Medicine and Health Sciences Commons^™

Multicilia Dynamically Transduce Sonic Hedgehog Signaling To Regulate Choroid Plexus Functions, Suifang Mao, Michael J Holtzman, Et Al.

2020-Current year OA Pubs

The choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or intraflagellar transport yields neonatal hydrocephalus, at least in part due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Sonic Hedgehog (Shh) signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by the Smoothened (Smo)/Gαi/cyclic AMP (cAMP) pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and …

Spatial And Seasonal Dynamics Of Mosquito Species In Harris County, Texas, Highlight Risk Of Arbovirus Introduction And Transmission, Morgan Jibowu, Maximea Vigilant, Andre Luis Costa-Da-Silva, Alisa Nelson, Heather T Essigmann, Eric L Brown, Sarah M Gunter

Faculty, Staff and Student Publications

Mosquito-borne diseases pose a significant public health threat, particularly in densely populated urban areas. Climate change, urbanization, and global connectivity have fueled the expansion of mosquitoes and their associated pathogens, increasing the disease burden. Harris County, Texas, is among the most vulnerable regions in the United States for mosquito-borne disease outbreaks, underscoring the critical need for localized insights into mosquito population dynamics to inform vector surveillance and control strategies. This study provides a comprehensive analysis of the population dynamics of mosquito species in Harris County by exploring their species composition, spatial distribution, and seasonal patterns. Our findings reveal the extensive …

Rapid Laser Ablation-Based Fabrication Of High-Density Polymer Microwell Arrays For High-Throughput Cellular Studies, Desh Deepak Dixit, Kavya L Singampalli, Amit S Niyogi, Amanda Montoya, Alexandre Reuben, Peter B Lillehoj

Faculty, Staff and Student Publications

Polymer-based microwell platforms have garnered much interest due to their usefulness in culturing and analyzing small quantities of biological cells and spheroids. Existing methods for fabricating polymer microwell arrays involve complex fabrication processes and/or are limited in their ability to create dense arrays of very small (< 50 μm in diameter) microwells. Here, we present a simple and rapid technique for fabricating high-density arrays of microwells ranging from 20 to 160 μm in diameter on a variety of polymer substrates. In this approach, a polymer surface is ablated using a CO2 laser that is rastered over a stainless steel mesh, which serves as a shadow mask. A theoretical laser-polymer interaction model was developed for predicting the microwell volume based on the substrate properties and laser settings. Microwell volumes predicted by the model were within 5.4% of fabricated microwell volumes determined experimentally. Cellulose acetate microwell arrays fabricated using this technique were used to culture Lewis lung carcinoma cells expressing ovalbumin (LLC-OVA), which were maintained for up to 72 h with a negligible (< 5%) loss in viability. As a second proof of principle demonstration, LLC-OVA cells grown in microwell arrays were co-cultured with OT-I T cells and measurements of interferon gamma (IFN-γ), a marker for T cell activation, were performed which revealed a positive correlation between LLC-OVA cell-T cell interaction time and T cell activation. These two in vitro demonstrations showcase the capability of this technique in generating polymer microwell arrays for high-throughput cellular studies, including cell growth dynamics studies and cell interaction studies. Furthermore, we envision that these platforms can be used with different cell types and for other biological applications, such as spheroid formation and single cell analysis, …

Tissue-Resident Ccr2+ Macrophage Trem-1/3 Signaling Is Necessary For Monocyte And Neutrophil Recruitment To Injured Hearts, Yuriko Terada, Wenjun Li, Junedh M Amrute, Amit I Bery, Charles R Liu, Venkatrao Nunna, Christian Corbin Frye, Hao Dun, Andrew L Koenig, Hannah P Luehmann, Gyu Seong Heo, Macee C Owen, Alexander N Wein, Yongjian Liu, Jon H Ritter, Sumanth D Prabhu, Ruben G Nava, Andrew E Gelman, Marina Cella, Marco Colonna, Kory J Lavine, Daniel Kreisel

2020-Current year OA Pubs

Triggering receptor expressed on myeloid cells 1 (TREM-1) has been shown to amplify inflammatory signals, such as Toll-like receptor signaling, after infection and sterile injury. While previous studies have demonstrated that TREM-1 activation in circulating immune cells promotes injury, the role of TREM-1 signaling in tissue-resident cells in the context of sterile inflammation remains poorly understood. Here, we used a cardiac transplantation model to dissect how Trem1/3 expression on heart-resident cells regulates sterile inflammation. TREM-1 is expressed in heart-resident C-C chemokine receptor 2 (CCR2)

Ovarian-Specific Cyp17a1 Overexpression In Female Mice: A Novel Model Of Endogenous Testosterone Excess, Serene Joseph, Vaibhave Ubba, Zhiqiang Wang, Mingxiao Feng, Milan K Dsilva, Sofia Suero, Danielle Waheed, Nathaniel W Snyder, Xiaofeng Yang, Hong Wang, Joanne S Richards, Chemyong J Ko, Sheng Wu

Faculty, Staff and Students Publications

Excessive androgen levels can severely affect female health. However, most existing models of androgen excess rely on exogenous androgen administration, which does not fully capture the effect of elevated local ovarian testosterone on reproductive and metabolic functions. Here, we report the development of a novel hyperandrogenic mouse model, Cyp17TM-625, generated by combining CRISPR-Cas9 and a Tet-On doxycycline system to induce Cyp17A1 overexpression in ovarian theca-interstitial cells. As a result, Cyp17TM-625 mice exhibited significantly elevated Cyp17A1 messenger RNA and protein levels, accompanied by increased testosterone concentrations without alterations in basal levels of estradiol, progesterone, luteinizing hormone, or follicle-stimulating hormone. These mice …

Radial Glia Integrin Avb8 Regulates Cell Autonomous Microglial Tgfβ1 Signaling That Is Necessary For Microglial Identity, Gabriel Mckinsey, Nicolas Santander, Xiaoming Zhang, Kilian Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E. S. Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky, Thomas Arnold

Department of Medicine Faculty Papers

Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers …

Islet Single-Cell Transcriptomic Profiling During Obesity-Induced Beta Cell Expansion In Female Mice, Peter M Masschelin, Scott A Ochsner, Sean M Hartig, Neil J Mckenna, Aaron R Cox

Faculty, Staff and Student Publications

Targeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-body

Ppdpf: Preventing Kidney Disease Through Nad+, Shin-Ichiro Imai

2020-Current year OA Pubs

Researchers have discovered PPDPF, a critical cellular factor that controls NAD

Distinct Attentional Characteristics Of Neurons With Visual Feature Coding In The Primate Brain, Jie Zhang, Runnan Cao, Xiaocang Zhu, Huihui Zhou, Shuo Wang

2020-Current year OA Pubs

Visual attention and object recognition are two critical cognitive functions that shape our perception of the world. While these neural processes converge in the temporal cortex, the nature of their interactions remains largely unclear. Here, we systematically investigated the interplay between visual attention and stimulus feature coding by training macaques to perform a free-gaze visual search task with natural stimuli. Recording from a large number of units across multiple brain areas, we found that units exhibiting visual feature coding showed stronger attentional modulation of responses and spike-local field potential coherence than units without feature coding. Across brain areas, attention directed …

Protocol To Study Inter-Tissue Communication Between The Hypothalamus And White Adipose Tissue And Lifespan Using A Chemogenetic Approach In Aged Mice, Kyohei Tokizane, Shin-Ichiro Imai

2020-Current year OA Pubs

Here, we present a protocol for assessing the impact of a chemogenetic manipulation in a subpopulation of the hypothalamic neurons on aging and lifespan control using a mouse model developed specifically for this purpose. We describe steps for stereotaxic viral injection and assess inter-tissue communication between protein phosphatase 1 regulatory subunit 17 (Ppp1r17)-expressing neurons in the dorsomedial hypothalamus and white adipose tissue. We then detail procedures for lifespan measurements following chemogenetic manipulation in aged mice. For complete details on the use and execution of this protocol, please refer to Tokizane et al.

Dependence Of Mitochondrial Calcium Signalling And Dynamics On The Disaggregase, Clpb, Donato D'Angelo, Víctor H. Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R. Cupo, Hilda Delgado De La Herran, Giorgia Ghirardo, James Shorter, Ron A. Wevers, Saskia B. Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. …

Adipose Progenitor Cell-Derived Extracellular Vesicles Suppress Macrophage M1 Program To Alleviate Midlife Obesity, Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang

Children’s Nutrition Research Center Staff Publications

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs …

Dna Damage Response Signatures Are Associated With Frontline Chemotherapy Response And Routes Of Tumor Evolution In Extensive Stage Small Cell Lung Cancer, Benjamin B Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R Tyson, Kyle Concannon, Kavya Ramkumar, C Allison Stewart, Robert J Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V Heymach, Barzin Y Nabet, David S Shames, Carl M Gay, Lauren A Byers

Faculty, Staff and Student Publications

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.

Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is …

The Night's Watch: Exploring How Sleep Protects Against Neurodegeneration, Samira Parhizkar, David M Holtzman

2020-Current year OA Pubs

Sleep loss is often regarded as an early manifestation of neurodegenerative diseases given its common occurrence and link to cognitive dysfunction. However, the precise mechanisms by which sleep disturbances contribute to neurodegeneration are not fully understood, nor is it clear why some individuals are more susceptible to these effects than others. This review addresses critical unanswered questions in the field, including whether sleep disturbances precede or result from neurodegenerative diseases, the functional significance of sleep changes during the preclinical disease phase, and the potential role of sleep homeostasis as an adaptive mechanism enhancing resilience against cognitive decline and neurodegeneration.

Icos-Expressing Car-T Cells Mediate Durable Eradication Of Triple-Negative Breast Cancer And Metastasis, Shelley Herbrich, Mehdi Chaib, Padmanee Sharma

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes. In their recent study, Cao et al introduced a B7H3-specific chimeric antigen receptor (CAR)-T cell with constitutive inducible co-stimulator (ICOS) expression (ICOS-B7H3-CAR-T), which demonstrated eradication of TNBC, including metastases, in preclinical models. These CAR-T cells exploit the expression of ICOS ligand on TNBC cells, enhancing antitumor cytotoxicity through ICOS signaling. Compared with conventional B7H3-CAR-T cells, the ICOS-B7H3-CAR-T cells exhibited superior antitumor efficacy, increased cytokine secretion, and prolonged survival in xenograft murine models. This study highlights ICOS as a promising co-stimulatory molecule for improving CAR-T …

The Autophagy Protein Atg14 Safeguards Against Unscheduled Pyroptosis Activation To Enable Embryo Transport During Early Pregnancy, Pooja Popli, Arin K Oestreich, Vineet K Maurya, Marina N Rowen, Yong Zhang, Michael J Holtzman, Ramya Masand, John P Lydon, Shizuo Akira, Kelle Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Recurrent pregnancy loss, characterized by two or more failed clinical pregnancies, poses a significant challenge to reproductive health. In addition to embryo quality and endometrial function, proper oviduct function is also essential for successful pregnancy establishment. Therefore, structural abnormalities or inflammation resulting from infection in the oviduct may impede the transport of embryos to the endometrium, thereby increasing the risk of miscarriage. However, our understanding of the biological processes that preserve the oviductal cellular structure and functional integrity is limited. Here, we report that autophagy-related protein ATG14 plays a crucial role in maintaining the cellular integrity of the oviduct by …

Guanine Nucleotide Biosynthesis Blockade Impairs Mll Complex Formation And Sensitizes Leukemias To Menin Inhibition, Xiangguo Shi, Minhua Li, Zian Liu, Jonathan Tiessen, Yuan Li, Jing Zhou, Yudan Zhu, Swetha Mahesula, Qing Ding, Lin Tan, Mengdie Feng, Yuki Kageyama, Yusuke Hara, Jacob J Tao, Xuan Luo, Kathryn A Patras, Philip L Lorenzi, Suming Huang, Alexandra M Stevens, Koichi Takahashi, Ghayas C Issa, Md Abul Hassan Samee, Michalis Agathocleous, Daisuke Nakada

Faculty, Staff and Student Publications

Targeting the dependency of MLL-rearranged (MLLr) leukemias on menin with small molecule inhibitors has opened new therapeutic strategies for these poor-prognosis diseases. However, the rapid development of menin inhibitor resistance calls for combinatory strategies to improve responses and prevent resistance. Here we show that leukemia stem cells (LSCs) of MLLr acute myeloid leukemia (AML) exhibit enhanced guanine nucleotide biosynthesis, the inhibition of which leads to myeloid differentiation and sensitization to menin inhibitors. Mechanistically, targeting inosine monophosphate dehydrogenase 2 (IMPDH2) reduces guanine nucleotides and rRNA transcription, leading to reduced protein expression of LEDGF and menin. Consequently, the formation and chromatin binding …

The Autophagy Protein Atg14 Safeguards Against Unscheduled Pyroptosis Activation To Enable Embryo Transport During Early Pregnancy, Pooja Popli, Arin K Oestreich, Vineet K Maurya, Marina N Rowen, Yong Zhang, Michael J Holtzman, Ramya Masand, John P Lydon, Shizuo Akira, Kelle Moley, Ramakrishna Kommagani

2020-Current year OA Pubs

Recurrent pregnancy loss, characterized by two or more failed clinical pregnancies, poses a significant challenge to reproductive health. In addition to embryo quality and endometrial function, proper oviduct function is also essential for successful pregnancy establishment. Therefore, structural abnormalities or inflammation resulting from infection in the oviduct may impede the transport of embryos to the endometrium, thereby increasing the risk of miscarriage. However, our understanding of the biological processes that preserve the oviductal cellular structure and functional integrity is limited. Here, we report that autophagy-related protein ATG14 plays a crucial role in maintaining the cellular integrity of the oviduct by …

Mistargeted Retinal Axons Induce A Synaptically Independent Subcircuit In The Visual Thalamus Of Albino Mice, Sean Mccracken, Liam Mccoy, Ziyi Hu, Julie A Hodges, Katia Valkova, Philip R Williams, Josh L Morgan

2020-Current year OA Pubs

In albino mice and EphB1 knockout mice, mistargeted retinal ganglion cell axons form dense islands of axon terminals in the dorsal lateral geniculate nuclei (dLGN). The formation of these islands of retinal input depends on developmental patterns of spontaneous retinal activity. We reconstructed the microcircuitry of the activity-dependent islands and found that the boundaries of the island represent a remarkably strong segregation within retinogeniculate connectivity. We conclude that when sets of retinal input are established in the wrong part of the dLGN, the developing circuitry responds by forming a synaptically isolated subcircuit within the otherwise fully connected network. The fact …

Impact Of Co-Mutations And Transcriptional Signatures In Non-Small Cell Lung Cancer Patients Treated With Adagrasib In The Krystal-1 Trial, Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach

Faculty, Staff and Student Publications

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: …

Identification Of Lysosomal Lipolysis As An Essential Noncanonical Mediator Of Adipocyte Fasting And Cold-Induced Lipolysis, Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Et Al.

2020-Current year OA Pubs

Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. …

The Gain-Of-Function Ube3aq588e Variant Causes Angelman-Like Neurodevelopmental Phenotypes In Mice, Kellan P Weston, Anna M Gunelson, Susan E Maloney, Xia Ge, Jalin A Stelzer, Kwang-Soo Kim, Shylyn Collier, Marissa M Mindt, Megan J Agajanian, Michael B Major, Dennis Goldfarb, Kevin K Noguchi, Jason J Yi

2020-Current year OA Pubs

Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in disease phenotypes which differ from classic Angelman syndrome. However, these phenotypes are highly heterogeneous raising questions about the mechanistic basis of such phenotypic diversity. Here, we characterize a mouse model harboring a Ube3a

Superior Preclinical Efficacy Of Co-Treatment With Brg1/Brm And Flt3 Inhibitor Against Aml Cells With Flt3 Mutations, Warren Fiskus, Christopher P Mill, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Lauren B Flores, Sanam Loghavi, Xiaoping Su, Courtney D Dinardo, Kapil N Bhalla

Faculty, Staff and Student Publications

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells. Findings of present studies demonstrate that treatment with FHD-286 induces lethality in AML cells, regardless of sensitivity or resistance to …

Reprogramming Aerobic Metabolism Mitigates Streptococcus Pyogenes Tissue Damage In A Mouse Necrotizing Skin Infection Model, Wei Xu, Tara R Bradstreet, Zongsen Zou, Suzanne Hickerson, Yuan Zhou, Hongwu He, Brian T Edelson, Michael G Caparon

2020-Current year OA Pubs

Disease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host's disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the …

Tunneling Nanotube-Like Structures Regulate Distant Cellular Interactions During Heart Formation, Lianjie Miao, Yangyang Lu, Anika Nusrat, Guizhen Fan, Shaohua Zhang, Luqi Zhao, Chia-Ling Wu, Hongyan Guo, Trang Le Nu Huyen, Yi Zheng, Zhen-Chuan Fan, Weinian Shou, Robert J Schwartz, Yu Liu, Ashok Kumar, Haixin Sui, Irina I Serysheva, Alan R Burns, Leo Q Wan, Bin Zhou, Sylvia M Evans, Mingfu Wu

Faculty, Staff and Student Publications

In the developing mammalian heart, the endocardium and the myocardium are separated by so-called cardiac jelly. Communication between the endocardium and the myocardium is essential for cardiac morphogenesis. How membrane-localized receptors and ligands achieve interaction across the cardiac jelly is not understood. Working in developing mouse cardiac morphogenesis models, we used a variety of cellular, imaging, and genetic approaches to elucidate this question. We found that myocardium and endocardium interacted directly through microstructures termed tunneling nanotube-like structures (TNTLs). TNTLs extended from cardiomyocytes (CMs) to contact endocardial cells (ECs) directly. TNTLs transported cytoplasmic proteins, transduced signals between CMs and ECs, and …

Expression Of A Single Inhibitory Member Of The Ly49 Receptor Family Is Sufficient To License Nk Cells For Effector Functions, Sytse J Piersma, Shasha Li, Pamela Wong, Michael D Bern, Jennifer Poursine-Laurent, Li-Ping Yang, Diana L Beckman, Bijal A Parikh, Wayne M Yokoyama

2020-Current year OA Pubs

Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s …

High-Throughput Repurposing Screen Reveals Compounds With Activity Against Toxoplasma Gondii Bradyzoites, Taher Uddin, Jing Xia, Yong Fu, Case W Mcnamara, Arnab K Chatterjee, L David Sibley

2020-Current year OA Pubs

No abstract provided.

Cranial Radiation Disrupts Dopaminergic Signaling And Connectivity In The Mammalian Brain, Die Zhang, Riya Thomas, Thanh Thai Lam, Ines Veselinovic, David R Grosshans

Faculty, Staff and Student Publications

Cognitive impairment is a common and challenging side effect of cranial radiation therapy for brain tumors, though its precise mechanisms remain unclear. The mesocortical dopaminergic pathway, known to play a key role in cognitive function, is implicated in several neuropsychiatric disorders, yet its involvement in radiation-induced cognitive dysfunction is unexplored. Here, with using in vivo multi-electrode array recordings of both anesthetized and free-moving rats to monitor the firing activities of dopamine neurons in the ventral tegmental area (VTA) and local field potentials in both the prefrontal cortex (PFC) and VTA, as well as the immunofluorescence assays and western blotting, we …

Structure-Guided Design Of Partial Agonists At An Opioid Receptor, Balazs R Varga, Sarah M Bernhard, Amal El Daibani, Jhoan Aguilar, Kevin Appourchaux, Alexa Kouvelis, Amynah Pradhan, Susruta Majumdar, Tao Che, Et Al.

2020-Current year OA Pubs

Chronic pain and opioid overdose deaths highlight the need for non-addictive analgesics with novel mechanisms. The δ opioid receptor (δOR) is a promising target, as it lacks the respiratory depression associated with µ opioid receptor (µOR) agonists. However, early δOR full agonists caused seizures, limiting their clinical use. Partial δOR agonists may offer more controlled receptor activation than full agonists, but their development has been hindered by uncertainty regarding the molecular mechanism of partial agonism. Here we show that C6-Quino, a bitopic ligand developed through structure-based design, acts as a selective δOR partial agonist. Functional studies reveal that C6-Quino shows …

Control Of Clostridioides Difficile Virulence And Physiology By The Flagellin Homeostasis Checkpoint Flic-Fliw-Csra In The Absence Of Motility, Duolong Zhu, Katherine J Wozniak, Firas Midani, Shaohui Wang, Xingmin Sun, Robert A Britton

Faculty, Staff and Students Publications

Mutations affecting Clostridioides difficile flagellin (FliC) have been shown to be hypervirulent in animal models and display increased toxin production and alterations in central metabolism. The regulation of flagellin levels in bacteria is governed by a tripartite regulatory network involving fliC, fliW, and csrA, which creates a feedback system to regulate flagella production. Through genomic analysis of C. difficile clade 5 strains (non-motile), we identified they have jettisoned many of the genes required for flagellum biosynthesis yet retain the major flagellin gene fliC and regulatory gene fliW. We therefore investigated the roles of fliC, fliW …