaceutical Sciences Faculty Publications

BACKGROUND: Artemisinin-based combination therapy (ACT) has been a mainstay for malaria prevention and treatment. However, emergence of drug resistance has incentivised development of new drugs. Defining the kinetics with which circulating parasitized red blood cells (pRBC) are lost after drug treatment, referred to as the "parasite clearance curve", has been critical for assessing drug efficacy; yet underlying mechanisms remain partly unresolved. The clearance curve may be shaped both by the rate at which drugs kill parasites, and the rate at which drug-affected parasites are removed from circulation.

METHODS: In this context, two anti-malarials, SJ733, and an ACT partner drug, pyronaridine …

Feasibility Of Administering Human Pancreatic Cancer Chemotherapy In A Spontaneous Pancreatic Cancer Mouse Model, Abagail M Delahoussaye, Joseph Abi Jaoude, Morgan Green, Tara N Fujimoto, Jessica Molkentine, Carolina J Garcia Garcia, Jason P Gay, Ningping Feng, Joseph Marszalek, Natalie Fowlkes, Cullen M Taniguchi

Faculty, Staff and Student Publications

Background: Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies.

Methods: KPC mice were created by breeding KrasLSL-G12D/+ to Trp53fl/fl;Ptf1αCre/+, resulting in KrasLSL-G12D/+;p53fl/+;Ptf1αCre/+ mice. At 14 weeks of age, mice were palpated for spontaneous tumor …

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …

Pharmacological Modulation Of Kv13 Potassium Channel Selectively Triggers Pathological B Lymphocyte Apoptosis In Vivo In A Genetic Cll Model, Filippo Severin, Andrea Urbani, Tatiana Varanita, Magdalena Bachmann, Michele Azzolini, Veronica Martini, Marco Pizzi, Angelo Paolo Dei Tos, Federica Frezzato, Andrea Mattarei, Paolo Ghia, Maria Teresa Sabrina Bertilaccio, Erich Gulbins, Cristina Paradisi, Mario Zoratti, Gianpietro Carlo Semenzato, Luigi Leanza, Livio Trentin, Ildiko Szabò

Faculty, Staff and Student Publications

Background: Ion channels are emerging as promising oncological targets. The potassium channels Kv1.3 and IKCa are highly expressed in the plasma membrane and mitochondria of human chronic lymphocytic leukemia (CLL) cells, compared to healthy lymphocytes. In vitro, inhibition of mitoKv1.3 by PAPTP was shown to kill ex vivo primary human CLL cells, while targeting IKCa with TRAM-34 decreased CLL cell proliferation.

Methods: Here we evaluated the effect of the above drugs in CLL cells from ibrutinib-resistant patients and in combination with Venetoclax, two drugs used in the clinical practice. The effects of the drugs were tested also in the Eμ-TCL1 …

Hydraulic Permeability And Compressive Properties Of Porcine And Human Synovium, Milad Rohanifar, Benjamin B Johnston, Alexandra L Davis, Young Guang, Kayla Nommensen, James A J Fitzpatrick, Christine N Pham, Lori A Setton

2020-Current year OA Pubs

The synovium is a multilayer connective tissue separating the intra-articular spaces of the diarthrodial joint from the extra-synovial vascular and lymphatic supply. Synovium regulates drug transport into and out of the joint, yet its material properties remain poorly characterized. Here, we measured the compressive properties (aggregate modulus, Young's modulus, and Poisson's ratio) and hydraulic permeability of synovium with a combined experimental-computational approach. A compressive aggregate modulus and Young's modulus for the solid phase of synovium were quantified from linear regression of the equilibrium confined and unconfined compressive stress upon strain, respectively (H

Relationships Between Correlated Spikes, Oxygen And Lfp In The Resting-State Primate, Jingfeng M Li, Benjamin T Acland, Alexander S Brenner, William J Bentley, Lawrence H Snyder

2020-Current year OA Pubs

Resting-state functional MRI (rsfMRI) provides a view of human brain organization based on correlation patterns of blood oxygen level dependent (BOLD) signals recorded across the whole brain. The neural basis of resting-state BOLD fluctuations and their correlation remains poorly understood. We simultaneously recorded oxygen level, spikes, and local field potential (LFP) at multiple sites in awake, resting monkeys. Following a spike, the average local oxygen and LFP voltage responses each resemble a task-driven BOLD response, with LFP preceding oxygen by 0.5 s. Between sites, features of the long-range correlation patterns of oxygen, LFP, and spikes are similar to features seen …

Treatment Preferences For Pharmacological Versus Psychological Interventions Among Primary Care Providers In Nepal: Mixed Methods Analysis Of A Pilot Cluster Randomized Controlled Trial., Anvita Bhardwaj, Dristy Gurung, Sauharda Rai, Bonnie N Kaiser, Cori L Cafaro, Kathleen J Sikkema, Crick Lund, Nagendra P Luitel, Brandon A. Kohrt

Psychiatry and Behavioral Sciences Faculty Publications

There is increasing evidence supporting the effectiveness of psychological interventions in low- and middle-income countries. However, primary care providers (PCPs) may prefer treating patients with medication. A secondary exploratory analysis of a pilot cluster randomized controlled trial was conducted to evaluate psychological vs. pharmacological treatment preferences among PCPs. Thirty-four health facilities, including 205 PCPs, participated in the study, with PCPs in 17 facilities assigned to a standard version of the mental health Gap Action Programme (mhGAP) training delivered by mental health specialists. PCPs in the other 17 facilities received mhGAP instruction delivered by specialists and people with lived experience of …

Fungal Mycobiome Drives Il-33 Secretion And Type 2 Immunity In Pancreatic Cancer, Aftab Alam, Eric Levanduski, Parker Denz, Helena Solleiro Villavicencio, Maulasri Bhatta, Lamees Alhorebi, Yali Zhang, Eduardo Cortes Gomez, Brian Morreale, Sharon Senchanthisai, Jun Li, Steven G Turowski, Sandra Sexton, Sheila Jani Sait, Prashant K Singh, Jianmin Wang, Anirban Maitra, Pawel Kalinski, Ronald A Depinho, Huamin Wang, Wenting Liao, Scott I Abrams, Brahm H Segal, Prasenjit Dey

Faculty, Staff and Student Publications

TH2 cells and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment are unknown. Here, we show that oncogenic KrasG12D increases IL-33 expression in pancreatic ductal adenocarcinoma (PDAC) cells, which recruits and activates TH2 and ILC2 cells. Correspondingly, cancer-cell-specific deletion of IL-33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, IL-33 secretion is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL-33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases …

Noncoding-Rna-Based Therapeutics With An Emphasis On Prostatic Carcinoma-Progress And Challenges., Victor E. Nava, Pin-Yu Perera, Nirbhay Kumar, Maneesh Jain

Pathology Faculty Publications

Noncoding RNAs (ncRNAs) defy the central dogma by representing a family of RNA molecules that are not translated into protein but can convey information encoded in their DNA. Elucidating the exact function of ncRNA has been a focus of discovery in the last decade and remains challenging. Nevertheless, the importance of understanding ncRNA is apparent since these molecules regulate gene expression at the transcriptional and post-transcriptional level exerting pleiotropic effects critical in development, oncogenesis, and immunity. NcRNAs have been referred to as "the dark matter of the nucleus", and unraveling their role in physiologic and pathologic processes will provide vast …

Reducing Influenza Virus Transmission: The Potential Value Of Antiviral Treatment, Frederick G Hayden, Jason Asher, Benjamin J Cowling, Aeron C Hurt, Hideyuki Ikematsu, Klaus Kuhlbusch, Annabelle Lemenuel-Diot, Zhanwei Du, Lauren Ancel Meyers, Pedro A Piedra, Takahiro Takazono, Hui-Ling Yen, Arnold S Monto

Faculty, Staff and Students Publications

Prompt antiviral treatment has the potential to reduce influenza virus transmission to close contacts, but rigorous data on the magnitude of treatment effects on transmission are limited. Animal model data indicate that rapid reductions in viral replication after antiviral treatment reduce the risk of transmission. Observational and clinical trial data with oseltamivir and other neuraminidase inhibitors indicate that prompt treatment of household index patients seems to reduce the risk of illness in contacts, although the magnitude of the reported effects has varied widely across studies. In addition, the potential risk of transmitting drug-resistant variants exists with all approved classes of …

Aloin Isoforms (A And B) Selectively Inhibits Proteolytic And Deubiquitinating Activity Of Papain Like Protease (Plpro) Of Sars-Cov-2 In Vitro., Devin S M Lewis, Joanna Ho, Savannah Wills, Anasha Kawall, Avini Sharma, Krishna Chavada, Maximilian C C J C Ebert, Stefania Evoli, Ajay Singh, Srujana Rayalam, Vicky Mody, Shashidharamurthy Taval

PCOM Scholarly Works

The most common host entry point of human adapted coronaviruses (CoV) including SARS-CoV-2 is through the initial colonization in the nostril and mouth region which is responsible for spread of the infection. Most recent studies suggest that the commercially available oral and nasal rinse products are effective in inhibiting the viral replication. However, the anti-viral mechanism of the active ingredients present in the oral rinses have not been studied. In the present study, we have assessed in vitro enzymatic inhibitory activity of active ingredients in the oral mouth rinse products: aloin A and B, chlorhexidine, eucalyptol, hexetidine, menthol, triclosan, methyl …