Medical Specialties Commons^™

Heartworm Adulticide Treatment: A Tropical Perspective, Filipe Dantas-Torres, Jennifer Ketzis, Gabriela Pérez Tort, Andrei Daniel Mihalca, Gad Baneth, Domenico Otranto, Malaika Watanabe, Bui Khanh Linh, Tawin Inpankaew, Pablo Borrás, Sangaran Arumugam, Barend Louis Penzhorn, Adrian Patalinghug Ybañez, Peter Irwin, Rebecca J Traub

Faculty, Staff and Student Publications

Dirofilaria immitis (the canine heartworm) is widespread in the tropics, with prevalence surpassing 30% in high-risk areas. In addition to the suitable climatic conditions that favour mosquito abundance and filarial larva development, there is low compliance with the recommended year-round use of preventives in these transmission hotspots. This represents a major concern, considering that melarsomine (first-line heartworm adulticide) is unavailable in several tropical countries, resulting in the so-called slow-kill protocol being the only available adulticide treatment option. In this article, the members of TroCCAP (Tropical Council for Companion Animal Parasites) review the current distribution of heartworm in the tropics and …

Positive Selection Of Somatically Mutated Clones Identifies Adaptive Pathways In Metabolic Liver Disease, Zixi Wang, Shijia Zhu, Yuemeng Jia, Yunguan Wang, Naoto Kubota, Naoto Fujiwara, Ruth Gordillo, Cheryl Lewis, Min Zhu, Tripti Sharma, Lin Li, Qiyu Zeng, Yu-Hsuan Lin, Meng-Hsiung Hsieh, Purva Gopal, Tao Wang, Matt Hoare, Peter Campbell, Yujin Hoshida, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in nonmalignant tissues accumulate with age and injury, but whether these mutations are adaptive on the cellular or organismal levels is unclear. To interrogate genes in human metabolic disease, we performed lineage tracing in mice harboring somatic mosaicism subjected to nonalcoholic steatohepatitis (NASH). Proof-of-concept studies with mosaic loss of Mboat7, a membrane lipid acyltransferase, showed that increased steatosis accelerated clonal disappearance. Next, we induced pooled mosaicism in 63 known NASH genes, allowing us to trace mutant clones side by side. This in vivo tracing platform, which we coined MOSAICS, selected for mutations that ameliorate lipotoxicity, including mutant genes …

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Miceb, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Resolution Of Cisplatin-Induced Fatigue Does Not Require Endogenous Interleukin-10 In Male Mice, Kiersten Scott, Nabila Boukelmoune, Cullen Taniguchi, A Phillip West, Cobi J Heijnen, Robert Dantzer

Faculty, Staff and Student Publications

Based on previous results showing a pivotal role of endogenous interleukin-10 (IL-10) in the recovery from cisplatin-induced peripheral neuropathy, the present experiments were carried out to determine whether this cytokine plays any role in the recovery from cisplatin-induced fatigue in male mice. Fatigue was measured by decreased voluntary wheel running in mice trained to run in a wheel in response to cisplatin. Mice were treated with a monoclonal neutralizing antibody (IL-10na) administered intranasally during the recovery period to neutralize endogenous IL-10. In the first experiment, mice were treated with cisplatin (2.83 mg/kg/day) for five days and IL-10na (12 μg/day for …

Bridging Clinic And Wildlife Care With Ai-Powered Pan-Species Computational Pathology, Khalid Abduljabbar, Simon P Castillo, Katherine Hughes, Hannah Davidson, Amy M Boddy, Lisa M Abegglen, Lucia Minoli, Selina Iussich, Elizabeth P Murchison, Trevor A Graham, Simon Spiro, Carlo C Maley, Luca Aresu, Chiara Palmieri, Yinyin Yuan

Faculty, Staff and Student Publications

Cancers occur across species. Understanding what is consistent and varies across species can provide new insights into cancer initiation and evolution, with significant implications for animal welfare and wildlife conservation. We build a pan-species cancer digital pathology atlas (panspecies.ai) and conduct a pan-species study of computational comparative pathology using a supervised convolutional neural network algorithm trained on human samples. The artificial intelligence algorithm achieves high accuracy in measuring immune response through single-cell classification for two transmissible cancers (canine transmissible venereal tumour, 0.94; Tasmanian devil facial tumour disease, 0.88). In 18 other vertebrate species (mammalia = 11, reptilia = 4, aves …

Modelling Radiation Cancer Treatment With A Death-Rate Term In Ordinary And Fractional Differential Equations, Nicole Wilson, Corina S Drapaca, Heiko Enderling, Jimmy J Caudell, Kathleen P Wilkie

Faculty, Staff and Student Publications

Fractional calculus has recently been applied to the mathematical modelling of tumour growth, but its use introduces complexities that may not be warranted. Mathematical modelling with differential equations is a standard approach to study and predict treatment outcomes for population-level and patient-specific responses. Here, we use patient data of radiation-treated tumours to discuss the benefits and limitations of introducing fractional derivatives into three standard models of tumour growth. The fractional derivative introduces a history-dependence into the growth function, which requires a continuous death-rate term for radiation treatment. This newly proposed radiation-induced death-rate term improves computational efficiency in both ordinary and …

Saturated Fatty Acids Dampen The Immunogenicity Of Cancer By Suppressing Sting, Blake R Heath, Wang Gong, Hülya F Taner, Luke Broses, Kohei Okuyama, Wanqing Cheng, Max Jin, Zackary R Fitzsimonds, Andriana Manousidaki, Yuesong Wu, Shaoping Zhang, Haitao Wen, Steven B Chinn, Eric Bartee, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show …

Combined Inhibition Of Bcl-2 And Mcl-1 Overcomes Bax Deficiency-Mediated Resistance Of Tp53-Mutant Acute Myeloid Leukemia To Individual Bh3 Mimetics, Bing Z Carter, Po Yee Mak, Wenjing Tao, Edward Ayoub, Lauren B Ostermann, Xuelin Huang, Sanam Loghavi, Steffen Boettcher, Yuki Nishida, Vivian Ruvolo, Paul E Hughes, Phuong K Morrow, Torsten Haferlach, Steven Kornblau, Muharrem Muftuoglu, Michael Andreeff

Faculty, Staff and Student Publications

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced …

A Small Secreted Protein Nicol Regulates Lumicrine-Mediated Sperm Maturation And Male Fertility, Daiji Kiyozumi, Kentaro Shimada, Michael Chalick, Chihiro Emori, Mayo Kodani, Seiya Oura, Taichi Noda, Tsutomu Endo, Martin M Matzuk, Daniel H Wreschner, Masahito Ikawa

Faculty, Staff and Students Publications

The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the …

Synthetic Errα/Β/Γ Agonist Induces An Errα-Dependent Acute Aerobic Exercise Response And Enhances Exercise Capacity, Cyrielle Billon, Sadichha Sitaula, Subhashis Banerjee, Ryan Welch, Bahaa Elgendy, Lamees Hegazy, Tae Gyu Oh, Melissa Kazantzis, Arindam Chatterjee, John Chrivia, Matthew E Hayes, Weiyi Xu, Angelica Hamilton, Janice M Huss, Lilei Zhang, John K Walker, Michael Downes, Ronald M Evans, Thomas P Burris

Faculty, Staff and Students Publications

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the …

Circadian Clock Control Of Mrtf/Srf Pathway Suppresses Beige Adipocyte Thermogenic Recruitment, Xuekai Xiong, Weini Li, Ruya Liu, Pradip Saha, Vijay Yechoor, Ke Ma

Faculty, Staff and Students Publications

The morphological transformation of adipogenic progenitors into mature adipocytes requires dissolution of actin cytoskeleton with loss of myocardin-related transcription factor (MRTF)/serum response factor (SRF) activity. Circadian clock confers temporal control in adipogenic differentiation, while the actin cytoskeleton-MRTF/SRF signaling transduces extracellular physical niche cues. Here, we define a novel circadian transcriptional control involved in actin cytoskeleton-MRTF/SRF signaling cascade that modulates beige fat thermogenic function. Key components of actin dynamic-MRTF/SRF pathway display circadian regulation in beige fat depot. The core clock regulator, brain and muscle arnt-like 1 (Bmal1), exerts direct transcriptional control of genes within the actin dynamic-MRTF/SRF cascade that impacts actin …

Loss-Of-Function Variants In Mycbp2 Cause Neurobehavioural Phenotypes And Corpus Callosum Defects, Lama Alabdi, Muriel Desbois, Domniţa-Valeria Rusnac, Raashda A Sulaiman, Jill A Rosenfeld, Seema Lalani, David R Murdock, Lindsay C Burrage, Ping Yee Billie Au, Shelley Towner, William G Wilson, Lawrence Wong, Theresa Brunet, Gertrud Strobl-Wildemann, Jennifer E Burton, George Hoganson, Kirsty Mcwalter, Amber Begtrup, Yuri A Zarate, Elyse L Christensen, Karla J Opperman, Andrew C Giles, Rana Helaby, Artur Kania, Ning Zheng, Brock Grill, Fowzan S Alkuraya

Faculty, Staff and Student Publications

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions …

Sptssa Variants Alter Sphingolipid Synthesis And Cause A Complex Hereditary Spastic Paraplegia, Siddharth Srivastava, Hagar Mor Shaked, Kenneth Gable, Sita D Gupta, Xueyang Pan, Niranjanakumari Somashekarappa, Gongshe Han, Payam Mohassel, Marc Gotkine, Elizabeth Doney, Paula Goldenberg, Queenie K G Tan, Yi Gong, Benjamin Kleinstiver, Brian Wishart, Heidi Cope, Claudia Brito Pires, Hannah Stutzman, Rebecca C Spillmann, Undiagnosed Disease Network, Reza Sadjadi, Orly Elpeleg, Chia-Hsueh Lee, Hugo J Bellen, Simon Edvardson, Florian Eichler, Teresa M Dunn

Faculty, Staff and Students Publications

Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting …

Rescue Of Glutaric Aciduria Type I In Mice By Liver-Directed Therapies, Mercedes Barzi, Collin G Johnson, Tong Chen, Ramona M Rodriguiz, Madeline Hemmingsen, Trevor J Gonzalez, Alan Rosales, James Beasley, Cheryl K Peck, Yunhan Ma, Ashlee R Stiles, Timothy C Wood, Raquel Maeso-Diaz, Anna Mae Diehl, Sarah P Young, Jeffrey I Everitt, William C Wetsel, William R Lagor, Beatrice Bissig-Choisat, Aravind Asokan, Areeg El-Gharbawy, Karl-Dimiter Bissig

Faculty, Staff and Students Publications

Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabolites in the brain are produced locally and do not cross the blood-brain barrier. In a series of experiments using knockout mice of the lysine catabolic pathway and liver cell transplantation, we uncovered that toxic GA-1 catabolites in the brain originated from the liver. Moreover, the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy …

Social Deprivation Induces Astrocytic Trpa1-Gaba Suppression Of Hippocampal Circuits, Yi-Ting Cheng, Junsung Woo, Estefania Luna-Figueroa, Ehson Maleki, Akdes Serin Harmanci, Benjamin Deneen

Faculty, Staff and Students Publications

Social experience is essential for the development and maintenance of higher order brain function. Social deprivation results in a host of cognitive deficits and cellular studies have largely focused on associated neuronal dysregulation; how astrocyte function is impacted by social deprivation is unknown. Here we show that hippocampal astrocytes from juvenile mice subjected to social isolation exhibit increased Ca2+ activity and global changes in gene expression. We found that the Ca2+ channel TRPA1 is upregulated in astrocytes after social deprivation and astrocyte-specific deletion of TRPA1 reverses the physiological and cognitive deficits associated with social deprivation. Mechanistically, TRPA1 inhibition of hippocampal …

Interspecies Interactions Within The Host: The Social Network Of Group B Streptococcus, Marlyd E Mejia, Clare M Robertson, Kathryn A Patras

Faculty, Staff and Students Publications

Group B Streptococcus (GBS) is a pervasive neonatal pathogen accounting for a combined half a million deaths and stillbirths annually. The most common source of fetal or neonatal GBS exposure is the maternal microbiota. GBS asymptomatically colonizes the gastrointestinal and vaginal mucosa of 1 in 5 individuals globally, although its precise role in these niches is not well understood. To prevent vertical transmission, broad-spectrum antibiotics are administered to GBS-positive mothers during labor in many countries. Although antibiotics have significantly reduced GBS early-onset neonatal disease, there are several unintended consequences, including an altered neonatal microbiota and increased risk for other microbial …

Lysosomal Lipid Peroxidation Regulates Tumor Immunity, Monika Bhardwaj, Jennifer J Lee, Amanda M Versace, Sandra L Harper, Aaron R Goldman, Mary Ann S Crissey, Vaibhav Jain, Mahendra Pal Singh, Megane Vernon, Andrew E. Aplin, Seokwoo Lee, Masao Morita, Jeffrey D Winkler, Qin Liu, David W Speicher, Ravi K Amaravadi

Department of Surgery Faculty Papers

Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport …

Distinct Astrocytic Modulatory Roles In Sensory Transmission During Sleep, Wakefulness, And Arousal States In Freely Moving Mice, Fushun Wang, Wei Wang, Simeng Gu, Dan Qi, Nathan A Smith, Weiguo Peng, Wei Dong, Jiajin Yuan, Binbin Zhao, Ying Mao, Peng Cao, Qing Richard Lu, Lee A Shapiro, S Stephen Yi, Erxi Wu, Jason H Huang

Faculty, Staff and Student Publications

Despite extensive research on astrocytic Ca2+ in synaptic transmission, its contribution to the modulation of sensory transmission during different brain states remains largely unknown. Here, by using two-photon microscopy and whole-cell recordings, we show two distinct astrocytic Ca2+ signals in the murine barrel cortex: a small, long-lasting Ca2+ increase during sleep and a large, widespread but short-lasting Ca2+ spike when aroused. The large Ca2+ wave in aroused mice was inositol trisphosphate (IP3)-dependent, evoked by the locus coeruleus-norepinephrine system, and enhanced sensory input, contributing to reliable sensory transmission. However, the small Ca2+ transient was IP3-independent and contributed to decreased extracellular K+, …

The Melanocortin Action Is Biased Toward Protection From Weight Loss In Mice, Hongli Li, Yuanzhong Xu, Yanyan Jiang, Zhiying Jiang, Joshua Otiz-Guzman, Jessie C Morrill, Jing Cai, Zhengmei Mao, Yong Xu, Benjamin R Arenkiel, Cheng Huang, Qingchun Tong

Faculty, Staff and Student Publications

The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. …

Microbubble Cavitation Restores Staphylococcus Aureus Antibiotic Susceptibility In Vitro And In A Septic Arthritis Model, Neil Zhao, Dylan Curry, Rachel E Evans, Selin Isguven, Theresa A. Freeman, John R. Eisenbrey, Flemming Forsberg, Jessica M Gilbertie, Sophie Boorman, Rachel Hilliard, Sana S. Dastgheyb, Priscilla Machado, Maria Stanczak, Marc I. Harwood, Antonia F Chen, Javad Parvizi, Irving Shapiro, Noreen J. Hickok, Thomas P Schaer

Department of Orthopaedic Surgery Faculty Papers

Treatment failure in joint infections is associated with fibrinous, antibiotic-resistant, floating and tissue-associated Staphylococcus aureus aggregates formed in synovial fluid (SynF). We explore whether antibiotic activity could be increased against Staphylococcus aureus aggregates using ultrasound-triggered microbubble destruction (UTMD), in vitro and in a porcine model of septic arthritis. In vitro, when bacterially laden SynF is diluted, akin to the dilution achieved clinically with lavage and local injection of antibiotics, amikacin and ultrasound application result in increased bacterial metabolism, aggregate permeabilization, and a 4-5 log decrease in colony forming units, independent of microbubble destruction. Without SynF dilution, amikacin + UTMD does …

Initiating And Imaging Cavitation From Infused Echo Contrast Agents Through The Ekosonic Catheter, Sonya R Kennedy, Maxime Lafond, Kevin J Haworth, Daniel Suarez Escudero, Dan Ionascu, Brion Frierson, Shaoling Huang, Melvin E Klegerman, Tao Peng, David D Mcpherson, Curtis Genstler, Christy K Holland

Faculty, Staff and Student Publications

Ultrasound-enhanced delivery of therapeutic-loaded echogenic liposomes is under development for vascular applications using the EkoSonic Endovascular System. In this study, fibrin-targeted echogenic liposomes loaded with an anti-inflammatory agent were characterized before and after infusion through an EkoSonic catheter. Cavitation activity was nucleated by Definity or fibrin-targeted, drug-loaded echogenic liposomes infused and insonified with EkoSonic catheters. Passive cavitation imaging was used to quantify and map bubble activity in a flow phantom mimicking porcine arterial flow. Cavitation was sustained during 3-min infusions of Definity or echogenic liposomes along the distal 6 cm treatment zone of the catheter. Though the EkoSonic catheter was …

Local Ocular Safety Of The Subconjunctival Injection Of Cetuximab In Rabbits, Hossein Aghaei, Ahmad Kheirkhah, Ali Mohammad Alizadeh, Acieh Es'haghi, Roshanak Aliakbar-Navahi, Zahra Keikha, Samira Chaibakhsh

Faculty, Staff and Student Publications

BACKGROUND: To evaluate the safety of different doses of subconjunctival cetuximab in rabbits.

METHODS: After general anesthesia rabbits received a subconjunctival injection of 2.5 mg in 0.5 ml, 5 mg in 1 ml, and 10 mg in 2 ml of cetuximab in their right eyes (two rabbits in each group). A similar volume of normal saline solution was injected subconjunctivally in the left eyes. The histopathologic changes were evaluated after enucleation with the aid of H&E staining.

RESULTS: No significant difference were observed between the treated and control eyes in terms of conjunctival inflammation, goblet cell density, or limbal blood …

Development Of A Corticosteroid-Immunosuppressed Mouse Model To Study The Pathogenesis And Therapy Of Influenza-Associated Pulmonary Aspergillosis, Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Foxi3 Pathogenic Variants Cause One Form Of Craniofacial Microsomia, Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro De Luca, Giuseppe Merla, Shouqin Zhao, Timothy C Cox, Andrew K Groves, James R Lupski, Qingguo Zhang, Yong-Biao Zhang, Stylianos E Antonarakis

Faculty, Staff and Students Publications

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in …

Mapping The Metabolic Reprogramming Induced By Sodium-Glucose Cotransporter 2 Inhibition, Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz

Faculty, Staff and Student Publications

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation …

Neuronal Birthdate Reveals Topography In A Vestibular Brainstem Circuit For Gaze Stabilization, Dena Goldblatt, Stephanie Huang, Marie R Greaney, Kyla R Hamling, Venkatakaushik Voleti, Citlali Perez-Campos, Kripa B Patel, Wenze Li, Elizabeth M C Hillman, Martha W Bagnall, David Schoppik

Faculty, Staff and Student Publications

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. …

Targeting The Mevalonate Pathway Suppresses Arid1a-Inactivated Cancers By Promoting Pyroptosis, Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R Goldman, Toshitha Kannan, Andrew V Kossenkov, Ronny Drapkin, Luis J Montaner, Daniel T Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Faculty, Staff and Student Publications

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC …

Bi-Allelic Variants In The Esam Tight-Junction Gene Cause A Neurodevelopmental Disorder Associated With Fetal Intracranial Hemorrhage, Mauro Lecca, Davut Pehlivan, Damià Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarella, Alberto Neri, Carlo Fusco, Dana Marafi, Tadahiro Mitani, Jennifer Ellen Posey, Sadik Etka Bayramoglu, Alper Gezdirici, Jessica Hernandez-Rodriguez, Emilia Amengual Cladera, Elena Miravet, Jorge Roldan-Busto, María Angeles Ruiz, Cristofol Vives Bauzá, Liat Ben-Sira, Sabine Sigaudy, Anaïs Begemann, Sheila Unger, Serdal Güngör, Semra Hiz, Ece Sonmezler, Yoav Zehavi, Michael Jerdev, Alessandra Balduini, Orsetta Zuffardi, Rita Horvath, Hanns Lochmüller, Anita Rauch, Livia Garavelli, Elisabeth Tournier-Lasserve, Ronen Spiegel, James R Lupski, Edoardo Errichiello

Faculty, Staff and Students Publications

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in …

The Impact Of Gamma Transcranial Alternating Current Stimulation (Tacs) On Cognitive And Memory Processes In Patients With Mild Cognitive Impairment Or Alzheimer’S Disease: A Literature Review, N.R. Nissim, D.V.H. Pham, T. Poddar, E. Blutt, R.H. Hamilton

Moss-Magee Rehabilitation Papers

BACKGROUND: Transcranial alternating current stimulation (tACS)-a noninvasive brain stimulation technique that modulates cortical oscillations through entrainment-has been demonstrated to alter oscillatory activity and enhance cognition in healthy adults. TACS is being explored as a tool to improve cognition and memory in patient populations with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

OBJECTIVE: To review the growing body of literature and current findings obtained from the application of tACS in patients with MCI or AD, highlighting the effects of gamma tACS on brain function, memory, and cognition. Evidence on the use of brain stimulation in animal models of AD is …

Pattern Dynamics And Stochasticity Of The Brain Rhythms, Clarissa Hoffman, Jingheng Cheng, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves—their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses “orderliness” of the waves’ features. The corresponding measures capture the waves’ characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns’ dynamics and the animal’s location, speed, and acceleration. Specifically, we …