Digital Commons Network^™

Human Plcg2 Haploinsufficiency Results In A Novel Natural Killer Cell Immunodeficiency, Joshua B Alinger, Emily M Mace, Justin R Porter, Annelise Y Mah-Som, Allyssa L Daugherty, Stephanie Li, Allison A Throm, Jeanette T Pingel, Nermina Saucier, Albert Yao, Ivan K Chinn, James R Lupski, Mohammad Ehlayel, Michael Keller, Greg R Bowman, Megan A Cooper, Jordan S Orange, Anthony R French

Faculty, Staff and Students Publications

Background:

Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in NK cells, lymphocytes which recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK cell and B cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date.

Objective:

We aimed to identify the genetic cause of NK cell immunodeficiency in two families, and herein describe the functional consequences of two novel loss-of-function …

Phenotypic And Functional Assessment Of Two Novel Kcnq2 Gain-Of-Function Variants Y141n And G239s And Effects Of Amitriptyline Treatment, Allan Bayat, Stefano Iavarone, Francesco Miceli, Anne V Jakobsen, Katrine M Johannesen, Marina Nikanorova, Rafal Ploski, Krystyna Szymanska, Robert Flamini, Edward C Cooper, Sarah Weckhuysen, Maurizio Taglialatela, Rikke S Møller

Faculty, Staff and Students Publications

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell …

Neutrophil-Derived Activin-A Moderates Their Pro-Netotic Activity And Attenuates Collateral Tissue Damage Caused By Influenza A Virus Infection, Georgios Divolis, Evgenia Synolaki, Athanasia Doulou, Ariana Gavriil, Christina C Giannouli, Anastasia Apostolidou, Martyn L Foster, Martin M Matzuk, Panagiotis Skendros, Ioanna-Evdokia Galani, Paschalis Sideras

Faculty, Staff and Students Publications

BACKGROUND: Pre-neutrophils, while developing in the bone marrow, transcribe the Inhba gene and synthesize Activin-A protein, which they store and release at the earliest stage of their activation in the periphery. However, the role of neutrophil-derived Activin-A is not completely understood.

METHODS:To address this issue, we developed a neutrophil-specific Activin-A-deficient animal model (S100a8-Cre/Inhba fl/fl mice) and analyzed the immune response to Influenza A virus (IAV) infection. More specifically, evaluation of body weight and lung mechanics, molecular and cellular analyses of bronchoalveolar lavage fluids, flow cytometry and cell sorting of lung cells, as well as histopathological analysis of lung tissues, …

Developing A Pathway To Clinical Trials For Cacna1a-Related Epilepsies: A Patient Organization Perspective, Pangkong M Fox, Sunitha Malepati, Lisa Manaster, Elsa Rossignol, Jeffrey L Noebels

Faculty, Staff and Students Publications

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function …

Ultradian Rhythms In Accelerometric And Autonomic Data Vary Based On Seizure Occurrence In Paediatric Epilepsy Patients, Solveig Vieluf, Sarah Cantley, Vaishnav Krishnan, Tobias Loddenkemper

Faculty, Staff and Students Publications

Ultradian rhythms are physiological oscillations that resonate with period lengths shorter than 24 hours. This study examined the expression of ultradian rhythms in patients with epilepsy, a disease defined by an enduring seizure risk that may vary cyclically. Using a wearable device, we recorded heart rate, body temperature, electrodermal activity and limb accelerometry in patients admitted to the paediatric epilepsy monitoring unit. In our case–control design, we included recordings from 29 patients with tonic–clonic seizures and 29 non-seizing controls. We spectrally decomposed each signal to identify cycle lengths of interest and compared average spectral power- and period-related markers between groups. …

A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment Of Drug-Resistant Tuberculosis, Nika Zielinski, Dragos Baiceanu, Antonela Dragomir, Jan Heyckendorf, Elmira Ibraim, Niklas Köhler, Christoph Leschczyk, Cristina Popa, Andrea Rachow, Jens Sachsenweger, Patricia Sanchez Carballo, Dagmar Schaub, Hajo Zeeb, Begna Tulu, Andrew R Dinardo, Christoph Lange, Maja Reimann

Faculty, Staff and Students Publications

BACKGROUND: Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation.

OBJECTIVE: We aimed to identify and validate a host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy.

METHODS: Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was …

Divergent Responses Of Human Intestinal Organoid Monolayers Using Commercial In Vitro Cytotoxicity Assays, Miranda A Lewis, Ketki Patil, Khalil Ettayebi, Mary K Estes, Robert L Atmar, Sasirekha Ramani

Faculty, Staff and Students Publications

In vitro models, such as primary cells and continuous cell lines routinely used for evaluating drug candidates, have limitations in their translational relevance to human diseases. Organotypic cultures are increasingly being used to assess therapeutics for various cancers and infectious diseases. Monitoring drug cytotoxicity in cell cultures is crucial in drug development, and several commercially available kits for cytotoxicity assessment offer distinct advantages and limitations. Given the complexity of organoid cultures, including donor-driven variability, we investigated drug-treated, tissue stem cell-derived human intestinal organoid responses with commonly used cell cytotoxicity assay kits. Using seven different compounds, we compared the cytotoxicity assay …

Treatment Guidelines For Hyponatremia: Stay The Course, Richard H Sterns, Helbert Rondon-Berrios, Horacio J Adrogué, Tomas Berl, Volker Burst, David M Cohen, Mirjam Christ-Crain, Martin Cuesta, Guy Decaux, Michael Emmett, Aoife Garrahy, Fabrice Gankam-Kengne, John K Hix, Ewout J Hoorn, Kamel S Kamel, Nicolaos E Madias, Alessandro Peri, Julie Refardt, Mitchell H Rosner, Mark Sherlock, Stephen M Silver, Alain Soupart, Chris J Thompson, Joseph G Verbalis

Faculty, Staff and Students Publications

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting …

Achieving Surgical, Obstetric, Trauma, And Anesthesia (Sota) Care For All In South Asia, Siddhesh Zadey, Shirish Rao, Isha Gondi, Natalie Sheneman, Chaitrali Patil, Anveshi Nayan, Himanshu Iyer, Arti Raj Kumar, Arun Prasad, G Allen Finley, Chellapuram Raja Krishna Prasad, Chintamani, Dhananjaya Sharma, Dhruva Ghosh, Gnanaraj Jesudian, Irum Fatima, Jogi Pattisapu, Justin Sangwook Ko, Lovenish Bains, Mashal Shah, Mohammed Shadrul Alam, Narmada Hadigal, Naveen Malhotra, Nilmini Wijesuriya, Prateek Shukla, Sadaf Khan, Sunil Pandya, Tariq Khan, Tashi Tenzin, Venkat Raja Hadiga, Daniel Peterson

Faculty, Staff and Students Publications

South Asia is a demographically crucial, economically aspiring, and socio-culturally diverse region in the world. The region contributes to a large burden of surgically-treatable disease conditions. A large number of people in South Asia cannot access safe and affordable surgical, obstetric, trauma, and anesthesia (SOTA) care when in need. Yet, attention to the region in Global Surgery and Global Health is limited. Here, we assess the status of SOTA care in South Asia. We summarize the evidence on SOTA care indicators and planning. Region-wide, as well as country-specific challenges are highlighted. We also discuss potential directions-initiatives and innovations-toward addressing these …

Vaccines Against Extraintestinal Pathogenic Escherichia Coli (Expec): Progress And Challenges, Ling Qiu, Dylan Chirman, Justin R Clark, Yikun Xing, Haroldo Hernandez Santos, Ellen E Vaughan, Anthony W Maresso

Faculty, Staff and Students Publications

The emergence of antimicrobial resistance (AMR) is a principal global health crisis projected to cause 10 million deaths annually worldwide by 2050. While the Gram-negative bacteria Escherichia coli is commonly found as a commensal microbe in the human gut, some strains are dangerously pathogenic, contributing to the highest AMR-associated mortality. Strains of E. coli that can translocate from the gastrointestinal tract to distal sites, called extraintestinal E. coli (ExPEC), are particularly problematic and predominantly afflict women, the elderly, and immunocompromised populations. Despite nearly 40 years of clinical trials, there is still no vaccine against ExPEC. One reason for this is …

Activation Of Mechanoreceptor Piezo1 Inhibits Enteric Neuronal Growth And Migration, Chioma Moneme, Oluyinka O Olutoye, Michał F Sobstel, Yuwen Zhang, Xinyu Zhou, Jacob L Kaminer, Britney A Hsu, Chengli Shen, Arabinda Mandal, Hui Li, Ling Yu, Swathi Balaji, Sundeep G Keswani, Lily S Cheng

Faculty, Staff and Students Publications

INTRODUCTION: Dysfunction of the enteric nervous system (ENS) is linked to a myriad of gastrointestinal (GI) disorders. Piezo1 is a mechanosensitive ion channel found throughout the GI tract, but its role in the ENS is largely unknown. We hypothesize that Piezo1 plays an important role in the growth and development of the ENS.

METHODS: Enteric neural crest-derived progenitor cells (ENPC) were isolated from adult mouse intestine and propagated in culture as neurospheres. ENPC-derived neurons were then subject to

RESULTS: Though stretch did not cause upregulation of Piezo1 expression in enteric neurons, both stretch and Piezo1 activation produced similar alterations in …

Pre-Clinical Protective Potentials Of Carica Papaya Constituents In Experimentally Induced Anemia, Hassan Abdulsalam Adewuyi, Adamu Yusuf Kabiru, Hadiza Lami Muhammad, Halimat Yusuf Lukman, Mayowa Solomon Owolabi, Ibrahim Jonathan, Ahmed M El-Gazzar, Mohamed H Mahmoud, Gaber El-Saber Batiha, Bashir Lawal

Faculty, Staff and Students Publications

OBJECTIVE: Anemia is a pathological condition characterized by reduced oxygen bioavailability and/or changes in hematological parameters. This study investigated the anti-anemic activities of

METHOD: Twenty-seven rats were randomized into nine groups of three rats as follows; group 1 was the normal (non-induced) group, 2-9 were anemic rats administered 1 mL distilled water, standard drug (3 mg/kg body weight (bw) ferrous sulphate), 100, 300 and 500 mg/kg bw of crude methanolic extract of CP (CMECP) of the leaf and 100, 300 and 500 mg/kg bw of CMECP of the seed respectively in the first stage of the study. In the second …

Revolutionizing Psoriasis Topical Treatment: Enhanced Efficacy Through Ceramide/Phospholipid Composite Cerosomes Co-Delivery Of Cyclosporine And Dithranol: In-Vitro, Ex-Vivo, And In-Vivo Studies, Sammar Fathy Elhabal, Nashwa Abdelaal, Saeed A S Al-Zuhairy, Mohamed Fathi Mohamed Elrefai, Mohamed Mansour Khalifa, Mohammad Ahmad Khasawneh, Ahmed Mohsen Elsaid Hamdan, Passant M Mohie, Rania A Gad, Soad L Kabil, Mohamed Kandeel El-Ashery, Bhaskara R Jasti, Nahla A Elzohairy, Nehal Elfar, Tayseer Elnawawy, Fatma E Hassan, Mohamed Ahmed El-Nabarawi

Faculty, Staff and Students Publications

PURPOSE: Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential. …

Ketogenic Diet In Treating Sepsis-Related Acquired Weakness: Is It Friend Or Foe?, Yanmei Miao, Leiyu Xie, Shaolin Chen, Xiaoming Zhang, Wenjie Liu, Peng Xie

Faculty, Staff and Students Publications

Background: Sepsis is the body's extreme response to an infection leading to organ dysfunction. Sepsis-related acquired weakness (SAW), a critical illness closely related to metabolic disorders, is characterized by generalized sepsis-induced skeletal muscle weakness, mainly manifesting as symmetrical atrophy of respiratory and limb muscles. Muscle accounts for 40% of the body's total mass and is one of the major sites of glucose and energy absorption. Diet affects skeletal muscle metabolism, which further impacts physiology and signaling pathways. The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that has shown benefits in patients with a variety of neuromuscular disorders. Patients with …

Cutting Edge Of Genetically Modified Pigs Targeting Complement Activation For Xenotransplantation, Qin Sun, Si-Yuan Song, Jiabao Ma, Danni Li, Yiping Wang, Zhengteng Yang, Yi Wang

Faculty, Staff and Students Publications

In the quest to address the critical shortage of donor organs for transplantation, xenotransplantation stands out as a promising solution, offering a more abundant supply of donor organs. Yet, its widespread clinical adoption remains hindered by significant challenges, chief among them being immunological rejection. Central to this issue is the role of the complement system, an essential component of innate immunity that frequently triggers acute and chronic rejection through hyperacute immune responses. Such responses can rapidly lead to transplant embolism, compromising the function of the transplanted organ and ultimately causing graft failure. This review delves into three key areas of …

Ginkgo Biloba For Tardive Dyskinesia And Plasma Mnsod Activity: Association With Mnsod Ala-9val Variant: A Randomized, Double-Blind Trial, Dongmei Wang, Yang Tian, Jiajing Chen, Rongrong Zhu, Jiaxin Li, Huixia Zhou, Dachun Chen, Li Wang, Thomas R Kosten, Xiang-Yang Zhang

Faculty, Staff and Students Publications

Background: Excessive free radicals are implicated in the pathophysiology of tardive dyskinesia (TD), and Ginkgo biloba extract (EGb761) scavenges free radicals, thereby enhancing antioxidant enzymes such as mitochondrial manganese superoxide dismutase (MnSOD). This study examined whether EGb761 treatment would improve TD symptoms and increase MnSOD activity, particularly in TD patients with specific MnSOD Val-9Ala genotype.

Methods: An EGb761 (240 mg/day) 12-week double-blind clinical trial with 157 TD patients was randomized. The severity of TD was measured by the Abnormal Involuntary Movement Scale (AIMS) and plasma MnSOD activity was assayed before and after 12 weeks of treatment. Further, in an expanded …

The Mars Complex: A Critical Mediator Of Immune Regulation And Homeostasis, Sharon Bright Amanya, Damilola Oyewole-Said, Keenan J Ernste, Nalini Bisht, Arnav Murthy, Jonathan Vazquez-Perez, Vanaja Konduri, William K Decker

Faculty, Staff and Students Publications

Over the course of evolution, many proteins have undergone adaptive structural changes to meet the increasing homeostatic regulatory demands of multicellularity. Aminoacyl tRNA synthetases (aaRS), enzymes that catalyze the attachment of each amino acid to its cognate tRNA, are such proteins that have acquired new domains and motifs that enable non-canonical functions. Through these new domains and motifs, aaRS can assemble into large, multi-subunit complexes that enhance the efficiency of many biological functions. Moreover, because the complexity of multi-aminoacyl tRNA synthetase (mARS) complexes increases with the corresponding complexity of higher eukaryotes, a contribution to regulation of homeostatic functions in multicellular …

The Zebrafish As A Potential Model For Vaccine And Adjuvant Development, Peter J Hotez, Maria Elena Bottazzi, Nelufa Yesmin Islam, Jungsoon Lee, Jeroen Pollet, Cristina Poveda, Ulrich Strych, Syamala Rani Thimmiraju, Nestor L Uzcategui, Leroy Versteeg, Daniel Gorelick

Faculty, Staff and Students Publications

Introduction: Zebrafishes represent a proven model for human diseases and systems biology, exhibiting physiological and genetic similarities and having innate and adaptive immune systems. However, they are underexplored for human vaccinology, vaccine development, and testing. Here we summarize gaps and challenges.

Areas covered: Zebrafish models have four potential applications: 1) Vaccine safety: The past successes in using zebrafishes to test xenobiotics could extend to vaccine and adjuvant formulations for general safety or target organs due to the zebrafish embryos' optical transparency. 2) Innate immunity: The zebrafish offers refined ways to examine vaccine effects through signaling via Toll-like or NOD-like receptors …

Choice Of Adjuvant And Antigen Composition Alters The Immunogenic Profile Of A Sars-Cov-2 Subunit Vaccine, William R Lykins, Jeroen Pollet, Jessica A White, Brian Keegan, Leroy Versteeg, Ulrich Strych, Wen-Hsiang Chen, Raodoh Mohamath, Gabi Ramer-Denisoff, Sierra Reed, Samuel Beaver, Alana Gerhardt, Emily A Voigt, Mark A Tomai, Robert Sitrin, Robert K M Choy, Frederick J Cassels, Peter J Hotez, Maria Elena Bottazzi, Christopher B Fox

Faculty, Staff and Students Publications

Introduction: Since their introduction, adjuvanted recombinant subunit vaccines against COVID-19 have played a pivotal role in protecting global populations. Optimizing the immune response's quality, amplitude, and durability to these vaccines depends on the appropriate adjuvant choice and dose in combination with the selected antigen.

Methods: Here, we employed a preclinical mouse model to study the adaptive humoral and cellular immune responses to a SARS-CoV-2 receptor binding domain (RBD) antigen formulated with one of four different immune agonists [GLA, 3M-052, CpG-1826 (CpG), and dmLT], in combination with one of two different immune-stimulating formulations, a stabilized squalene emulsion (SE) or aluminum hydroxide …

Liver Directed Adeno-Associated Viral Vectors To Treat Metabolic Disease, Marcel A Chuecos, William R Lagor

Faculty, Staff and Students Publications

The liver is the metabolic center of the body and an ideal target for gene therapy of inherited metabolic disorders (IMDs). Adeno-associated viral (AAV) vectors can deliver transgenes to the liver with high efficiency and specificity and a favorable safety profile. Recombinant AAV vectors contain only the transgene cassette, and their payload is converted to non-integrating circular double-stranded DNA episomes, which can provide stable expression from months to years. Insights from cellular studies and preclinical animal models have provided valuable information about AAV capsid serotypes with a high liver tropism. These vectors have been applied successfully in the clinic, particularly …

Artificial Intelligence-Powered Discovery Of Small Molecules Inhibiting Ctla-4 In Cancer, Navid Sobhani, Dana Rae Tardiel-Cyril, Dafei Chai, Daniele Generali, Jian-Rong Li, Jonathan Vazquez-Perez, Jing Ming Lim, Rachel Morris, Zaniqua N Bullock, Aram Davtyan, Chao Cheng, William K Decker, Yong Li

Faculty, Staff and Students Publications

BACKGROUND/OBJECTIVES: Checkpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.

SUBJECTS/METHODS: In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the …

Advances In The Clinical Application Of High-Throughput Proteomics, Miao Cui, Fei Deng, Mary L Disis, Chao Cheng, Lanjing Zhang

Faculty, Staff and Students Publications

High-throughput proteomics has become an exciting field and a potential frontier of modern medicine since the early 2000s. While significant progress has been made in the technical aspects of the field, translating proteomics to clinical applications has been challenging. This review summarizes recent advances in clinical applications of high-throughput proteomics and discusses the associated challenges, advantages, and future directions. We focus on research progress and clinical applications of high-throughput proteomics in breast cancer, bladder cancer, laryngeal squamous cell carcinoma, gastric cancer, colorectal cancer, and coronavirus disease 2019. The future application of high-throughput proteomics will face challenges such as varying protein …

The Next-Generation Dna Vaccine Platforms And Delivery Systems: Advances, Challenges And Prospects, Bowen Lu, Jing Ming Lim, Boyue Yu, Siyuan Song, Praveen Neeli, Navid Sobhani, Pavithra K, Srinivasa Reddy Bonam, Rajendra Kurapati, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

Vaccines have proven effective in the treatment and prevention of numerous diseases. However, traditional attenuated and inactivated vaccines suffer from certain drawbacks such as complex preparation, limited efficacy, potential risks and others. These limitations restrict their widespread use, especially in the face of an increasingly diverse range of diseases. With the ongoing advancements in genetic engineering vaccines, DNA vaccines have emerged as a highly promising approach in the treatment of both genetic diseases and acquired diseases. While several DNA vaccines have demonstrated substantial success in animal models of diseases, certain challenges need to be addressed before application in human subjects. …

A Mini Chalk Talk Workshop For Fourth-Year Medical Students: Facilitating The Transition From Student To Resident Educator, Trevor Jamison, Zaven Sargsyan, Uma Ayyala, Stephanie Sherman, Holland Kaplan

Faculty, Staff and Students Publications

INTRODUCTION: There is increasing recognition that incoming interns benefit from formal training in teaching skills during UME. Many medical schools have capstone courses well suited for teacher-training content. Mini chalk talks (MCTs) are a common clinical teaching modality requiring a variety of teaching skills. We developed a session for our institution's capstone course in which students prepared and delivered MCTs.

METHODS: The voluntary flipped classroom session was offered virtually in 2021 and in person in 2022. Before the session, students reviewed materials on creating effective MCTs and developed and practiced their own MCT. During the 90-minute session, students presented their …

Β2-Glycoprotein I Promotes The Clearance Of Circulating Mitochondria, Swapan Kumar Dasgupta, Jahnavi Gollamudi, Stefanie Rivera, Ross A Poche, Rolando E Rumbaut, Perumal Thiagarajan

Faculty, Staff and Students Publications

β2-glycoprotein I (β2-Gp1) is a cardiolipin-binding plasma glycoprotein. It is evolutionarily conserved from invertebrates, and cardiolipin-bound β2-Gp1 is a major target of antiphospholipid antibodies seen in autoimmune disorders. Cardiolipin is almost exclusively present in mitochondria, and mitochondria are present in circulating blood. We show that β2-Gp1 binds to cell-free mitochondria (CFM) in the circulation and promotes its phagocytosis by macrophages at physiological plasma concentrations. Exogenous CFM had a short circulation time of less than 10 minutes in mice. Following infusion of CFM, β2-Gp1-deficient mice had significantly higher levels of transfused mitochondria at 5 minutes (9.9 ± 6.4 pg/ml versus 4.0 …

Preclinical Evaluation Of A Novel Antibiotic-Eluting Bioenvelope For Cied Infection Prevention, Zerelda Esquer Garrigos, John N Catanzaro, Daniel Deegan, Ji Zhang, M Rizwan Sohail

Faculty, Staff and Students Publications

The risk of infection remains a significant concern with cardiovascular implantable electronic devices, necessitating the development of new strategies. This study explores the efficacy of a novel antibiotic-eluting biologic envelope designed to mitigate infection risk through localized antibiotic delivery while preserving the regenerative properties of biological matrix. Antibiotics, rifampin and minocycline, are released through polymer discs, ensuring extended drug release. Utilizing an established model of infection in a New Zealand White rabbit, the study assessed performance against Gram-positive bacterial strains, including common pathogens such as Staphylococcus aureus and S. epidermidis associated with CIED infections, and Gram-negative bacterial strains. Results demonstrated …

Should Targeted Temperature Management Be Used In Cardiogenic Shock Patients? Systematic Review And Meta-Analysis, Adam Nieborek, Jerzy R Ladny, Milosz J Jaguszewski, Andrea Denegri, Aleksandra Sikora, Szymon Pucylo, Aleksandra Gasecka, Michal Pruc, Ivan Savytsky, Lukasz Szarpak

Faculty, Staff and Students Publications

BACKGROUND: Therapeutic hypothermia, or targeted temperature management (TTM), is a strategy of reducing the core body temperature of survivors of sudden cardiac arrest, cardiogenic shock (CS) or stroke. Therefore, a systematic literature review and meta-analysis were performed to tackle the question about whether the implementation of TTM is actually beneficial for patients with CS.

METHODS: Study was designed as a systematic review and meta-analysis. PubMed, Cochrane Library, Web of Science and Scopus were searched from these databases inception to July 17, 2022. Eligible studies were those comparing TTM and non-TTM treatment in CS patients. Data were pooled with the Mantel-Haenszel …

The Maternal Gut Microbiome In Pregnancy: Implications For The Developing Immune System, Omry Koren, Liza Konnikova, Petter Brodin, Indira U Mysorekar, Maria Carmen Collado

Faculty, Staff and Students Publications

The gut microbiome has important roles in host metabolism and immunity, and microbial dysbiosis affects human physiology and health. Maternal immunity and microbial metabolites during pregnancy, microbial transfer during birth, and transfer of immune factors, microorganisms and metabolites via breastfeeding provide critical sources of early-life microbial and immune training, with important consequences for human health. Only a few studies have directly examined the interactions between the gut microbiome and the immune system during pregnancy, and the subsequent effect on offspring development. In this Review, we aim to describe how the maternal microbiome shapes overall pregnancy-associated maternal, fetal and early neonatal …

Triobp Modulates Β-Catenin Signaling By Regulation Of Mir-29b In Idiopathic Pulmonary Fibrosis, Lan Wang, Wenyu Zhao, Cong Xia, Shuaichen Ma, Zhongzheng Li, Ningdan Wang, Linke Ding, Yaxuan Wang, Lianhui Cheng, Huibing Liu, Juntang Yang, Yajun Li, Ivan Rosas, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited …

Co-Transmitting Interneurons In The Mouse Olfactory Bulb Regulate Olfactory Detection And Discrimination, Ariel M Lyons-Warren, Evelyne K Tantry, Elizabeth H Moss, Mikhail Y Kochukov, Benjamin D W Belfort, Joshua Ortiz-Guzman, Zachary Freyberg, Benjamin R Arenkiel

Faculty, Staff and Students Publications

Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial short-axon cells in the olfactory bulb release both dopamine and γ-aminobutyric acid (GABA), yet the specific targets of these neurotransmitters and their respective roles in olfaction have remained unknown. Here, we implement intersectional genetics in mice to selectively block GABA or dopamine release from superficial short-axon cells to identify their distinct cellular targets, impact on circuit function, and behavioral contribution of each neurotransmitter toward olfactory behaviors. We provide functional and anatomical evidence for divergent superficial short-axon cell signaling onto downstream neurons …