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Dicer1 Tumor Predisposition Syndrome: An Evolving Story Initiated With The Pleuropulmonary Blastoma, Iván A González, Douglas R Stewart, Kris Ann P Schultz, Amanda P Field, D Ashley Hill, Louis P Dehner

Open Access Publications

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation …

Mutation Of The Epha2 Tyrosine-Kinase Domain Dysregulates Cell Pattern Formation And Cytoskeletal Gene Expression In The Lens, Yuefang Zhou, Thomas M Bennett, Philip A Ruzycki, Alan Shiels

Open Access Publications

Genetic variations in ephrin type-A receptor 2 (EPHA2) have been associated with inherited and age-related forms of cataract in humans. Here, we have characterized the eye lens phenotype and transcript profile of germline

Genetic Characterization, Current Model Systems And Prognostic Stratification In Pax Fusion-Negative Vs. Pax Fusion-Positive Rhabdomyosarcoma, Carina A Dehner, Amy E Armstrong, Marielle Yohe, Jack F Shern, Angela C Hirbe

Open Access Publications

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (

Antibiotic-Induced Disturbances Of The Gut Microbiota Result In Accelerated Breast Tumor Growth, Alastair M Mckee, Katherine N Weilbaecher, Et Al

Open Access Publications

The gut microbiota's function in regulating health has seen it linked to disease progression in several cancers. However, there is limited research detailing its influence in breast cancer (BrCa). This study found that antibiotic-induced perturbation of the gut microbiota significantly increases tumor progression in multiple BrCa mouse models. Metagenomics highlights the common loss of several bacterial species following antibiotic administration. One such bacteria,

Intestinal Antiviral Signaling Is Controlled By Autophagy Gene Epg5 Independent Of The Microbiota, Sanghyun Lee, Gowri Kalugotla, Harshad Ingle, Rachel Rodgers, Yating Wang, Yuhao Li, Nicolette R Borella, Hongju Deng, Lindsay Droit, Ryan Hill, Stefan T Peterson, Chandni Desai, Dylan Lawrence, Megan T Baldridge, Et Al

Open Access Publications

Mutations in the macroautophagy/autophagy gene

Neuropathic Pain: Biomolecular Intervention And Imaging Via Targeting Microglia Activation, Aijun Ji, Jinbin Xu

Open Access Publications

Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying symptoms of suffering in many conditions and the life quality of NP patient is seriously affected. Due to complex causes, the effects of clinical treatments have been very unsatisfactory. Many experts have found that neuron-microglia interaction plays an essential role in NP occurrence and development. Therefore, the activation of microglia, related inflammatory mediators and molecular and cellular signaling pathways have become the focus of NP research. With the help of modern functional imaging technology, advanced pre-and clinical studies have been carried out and NP …

Signaling Through Retinoic Acid Receptors Is Essential For Mammalian Uterine Receptivity And Decidualization, Yan Yin, Meade E. Haller, Sangappa B. Chadchan, Ramakrishna Kommagani, Liang Ma

Open Access Publications

Retinoic acid (RA) signaling has long been speculated to regulate embryo implantation, because many enzymes and proteins responsible for maintaining RA homeostasis and transducing RA signals are tightly regulated in the endometrium during this critical period. However, due to a lack of genetic data, it was unclear whether RA signaling is truly required for implantation and which specific RA signaling cascades are at play. Herein we utilize a genetic murine model that expresses a dominant-negative form of RA receptor (RAR) specifically in female reproductive organs to show that functional RA signaling is fundamental to female fertility, particularly implantation and decidualization. …

Racial Disparities In Modifiable Risk Factors And Statin Usage In Black Patients With Familial Hypercholesterolemia, Anandita Agarwala, Nathan Bekele, Elena Deych, Michael W Rich, Aliza Hussain, Laney K Jones, Amy C Sturm, Karen Aspry, Elizabeth Nowak, Zahid Ahmad, Christie M Ballantyne, Anne C Goldberg

Open Access Publications

Background Black men and women are at higher risk for, and suffer greater morbidity and mortality from, atherosclerotic cardiovascular disease (ASCVD) compared with adults of European Ancestry (EA). Black patients with familial hypercholesterolemia are at particularly high risk for ASCVD complications because of lifelong exposure to elevated levels of low-density-lipoprotein cholesterol. Methods and Results This retrospective study analyzed ASCVD prevalence and risk factors in 808 adults with heterozygous familial hypercholesterolemia from 5 US-based lipid clinics, and compared findings in Black versus EA patients. Multivariate logistic regression models were used to determine the strongest predictors of ASCVD as a function of …

Phagocytes Produce Prostaglandin E2 In Response To Cytosolic Listeria Monocytogenes, Courtney E. Mcdougal, Zachary T. Morrow, Tighe Christopher, Seonyoung Kim, Drake Carter, David M. Stevenson, Daniel Amador-Noguez, Mark J. Miller, John-Demian Sauer

Open Access Publications

Listeria monocytogenes is an intracellular bacterium that elicits robust CD8+ T-cell responses. Despite the ongoing development of L. monocytogenes-based platforms as cancer vaccines, our understanding of how L. monocytogenes drives robust CD8+ T-cell responses remains incomplete. One overarching hypothesis is that activation of cytosolic innate pathways is critical for immunity, as strains of L. monocytogenes that are unable to access the cytosol fail to elicit robust CD8+ T-cell responses and in fact inhibit optimal T-cell priming. Counterintuitively, however, activation of known cytosolic pathways, such as the inflammasome and type I IFN, lead to impaired immunity. Conversely, production of prostaglandin E2 …

Endothelial Fgf Signaling Is Protective In Hypoxia-Induced Pulmonary Hypertension, Kel Vin Woo, Isabel Y Shen, Carla J Weinheimer, Attila Kovacs, Jessica Nigro, Chieh-Yu Lin, Murali Chakinala, Derek E Byers, David M Ornitz

Open Access Publications

Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition …

Memory-Like Differentiation Enhances Nk Cell Responses To Melanoma, Nancy D Marin, Bradley A Krasnick, Michelle Becker-Hapak, Leah Conant, Simon P Goedegebuure, Melissa M Berrien-Elliott, Keenan J Robbins, Jennifer A Foltz, Mark Foster, Pamela Wong, Celia C Cubitt, Jennifer Tran, Christopher B Wetzel, Miriam Jacobs, Alice Y Zhou, David Russler-Germain, Lynne Marsala, Timothy Schappe, Ryan C Fields, Todd A Fehniger

Open Access Publications

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined.

EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK …

Interplay Of Trypanosome Lytic Factor And Innate Immune Cells In The Resolution Of Cutaneous Leishmania Infection, Jyoti Pant, Marie Samanovic, Maria T. Nelson, Mert K. Keceli, Joseph Verdi, Stephen M. Beverley, Jayne Raper

Open Access Publications

Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei, to which it confers sterile immunity. We previously showed that TLF could act against an intracellular pathogen Leishmania, and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are …

Evaluation Of Admission Chest X-Ray Findings In Patients With Respiratory Infection During The Covid-19 Pandemic, Dimitrios Velissaris, Maria Lagadinou, Themistoklis Paraskevas, Eleousa Oikonomou, Vasileios Karamouzos, Fotios Sampsonas, Markos Marangos, Menelaos Karanikolas

Open Access Publications

AIMS: To evaluate the prevalence of X-ray findings in hospitalized patients requiring hospitalization with suspected Coronavirus disease 2019 (COVID-19) infection and potential differences in the laboratory values and clinical outcomes related to the presence of abnormal chest X-ray (CXR) findings.

METHODS:

RESULTS:

CONCLUSION: CXR is a routine examination in all patients with symptoms of lower respiratory tract disease and its findings relate to in-hospital mortality and PaO

Efficacy And Safety Of Belimumab In Paediatric And Adult Patients With Systemic Lupus Erythematosus: An Across-Study Comparison, Hermine Brunner, Carlos Abud-Mendoza, Masaaki Mori, Clarissa Pilkington, Reema Syed, Syuji Takei, Diego Viola, Richard Furie, Sandra Navarra, Fengchun Zhang, Damon Bass, Gina Eriksson, Anne Hammer, Beulah Ji, Mohamed Okily, David Roth, Holly Quasny, Nicolino Ruperto

Open Access Publications

OBJECTIVE: To assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).

METHODS: We performed across-study comparisons of patients with active SLE who received belimumab or placebo, plus standard therapy, in PLUTO (paediatric phase II) and BLISS-52, BLISS-76, BLISS-NEA and EMBRACE (adult phase III). Analysed efficacy data included Week 52 SLE Responder Index (SRI)-4 response rate (EMBRACE: SRI with modified Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) proteinuria scoring (SRI-S2K)); SRI-4 response rate (EMBRACE: SRI-S2K) according to baseline disease activity indicators (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity …

Lung Epithelial Signaling Mediates Early Vaccine-Induced Cd4 + T Cell Activation And Mycobacterium Tuberculosis Control, Shibali Das, Nancy D Marin, Ekaterina Esaulova, Mushtaq Ahmed, Amanda Swain, Bruce A Rosa, Makedonka Mitreva, Javier Rangel-Moreno, Mihai G Netea, Luis B Barreiro, Maziar Divangahi, Maxim N Artyomov, Deepak Kaushal, Shabaana A Khader

Open Access Publications

Tuberculosis (TB) is one of the leading causes of death due to a single infectious agent. The development of a TB vaccine that induces durable and effective immunity to Mycobacterium tuberculosis (

Vesicular Stomatitis Virus Chimeras Expressing The Oropouche Virus Glycoproteins Elicit Protective Immune Responses In Mice, Sarah Hulsey Stubbs, Marjorie Cornejo Pontelli, Nischay Mishra, Changhong Zhou, Juliano De Paula Souza, Rosa Maria Mendes Viana, W Ian Lipkin, David M Knipe, Eurico Arruda, Sean P J Whelan

Open Access Publications

Oropouche virus (OROV) infection of humans is associated with a debilitating febrile illness that can progress to meningitis or encephalitis. First isolated from a forest worker in Trinidad and Tobago in 1955, the arbovirus OROV has since been detected throughout the Amazon basin with an estimated 500,000 human infections over 60 years. Like other members of the family

Critical Care Service Delivery Across Healthcare Systems In Low-Income And Low-Middle-Income Countries: Protocol For A Systematic Review, Andrew George Lim, Nicole Benzoni, Et Al

Open Access Publications

INTRODUCTION: Critical care in low-income and low-middle income countries (LLMICs) is an underdeveloped component of the healthcare system. Given the increasing growth in demand for critical care services in LLMICs, understanding the current capacity to provide critical care is imperative to inform policy on service expansion. Thus, our aim is to describe the provision of critical care in LLMICs with respect to patients, providers, location of care and services and interventions delivered.

METHODS AND ANALYSIS: We will search PubMed/MEDLINE, Web of Science and EMBASE for full-text original research articles available in English describing critical care services that specify the location …

Sars-Cov-2 Infection Of The Pancreas Promotes Thrombofibrosis And Is Associated With New-Onset Diabetes, Mirza Muhammad Fahd Qadir, Manika Bhondeley, Wandy Beatty, Dina D Gaupp, Lara A Doyle-Meyers, Tracy Fischer, Ishitri Bandyopadhyay, Robert V Blair, Rudolf Bohm, Jay Rappaport, Eric Lazartigues, Richard S Vander Heide, Jay K Kolls, Xuebin Qin, Franck Mauvais-Jarvis

Open Access Publications

Evidence suggests an association between severe acute respiratory syndrome-cornavirus-2 (SARS-CoV-2) infection and the occurrence of new-onset diabetes. We examined pancreatic expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), the cell entry factors for SARS-CoV-2, using publicly available single-cell RNA sequencing data sets, and pancreatic tissue from control male and female nonhuman primates (NHPs) and humans. We also examined SARS-CoV-2 immunolocalization in pancreatic cells of SARS-CoV-2-infected NHPs and patients who had died from coronavirus disease 2019 (COVID-19). We report expression of ACE2 in pancreatic islet, ductal, and endothelial cells in NHPs and humans. In pancreata from SARS-CoV-2-infected …

Evaluation Of Total Body Weight Versus Adjusted Body Weight Liposomal Amphotericin B Dosing In Obese Patients, Michelle H Ting, Andrej Spec, Scott T Micek, David J Ritchie, Tamara Krekel

Open Access Publications

Liposomal amphotericin B (LAmB) is used for various fungal infections, but it is unclear which dosing weight to use in obese patients. The purpose of this study was to compare clinical outcomes of adjusted body weight (adjBW) versus total body weight (TBW) dosing of LAmB. This single-center, retrospective cohort study included patients who received LAmB for definitive therapy and whose TBW exceeded 120% of their ideal body weight (IBW). Analyses were conducted for 3 mg/kg for adjBW versus TBW and 5 mg/kg for adjBW versus TBW. A total of 238 patients were included. For the 68 patients who received LAmB …

Modulation Of The Effects Of Class Ib Antiarrhythmics On Cardiac Nav1.5-Encoded Channels By Accessory Navβ Subunits, Wandi Zhu, Wei Wang, Paweorn Angsutararux, Rebecca L. Mellor, Lori L. Isom, Jeanne M. Nerbonne, Jonathan R. Silva

Open Access Publications

Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib …

Taspase1 Orchestrates Fetal Liver Hematopoietic Stem Cell And Vertebrae Fates By Cleaving Tfiia, Hidetaka Niizuma, Adam C. Searleman, Shugaku Takeda, Scott A. Armstrong, Christopher Y. Park, Emily H. Cheng, James J. Hsieh

Open Access Publications

Taspase1, a highly conserved threonine protease encoded by TASP1, cleaves nuclear histone-modifying factors and basal transcription regulators to orchestrate diverse transcription programs. Hereditary loss-of-function mutation of TASP1 has recently been reported in humans as resulting in an anomaly complex syndrome, which manifests with hematological, facial, and skeletal abnormalities. Here, we demonstrate that Taspase1-mediated cleavage of TFIIAα-β, rather than of MLL1 or MLL2, in mouse embryos was required for proper fetal liver hematopoiesis and correct segmental identities of the axial skeleton. Homozygous genetic deletion of Taspase1 disrupted embryonic hematopoietic stem cell self-renewal and quiescence states and axial skeleton fates. Strikingly, mice …

Efficient Crispr/Cas9 Mutagenesis For Neurobehavioral Screening In Adult Zebrafish, Dana Shaw, Mayssa Mokalled

Open Access Publications

Adult zebrafish are widely used to interrogate mechanisms of disease development and tissue regeneration. Yet, the prospect of large-scale genetics in adult zebrafish has traditionally faced a host of biological and technical challenges, including inaccessibility of adult tissues to high-throughput phenotyping and the spatial and technical demands of adult husbandry. Here, we describe an experimental pipeline that combines high-efficiency CRISPR/Cas9 mutagenesis with functional phenotypic screening to identify genes required for spinal cord repair in adult zebrafish. Using CRISPR/Cas9 dual-guide ribonucleic proteins, we show selective and combinatorial mutagenesis of 17 genes at 28 target sites with efficiencies exceeding 85% in adult …

Modern Acinetobacter Baumannii Clinical Isolates Replicate Inside Spacious Vacuoles And Egress From Macrophages, Gabriela Sycz, Gisela Di Venanzio, Jesus S. Distel, Mariana G. Sartorio, Nguyen-Hung Le, Nichollas E. Scott, Wandy L. Beatty, Mario F. Feldman

Open Access Publications

Multidrug-resistant Acinetobacter baumannii infections are increasing at alarming rates. Therefore, novel antibiotic-sparing treatments to combat these A. baumannii infections are urgently needed. The development of these interventions would benefit from a better understanding of this bacterium's pathobiology, which remains poorly understood. A. baumannii is regarded as an extracellular opportunistic pathogen. However, research on Acinetobacter has largely focused on common lab strains, such as ATCC 19606, that have been isolated several decades ago. These strains exhibit reduced virulence when compared to recently isolated clinical strains. In this work, we demonstrate that, unlike ATCC 19606, several modern A. baumannii clinical isolates, including …

Air Pollution Particulate Matter Exposure And Chronic Cerebral Hypoperfusion And Measures Of White Matter Injury In A Murine Model, Qinghai Liu, Michelle Connor, Et Al

Open Access Publications

BACKGROUND: Exposure to ambient air pollution particulate matter (PM) is associated with increased risk of dementia and accelerated cognitive loss. Vascular contributions to cognitive impairment are well recognized. Chronic cerebral hypoperfusion (CCH) promotes neuroinflammation and blood-brain barrier weakening, which may augment neurotoxic effects of PM.

OBJECTIVES: This study examined interactions of nanoscale particulate matter (nPM; fine particulate matter with aerodynamic diameter

METHODS: nPM was collected using a particle sampler near a Los Angeles, California, freeway. Mice were exposed to 10 wk of reaerosolized nPM or filtered air (FA) for 150 h. CCH was induced by BCAS surgery. Mice (C57BL/6J males) …

Decreased Antiviral Immune Response Within The Central Nervous System Of Aged Mice Is Associated With Increased Lethality Of West Nile Virus Encephalitis, Kristen E Funk, Artem D Arutyunov, Pritesh Desai, James P White, Allison L Soung, Sarah F Rosen, Michael S Diamond, Robyn S Klein

Open Access Publications

West Nile virus (WNV) is an emerging pathogen that causes disease syndromes ranging from a mild flu-like illness to encephalitis. While the incidence of WNV infection is fairly uniform across age groups, the risk of lethal encephalitis increases with advanced age. Prior studies have demonstrated age-related, functional immune deficits that limit systemic antiviral immunity and increase mortality; however, the effect of age on antiviral immune responses specifically within the central nervous system (CNS) is unknown. Here, we show that aged mice exhibit increased peripheral organ and CNS tissue viral burden, the latter of which is associated with alterations in activation …

An Intranasal Vaccine Durably Protects Against Sars-Cov-2 Variants In Mice, Ahmed O Hassan, Swathi Shrihari, Matthew J Gorman, Baoling Ying, Dansu Yaun, Saravanan Raju, Rita E Chen, Igor P Dmitriev, Elena Kashentseva, Lucas J Adams, Colin Mann, Meredith E Davis-Gardner, Mehul S Suthar, Pei-Yong Shi, Erica Ollmann Saphire, Daved H Fremont, David T Curiel, Galit Alter, Michael S Diamond

Open Access Publications

SARS-CoV-2 variants that attenuate antibody neutralization could jeopardize vaccine efficacy. We recently reported the protective activity of an intranasally administered spike protein-based chimpanzee adenovirus-vectored vaccine (ChAd-SARS-CoV-2-S) in animals, which has advanced to human trials. Here, we assessed its durability, dose response, and cross-protective activity in mice. A single intranasal dose of ChAd-SARS-CoV-2-S induced durably high neutralizing and Fc effector antibody responses in serum and S-specific IgG and IgA secreting long-lived plasma cells in the bone marrow. Protection against a historical SARS-CoV-2 strain was observed across a 100-fold vaccine dose range and over a 200-day period. At 6 weeks or 9 …

Predicting Mortality Risk For Preterm Infants Using Deep Learning Models With Time-Series Vital Sign Data, Jiarui Feng, Jennifer Lee, Zachary A Vesoulis, Fuhai Li

Open Access Publications

Mortality remains an exceptional burden of extremely preterm birth. Current clinical mortality prediction scores are calculated using a few static variable measurements, such as gestational age, birth weight, temperature, and blood pressure at admission. While these models do provide some insight, numerical and time-series vital sign data are also available for preterm babies admitted to the NICU and may provide greater insight into outcomes. Computational models that predict the mortality risk of preterm birth in the NICU by integrating vital sign data and static clinical variables in real time may be clinically helpful and potentially superior to static prediction models. …

Systematic Analysis Of Sars-Cov-2 Infection Of An Ace2-Negative Human Airway Cell, Maritza Puray-Chavez, Kyle M Lapak, Jennifer L Elliott, Dhaval P Bhatt, Ria Jasuja, Dana Q Lawson, Keanu Davis, Paul W Rothlauf, Zhuoming Liu, Nakyung Lee, Kasyap Tenneti, Jenna E Eschbach, Christian Shema Mugisha, Hung R Vuong, Laura A Vanblargan, Adam L Bailey, Michael S Diamond, Sean P J Whelan, Amjad Horani, Steven L Brody, Dennis Goldfarb, M Ben Major, Sebla B Kutluay, Et Al

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains …

A Deep Learning Algorithm To Translate And Classify Cardiac Electrophysiology, Parya Aghasafari, Pei-Chi Yang, Divya C. Kernik, Kazuho Sakamoto, Yasunari Kanda, Junko Kurokawa, Igor Vorobyov, Colleen E. Clancy

Open Access Publications

The development of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been a critical in vitro advance in the study of patient-specific physiology, pathophysiology, and pharmacology. We designed a new deep learning multitask network approach intended to address the low throughput, high variability, and immature phenotype of the iPSC-CM platform. The rationale for combining translation and classification tasks is because the most likely application of the deep learning technology we describe here is to translate iPSC-CMs following application of a perturbation. The deep learning network was trained using simulated action potential (AP) data and applied to classify cells into the drug-free …

Npc1 Regulates The Distribution Of Phosphatidylinositol 4-Kinases At Golgi And Lysosomal Membranes, Candice Kutchukian, Oscar Vivas, Maria Casas, Julia G Jones, Scott A Tiscione, Sergi Simó, Daniel S Ory, Rose E Dixon, Eamonn J Dickson

Open Access Publications

Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIβ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P …