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Bacillus Licheniformis Suppresses Clostridium Perfringens Infection Via Modulating Inflammatory Response, Antioxidant Status, Inflammasome Activation And Microbial Homeostasis In Broilers, Xiao Xiao, Songke Qin, Tiantian Cui, Jinsong Liu, Yanping Wu, Yifan Zhong, Caimei Yang

Faculty, Staff and Student Publications

Pathogenic bacteria infection, especially Clostridium perfringens (C. perfringens), markedly threatened the health of animals, and further caused huge economic loss. In this study, Bacillus licheniformis HJ0135 (BL) was used. Oxford cup bacteriostatic test and inhibitory rate test were conducted to evaluate the antibacterial ability of BL. Results showed the strongest inhibitory role of BL on C. perfringens (P < 0.05). Afterwards, 540 one-day-old yellow-feather broilers (32.7 ± 0.2 g) were randomly allocated into 3 groups, including CON group (basal diet), CP group (basal diet + 1 × 109 CFU C. perfringens in gavage), and BL + CP group (basal diet containing 7.5 × 106 CFU/g BL + 1 × 109 CFU C. perfringens in gavage). At d 70, broilers in the CP and BL + CP groups were treated with C. perfringens by continuously oral administration for 5 d. The experiment lasted for 75 d. The serum, immune organs, jejunal mucosa, and cecal contents were collected for analysis. In vivo experiment showed that BL supplementation markedly improved (P < 0.05) BW, ADG, thymus index, serum immunoglobins and antioxidases, reduced feed conversion ratio (FCR) and serum pro-inflammatory cytokines of C. perfringens-infected broilers. Furthermore, the increased jejunal injury and levels of pro-inflammatory cytokines, decreased gene expressions of tight junction proteins in the jejunal mucosa were significantly alleviated (P < 0.05) by BL. More importantly, the activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome was inhibited (P < 0.05) by BL to further attenuate jejunal damage. Besides, BL supplementation markedly increased (P < 0.05) the cecal isobutyric acid and isovaleric acid. Microbial analysis showed that BL changed the composition and relative abundances of microbiota in the cecal contents (P < 0.05), especially the short chain fatty acids (SCFAs)-producing bacteria including Eubacterium_coprostanoligenes_group, Megamonas, Faecalibacterium, and Lactobacillus, which further protected against C. perfringens-induced jejunal inflammation in broilers. Our study laid a theoretical basis for the application of probiotics in lessening C. perfringens-related diseases in poultry farming.

Calcineurin Inhibition Enhances Caenorhabditis Elegans Lifespan By Defecation Defects-Mediated Calorie Restriction And Nuclear Hormone Signaling, Priyanka Das, Alejandro Aballay, Jogender Singh

Faculty, Staff and Student Publications

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. …

Car-Redirected Natural Killer T Cells Demonstrate Superior Antitumor Activity To Car-T Cells Through Multimodal Cd1d-Dependent Mechanisms, Xin Zhou, Ying Wang, Zhangqi Dou, Gloria Delfanti, Ourania Tsahouridis, Caroline Marnata Pellegry, Manuela Zingarelli, Gatphan Atassi, Mark G Woodcock, Giulia Casorati, Paolo Dellabona, William Y Kim, Linjie Guo, Barbara Savoldo, Ageliki Tsagaratou, J Justin Milner, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells …

Synaptic Plasticity In The Injured Brain Depends On The Temporal Pattern Of Stimulation, Quentin S Fischer, Djanenkhodja Kalikulov, Gonzalo Viana Di Prisco, Carrie A Williams, Philip R Baldwin, Michael J Friedlander

Faculty, Staff and Students Publications

Neurostimulation protocols are increasingly used as therapeutic interventions, including for brain injury. In addition to the direct activation of neurons, these stimulation protocols are also likely to have downstream effects on those neurons' synaptic outputs. It is well known that alterations in the strength of synaptic connections (long-term potentiation, LTP; long-term depression, LTD) are sensitive to the frequency of stimulation used for induction; however, little is known about the contribution of the temporal pattern of stimulation to the downstream synaptic plasticity that may be induced by neurostimulation in the injured brain. We explored interactions of the temporal pattern and frequency …

Challenges And Rewards Of In Vivo Synaptic Density Imaging, And Its Application To The Study Of Depression, Ruth H Asch, Chadi G Abdallah, Richard E Carson, Irina Esterlis

Faculty, Staff and Students Publications

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a …

A Comparison Of The Diagnostic Capability Of Kato-Katz And Real-Time Pcr For The Assessment Of Treatment Efficacy Of Ivermectin And Albendazole Combination Against T Trichiura Infections, Gabriela Matamoros, Ana Sanchez, Ruben Cimino, Alejandro Krolewiecki, Rojelio Mejia

Faculty, Staff and Students Publications

BACKGROUND: Trichuris trichiura is humans' second most prevalent soil-transmitted helminth (STH) infection after Ascaris lumbricoides, affecting approximately 460 million people worldwide. Despite its sub-optimal sensitivity, especially in low prevalence and infection intensity settings, the modified Kato-Katz (K-K) is still recommended as a diagnostic method by the World Health organization (WHO) guidelines.

METHODOLOGY/PRINCIPAL FINDINGS: Within a randomized clinical trial (RCT) comprising four treatment arms with two different anthelmintics, the present study reports an important secondary research objective to determine the diagnostic agreement between K-K and real-time PCR evaluating treatment efficacy against T. trichiura. The parasitological results were analyzed, including cure rates …

Macrophage Iron Dyshomeostasis Promotes Aging-Related Renal Fibrosis, Lingzhi Wu, Hongchun Lin, Shaomin Li, Yuebo Huang, Yuxiang Sun, Shuangshuang Shu, Ting Luo, Tiantian Liang, Weiyan Lai, Jialing Rao, Zhaoyong Hu, Hui Peng

Faculty, Staff and Students Publications

Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular …

Effects Of Tranexamic Acid On Human Osteoblasts As Proxy For Fracture Healing, Alexander Abraham, D Nicole Meyers, William D Rieger, Ryan Anthony, Humberto Aparicio, Adam Y Park, James F Kellam, Catherine G Ambrose

Faculty, Staff and Student Publications

Objectives: To investigate the effect of tranexamic acid (TXA) through in vitro culture of primary human osteoblasts (HOB) and in vivo using an operative rat femur fracture model. It was hypothesized that there would not be any effect on fracture healing in both studies.

Methods: Primary HOBs were exposed to varying concentrations of TXA over different time periods. Cells were assessed for viability, metabolism, and mineralization. For the in vivo model, fractures were created in the femora of adult rats, exposed to either TXA or saline, and then assessed for healing at different time points. A modified radiographic union score …

Translation Of Monosynaptic Circuits Underlying Amygdala Fmri Neurofeedback Training, Lucas Trambaiolli, Chiara Maffei, Evan Dann, Claudinei Biazoli, Gleb Bezgin, Anastasia Yendiki, Suzanne Haber

Faculty, Staff and Student Publications

fMRI neurofeedback using autobiographical memory recall to upregulate the amygdala is associated with resting-state functional connectivity (rsFC) changes between the amygdala and the salience and default mode networks (SN and DMN, respectively). We hypothesize the existence of anatomical circuits underlying these rsFC changes. Using a cross-species brain parcellation, we identified in non-human primates locations homologous to the regions of interest (ROIs) from studies showing pre-to-post-neurofeedback changes in rsFC with the left amygdala. We injected bidirectional tracers in the basolateral, lateral, and central amygdala nuclei of adult macaques and used bright- and dark-field microscopy to identify cells and axon terminals in …

Cross-Species Striatal Hubs: Linking Anatomy To Resting-State Connectivity, Xiaolong Peng, Lucas R Trambaiolli, Eun Young Choi, Julia F Lehman, Gary Linn, Brian E Russ, Charles E Schroeder, Suzanne N Haber, Hesheng Liu

Faculty, Staff and Student Publications

Corticostriatal connections are essential for motivation, cognition, and behavioral flexibility. There is broad interest in using resting-state functional magnetic resonance imaging (rs-fMRI) to link circuit dysfunction in these connections with neuropsychiatric disorders. In this paper, we used tract-tracing data from non-human primates (NHPs) to assess the likelihood of monosynaptic connections being represented in rs-fMRI data of NHPs and humans. We also demonstrated that existing hub locations in the anatomical data can be identified in the rs-fMRI data from both species. To characterize this in detail, we mapped the complete striatal projection zones from 27 tract-tracer injections located in the orbitofrontal …

White Matter And Latency Of Visual Evoked Potentials During Maturation: A Miniature Pig Model Of Adolescent Development, Peter Kochunov, L Elliot Hong, Ann Summerfelt, Si Gao, P Leon Brown, Matthew Terzi, Ashley Acheson, Marty G Woldorff, Els Fieremans, Ali Abdollahzadeh, Korrapati V Sathyasaikumar, Sarah M Clark, Robert Schwarcz, Paul D Shepard, Greg I Elmer

Faculty, Staff and Student Publications

Background: Continuous myelination of cerebral white matter (WM) during adolescence overlaps with the formation of higher cognitive skills and the onset of many neuropsychiatric disorders. We developed a miniature-pig model of adolescent brain development for neuroimaging and neurophysiological assessment during this critical period. Minipigs have gyroencephalic brains with a large cerebral WM compartment and a well-defined adolescence period.

Methods: Eight Sinclair™ minipigs (Sus scrofa domestica) were evaluated four times during weeks 14-28 (40, 28 and 28 days apart) of adolescence using monocular visual stimulation (1 Hz)-evoked potentials and diffusion MRI (dMRI) of WM. The latency for the pre-positive 30 ms …

The Evolving Pathophysiology Of Tbi And The Advantages Of Temporally-Guided Combination Therapies, Laura Zima, Anthony N Moore, Paul Smolen, Nobuhide Kobori, Brian Noble, Dustin Robinson, Kimberly N Hood, Ryota Homma, Amar Al Mamun, John B Redell, Pramod K Dash

Faculty, Staff and Student Publications

Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over …

Loss-Of-Function In Rbbp5 Results In A Syndromic Neurodevelopmental Disorder Associated With Microcephaly, Yue Huang, Kristy L Jay, Alden Yen-Wen Huang, Jijun Wan, Sharayu V Jangam, Odelia Chorin, Annick Rothschild, Ortal Barel, Milena Mariani, Maria Iascone, Han Xue, Undiagnosed Diseases Network, Jing Huang, Cyril Mignot, Boris Keren, Virginie Saillour, Annelise Y Mah-Som, Stephanie Sacharow, Farrah Rajabi, Carrie Costin, Shinya Yamamoto, Oguz Kanca, Hugo J Bellen, Jill A Rosenfeld, Christina G S Palmer, Stanley F Nelson, Michael F Wangler, Julian A Martinez-Agosto

Faculty, Staff and Students Publications

PURPOSE: Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 and has not been implicated in human disease.

METHODS: We identify 5 unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and 2 missense variants were identified in probands with neurodevelopmental symptoms, including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models.

RESULTS: Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the …

Xenomake: A Pipeline For Processing And Sorting Xenograft Reads From Spatial Transcriptomic Experiments, Benjamin S Strope, Katherine E Pendleton, William Z Bowie, Gloria V Echeverria, Qian Zhu

Faculty, Staff and Students Publications

SUMMARY: Xenograft models are attractive models that mimic human tumor biology and permit one to perturb the tumor microenvironment and study its drug response. Spatially resolved transcriptomics (SRT) provides a powerful way to study the organization of xenograft models, but currently there is a lack of specialized pipeline for processing xenograft reads originated from SRT experiments. Xenomake is a standalone pipeline for the automated handling of spatial xenograft reads. Xenomake handles read processing, alignment, xenograft read sorting, and connects well with downstream spatial analysis packages. We additionally show that Xenomake can correctly assign organism-specific reads, reduce sparsity of data by …

Concurrent Optogenetic Motor Mapping Of Multiple Limbs In Awake Mice Reveals Cortical Organization Of Coordinated Movements, Nischal Khanal, Jonah A Padawer-Curry, Trevor Voss, Kevin A Schulte, Annie R Bice, Adam Q Bauer

2020-Current year OA Pubs

BACKGROUND: Motor mapping allows for determining the macroscopic organization of motor circuits and corresponding motor movement representations on the cortex. Techniques such as intracortical microstimulation (ICMS) are robust, but can be time consuming and invasive, making them non-ideal for cortex-wide mapping or longitudinal studies. In contrast, optogenetic motor mapping offers a rapid and minimally invasive technique, enabling mapping with high spatiotemporal resolution. However, motor mapping has seen limited use in tracking 3-dimensonal, multi-limb movements in awake animals. This gap has left open questions regarding the underlying organizational principles of motor control of coordinated, ethologically-relevant movements involving multiple limbs.

OBJECTIVE: Our …

Il-10r Inhibition Reprograms Tumor-Associated Macrophages And Reverses Drug Resistance In Multiple Myeloma, Jennifer Sun, Monica Shokeen, Barbara Muz, Kinan Alhallak, Chaelee Park, Berit Lubben, Yixuan Chen, Ola Adebayo, Hannah Bash, Sarah Kelley, Mark Fiala, Diane E Bender, Ravi Vij, Abdel Kareem Azab, Et Al.

2020-Current year OA Pubs

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In …

Attention-Based Cnn-Bilstm For Sleep State Classification Of Spatiotemporal Wide-Field Calcium Imaging Data, Xiaohui Zhang, Eric C Landsness, Hanyang Miao, Wei Chen, Michelle J Tang, Lindsey M Brier, Joseph P Culver, Jin-Moo Lee, Mark A Anastasio

2020-Current year OA Pubs

BACKGROUND: Wide-field calcium imaging (WFCI) with genetically encoded calcium indicators allows for spatiotemporal recordings of neuronal activity in mice. When applied to the study of sleep, WFCI data are manually scored into the sleep states of wakefulness, non-REM (NREM) and REM by use of adjunct EEG and EMG recordings. However, this process is time-consuming, invasive and often suffers from low inter- and intra-rater reliability. Therefore, an automated sleep state classification method that operates on spatiotemporal WFCI data is desired.

NEW METHOD: A hybrid network architecture consisting of a convolutional neural network (CNN) to extract spatial features of image frames and …

Mitochondrial Genome Analysis Across Different Populations Reveals The Intraspecific Variation And Phylogeography Of The Caucasian Soft Tick Relapsing Fever Vector, Ornithodoros (Pavlovskyella) Verrucosus (Ixodida: Argasidae), Serhii Filatov, Alexander R Kneubehl, Aparna Krishnavajhala, Giorgi Melashvili, Ana Tsitsishvili, Küşver Mamedova, Perot Saelao, Adalberto Á Pérez De León, Job E Lopez

Faculty, Staff and Students Publications

Territories in southern parts of Eastern Europe and in the Caucasus are endemic for tick-borne relapsing fever (TBRF), caused by Borrelia caucasica. This spirochete is transmitted exclusively by the bites of Ornithodoros verrucosus; however, the distribution and genetic diversity of the tick vector have not been explored. To address this, we performed a phylogeographic study of O. verrucosus specimens collected across a large geographic distribution. We sequenced and analyzed complete mitochondrial genomes of 54 individual O. verrucosus ticks representing 23 geographically diverse populations from Ukraine, Georgia, and Azerbaijan. We detected 47 unique haplotypes, with every collection site exhibiting distinct polymorphisms. …

Pdgf-Bb Overexpression In P53 Null Oligodendrocyte Progenitors Increases H3k27me3 And Induces Transcriptional Changes Which Favor Proliferation, Dennis Huang, Angeliki Mela, Natarajan V Bhanu, Benjamin A Garcia, Peter Canoll, Patrizia Casaccia

2020-Current year OA Pubs

Proneural gliomas are brain tumors characterized by enrichment of oligodendrocyte progenitor cell (OPC) transcripts and genetic alterations. In this study we sought to identify transcriptional and epigenetic differences between OPCs with Trp53 deletion and PDGF-BB overexpression (BB-p53n) and those carrying only p53 deletion (p53n). In culture, the BB-p53n OPCs display growth characteristics more similar to glioma cells than p53n OPCs. When injected in mouse brains, BB-p53n OPC form tumors, while the p53n OPCs do not. Unbiased histone proteomics and transcriptomic analysis on these OPC populations identified higher levels of the histone H3K27me3 mark and lower levels of the histone H4K20me3. …

Diclofenac Sensitizes Multi-Drug Resistant Acinetobacter Baumannii To Colistin, Fabiana Bisaro, Clay D. Jackson-Litteken, Jenna C. Mcguffey, Anna J. Hooppaw, Sophie Bodrog, Leila Jebeli, Manon Janet-Maitre, Juan C. Ortiz-Marquez, Tim Van Opijnen, Nichollas E. Scott, Gisela Di Venanzio, Mario F. Feldman

2020-Current year OA Pubs

Acinetobacter baumannii causes life-threatening infections that are becoming difficult to treat due to increasing rates of multi-drug resistance (MDR) among clinical isolates. This has led the World Health Organization and the CDC to categorize MDR A. baumannii as a top priority for the research and development of new antibiotics. Colistin is the last-resort antibiotic to treat carbapenem-resistant A. baumannii. Not surprisingly, reintroduction of colistin has resulted in the emergence of colistin-resistant strains. Diclofenac is a non-steroidal anti-inflammatory drug used to treat pain and inflammation associated with arthritis. In this work, we show that diclofenac sensitizes colistin-resistant A. baumannii clinical strains …

Bcl-Xl Is Translocated To The Nucleus Via Ctbp2 To Epigenetically Promote Metastasis, Tiantian Zhang, Sha Li, Yingcai Adrian Tan, Xiang Chen, Cheryl Zhang, Zhengming Chen, Bikash Mishra, Joseph Hyungjoon Na, Soyoung Choi, Sandra J Shin, Priyadarshan Damle, Kranthi Kumar Chougoni, Steven R Grossman, Dunrui Wang, Xuejun Jiang, Yi Li, Erika Hissong, Yao-Tseng Chen, Jenny Z Xiang, Yi-Chieh Nancy Du

Faculty, Staff and Students Publications

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and …

Transcriptomic And Epigenomic Signatures Distinguish High- And Low-Risk Endotypes For Liver Tumor Development, Sandra L Grimm, Tia Talley, Rahul K Jangid, Amrit Koirala, Micah B Castillo, Preethi H Gunaratne, Cristian Coarfa, Cheryl L Walker

Faculty, Staff and Students Publications

The epigenome is a target for environmental exposures and a potential determinant of inter-individual differences in response. In genetically identical C57Bl/6 mice exposed from gestation to weaning to the endocrine-disrupting chemical (EDC) tributyltin (TBT), hepatic tumor development later in life varied across multiple cohorts over time and depending on sex and diet. In one cohort where approximately half of TBT-exposed male mice developed liver tumors at 10 months (Katz et al. Hepatic tumor formation in adult mice developmentally exposed to organotin, Environmental Health Perspectives, 128 (1), 17010, 2020), transcriptomic (RNA-seq) and epigenomic (ChIP-seq) profiling was performed on blood and liver …

Trade-Offs In A Reef-Building Coral After Six Years Of Thermal Acclimation, Anna Roik, Marlene Wall, Melina Dobelmann, Samuel Nietzer, Anna Fiesinger, Miriam Reverter, David Brefeld, Peter J Schupp, Matthew Jackson, Marie Rutsch, Julia Strahl

School of Biological and Marine Sciences

There is growing evidence that reef-building corals can acclimate to novel and challenging thermal conditions. However, potential trade-offs that accompany acclimation remain largely unexplored. We investigated physiological trade-offs in colonies of a globally abundant coral species (Pocillopora acuta) that were acclimated ex situ to an elevated temperature of 31 °C (i.e., 1 °C above their bleaching threshold) for six years. By comparing them to conspecifics maintained at a cooler temperature, we found that the energy storage of corals was prioritized over skeletal growth at the elevated temperature. This was associated with the formation of higher density skeletons, lower calcification rates …

An Ancient Ecospecies Of Helicobacter Pylori, Elise Tourrette, Roberto C Torres, Sarah L Svensson, Takashi Matsumoto, Muhammad Miftahussurur, Kartika Afrida Fauzia, Ricky Indra Alfaray, Ratha-Korn Vilaichone, Vo Phuoc Tuan, Helicobacter Genomics Consortium, Difei Wang, Abbas Yadegar, Lisa M Olsson, Zhemin Zhou, Yoshio Yamaoka, Kaisa Thorell, Daniel Falush

Faculty, Staff and Students Publications

Helicobacter pylori disturbs the stomach lining during long-term colonization of its human host, with sequelae including ulcers and gastric cancer1,2. Numerous H. pylori virulence factors have been identified, showing extensive geographic variation1. Here we identify a ‘Hardy’ ecospecies of H. pylori that shares the ancestry of ‘Ubiquitous’ H. pylori from the same region in most of the genome but has nearly fixed single-nucleotide polymorphism differences in 100 genes, many of which encode outer membrane proteins and host interaction factors. Most Hardy strains have a second urease, which uses iron as a cofactor rather than …

Solid Tumour-Induced Systemic Immunosuppression Involves Dichotomous Myeloid-B Cell Interactions, Xiaoxin Hao, Yichao Shen, Jun Liu, Angela Alexander, Ling Wu, Zhan Xu, Liqun Yu, Yang Gao, Fengshuo Liu, Hilda L Chan, Che-Hsing Li, Yunfeng Ding, Weijie Zhang, David G Edwards, Nan Chen, Azadeh Nasrazadani, Naoto T Ueno, Bora Lim, Xiang H-F Zhang

Faculty, Staff and Students Publications

Solid tumours induce systemic immunosuppression that involves myeloid and T cells. B cell-related mechanisms remain relatively understudied. Here we discover two distinct patterns of tumour-induced B cell abnormality (TiBA; TiBA-1 and TiBA-2), both associated with abnormal myelopoiesis in the bone marrow. TiBA-1 probably results from the niche competition between pre-progenitor-B cells and myeloid progenitors, leading to a global reduction in downstream B cells. TiBA-2 is characterized by systemic accumulation of a unique early B cell population, driven by interaction with excessive neutrophils. Importantly, TiBA-2-associated early B cells foster the systemic accumulation of exhaustion-like T cells. Myeloid and B cells from …

Blocking Il-17a Signaling Decreases Lung Inflammation And Improves Alveolarization In Experimental Bronchopulmonary Dysplasia, Meagan Goates, Amrit Shrestha, Shyam Thapa, Matthew Bettini, Roberto Barrios, Binoy Shivanna

Faculty, Staff and Students Publications

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of preterm infants that is associated with life-long morbidities. Inflammatory insults contribute to BPD pathogenesis. Although the proinflammatory cytokine, IL-17a, plays a role in various neonatal inflammatory disorders, its role in BPD pathogenesis is unclear. To test the hypothesis that blocking IL-17a signaling decreases lipopolysaccharide (LPS)-mediated experimental BPD in neonatal mice, wild-type mice were injected intraperitoneally with phosphate-buffered saline or LPS during the saccular lung developmental phase. Pulmonary IL-17a expression was determined by enzyme-linked immunosorbent assay and by flow cytometry. LPS-injected mice had higher pulmonary IL-17a protein levels and IL-17a

Pkc-Mediated Phosphorylation Governs The Stability And Function Of Celf1 As A Driver Of Emt In Breast Epithelial Cells, Shebna Massey, Natee Kongchan, Yang Gao, Arindam Chaudhury, Emuejevoke Olokpa, Jason Karch, Anna Malovannaya, Chonghui Cheng, Xiang Zhang, Joel R Neilson

Faculty, Staff and Students Publications

Epithelial to mesenchymal transition (EMT) is believed to be a principal factor contributing to cancer metastasis. The post-transcriptional and post-translational mechanisms underlying EMT are comparatively underexplored. We previously demonstrated that the CELF1 RNA binding protein is necessary and sufficient to drive the EMT of breast epithelial cells, and that the relative protein expression of CELF1 in this context was dictated at the post-translational level. Here, we elucidate the mechanism of this regulation. Mass spectrometric analysis of CELF1 isolated from mesenchymal MCF-10A cells identified multiple sites of serine and threonine phosphorylation on the protein, correlating with the increased stability of this …

Limitations And Potential Of Κor Biased Agonists For Pain And Itch Management, Amal El Daibani, Manish K Madasu, Ream Al-Hasani, Tao Che

2020-Current year OA Pubs

The concept of ligand bias is based on the premise that different agonists can elicit distinct responses by selectively activating the same receptor. These responses often determine whether an agonist has therapeutic or undesirable effects. Therefore, it would be highly advantageous to have agonists that specifically trigger the therapeutic response. The last two decades have seen a growing trend towards the consideration of ligand bias in the development of ligands to target the κ-opioid receptor (κOR). Most of these ligands selectively favor G-protein signaling over β-arrestin signaling to potentially provide effective pain and itch relief without adverse side effects associated …

Evidence Of Human Bourbon Virus Infections, North Carolina, Usa, Diana L Zychowski, Gayan Bamunuarachchi, Scott P Commins, Ross M Boyce, Adrianus C M Boon

2020-Current year OA Pubs

Bourbon virus is a tickborne virus that can cause human disease. Cases have been reported in Kansas, Oklahoma, and Missouri, USA. We identified Bourbon virus-specific neutralizing antibodies in patients from North Carolina. Bourbon virus infections are likely more common than previously thought, highlighting the need for improved diagnostics and surveillance.

Biallelic Loss-Of-Function Variants In Ubap1l And Nonsyndromic Retinal Dystrophies, Ehsan Ullah, Siying Lin, Jiaxiong Lu, Chelsea Bender, Andrew R Webster, Samantha Malka, Savita Madhusudhan, Emma Rees, Denise Williams, Aime R Agather, Catherine A Cukras, Robert B Hufnagel, Rui Chen, Laryssa A Huryn, Gavin Arno, Bin Guan

Faculty, Staff and Students Publications

Importance: Inherited retinal dystrophies (IRDs) present a challenge in clinical diagnostics due to their pronounced genetic heterogeneity. Despite advances in next-generation sequencing (NGS) technologies, a substantial portion of the genetic basis underlying IRDs remains elusive. Addressing this gap seems important for gaining insights into the genetic landscape of IRDs, which may help improve diagnosis and prognosis and develop targeted therapies in the future.

Objective: To provide a clinical and molecular characterization of 6 patients with IRDs with biallelic disease-causing variants in a novel candidate IRD disease gene.

Design, setting, and participants: This multicenter case series study included 6 patients with …