Medical Specialties Commons^™

Prevalence Of Ddc Genotypes In Patients With Aromatic L-Amino Acid Decarboxylase (Aadc) Deficiency And In Silico Prediction Of Structural Protein Changes, Nastassja Himmelreich, Mariarita Bertoldi, Majid Alfadhel, Malak Ali Alghamdi, Yair Anikster, Xinhua Bao, Fahad A Bashiri, Bruria Ben Zeev, Giovanni Bisello, Ahmet Cevdet Ceylan, Yin-Hsiu Chien, Yew Sing Choy, Sarah H Elsea, Lisa Flint, Àngels García-Cazorla, Charul Gijavanekar, Emel Yılmaz Gümüş, Muddathir H Hamad, Burcu Hişmi, Tomas Honzik, Oya Kuseyri Hübschmann, Wuh-Liang Hwu, Salvador Ibáñez-Micó, Kathrin Jeltsch, Natalia Juliá-Palacios, Çiğdem Seher Kasapkara, Manju A Kurian, Katarzyna Kusmierska, Ning Liu, Lock Hock Ngu, John D Odom, Winnie Peitee Ong, Thomas Opladen, Mari Oppeboen, Phillip L Pearl, Belén Pérez, Roser Pons, Agnieszka Magdalena Rygiel, Tan Ee Shien, Robert Spaull, Jolanta Sykut-Cegielska, Brahim Tabarki, Trine Tangeraas, Beat Thöny, Tessa Wassenberg, Yongxin Wen, Yusnita Yakob, Jasmine Goh Chew Yin, Jiri Zeman, Nenad Blau

Faculty, Staff and Students Publications

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, …

Proteomic Analysis Identifies Circulating Proteins Associated With Plasma Amyloid-Β And Incident Dementia, Adrienne Tin, Kevin J Sullivan, Keenan A Walker, Jan Bressler, Rajesh Talluri, Bing Yu, Jeanette Simino, Valborg Gudmundsdottir, Valur Emilsson, Lori L Jennings, Lenore Launer, Hao Mei, Eric Boerwinkle, B Gwen Windham, Rebecca Gottesman, Vilmundur Gudnason, Josef Coresh, Myriam Fornage, Thomas H Mosley

Faculty, Staff and Student Publications

BACKGROUND: Plasma amyloid-β (Aβ) (Aβ

METHODS: We analyzed the association of these 3 plasma Aβ measures with 4638 circulating proteins among a subset of the participants of the Atherosclerosis Risk in Communities (ARIC) study (midlife:

RESULTS: At midlife, of the 296 Aβ-associated proteins, 8 were associated with incident dementia from midlife and late life in the ARIC study, and NPPB, IBSP, and THBS2 were replicated in the AGES-Reykjavik Study. At late life, of the 34 Aβ-associated proteins, none were associated with incident dementia at midlife, and kidney function explained 10%, 12%, and 0.2% of the variance of Aβ

CONCLUSIONS: This …

Suitability Of Double-Stranded Dna As A Molecular Standard For The Validation Of Analytical Ultracentrifugation Instruments, Maduni Ranasinghe, Jonathan M Fogg, Daniel J Catanese, Lynn Zechiedrich, Borries Demeler

Faculty, Staff and Students Publications

To address the current lack of validated molecular standards for analytical ultracentrifugation (AUC), we investigated the suitability of double-stranded DNA molecules. We compared the hydrodynamic properties of linear and circular DNA as a function of temperature. Negatively supercoiled, nicked, and linearized 333 and 339 bp minicircles were studied. We quantified the hydrodynamic properties of these DNAs at five different temperatures, ranging from 4 to 37 °C. To enhance the precision of our measurements, each sample was globally fitted over triplicates and five rotor speeds. The exceptional stability of DNA allowed each sample to be sedimented repeatedly over the course of …

Machine Learning For Ecg Diagnosis And Risk Stratification Of Occlusion Myocardial Infarction, Salah S Al-Zaiti, Christian Martin-Gill, Jessica K Zègre-Hemsey, Zeineb Bouzid, Ziad Faramand, Mohammad O Alrawashdeh, Richard E Gregg, Stephanie Helman, Nathan T Riek, Karina Kraevsky-Phillips, Gilles Clermont, Murat Akcakaya, Susan M Sereika, Peter Van Dam, Stephen W Smith, Yochai Birnbaum, Samir Saba, Ervin Sejdic, Clifton W Callaway

Faculty, Staff and Students Publications

Patients with occlusion myocardial infarction (OMI) and no ST-elevation on presenting electrocardiogram (ECG) are increasing in numbers. These patients have a poor prognosis and would benefit from immediate reperfusion therapy, but, currently, there are no accurate tools to identify them during initial triage. Here we report, to our knowledge, the first observational cohort study to develop machine learning models for the ECG diagnosis of OMI. Using 7,313 consecutive patients from multiple clinical sites, we derived and externally validated an intelligent model that outperformed practicing clinicians and other widely used commercial interpretation systems, substantially boosting both precision and sensitivity. Our derived …

Genome-Wide Association Analyses Define Pathogenic Signaling Pathways And Prioritize Drug Targets For Iga Nephropathy, Krzysztof Kiryluk, Elena Sanchez-Rodriguez, Xu-Jie Zhou, Francesca Zanoni, Lili Liu, Nikol Mladkova, Atlas Khan, Maddalena Marasa, Jun Y Zhang, Olivia Balderes, Simone Sanna-Cherchi, Andrew S Bomback, Pietro A Canetta, Gerald B Appel, Jai Radhakrishnan, Hernan Trimarchi, Ben Sprangers, Daniel C Cattran, Heather Reich, York Pei, Pietro Ravani, Kresimir Galesic, Dita Maixnerova, Vladimir Tesar, Benedicte Stengel, Marie Metzger, Guillaume Canaud, Nicolas Maillard, Francois Berthoux, Laureline Berthelot, Evangeline Pillebout, Renato Monteiro, Raoul Nelson, Robert J Wyatt, William Smoyer, John Mahan, Al-Akash Samhar, Guillermo Hidalgo, Alejandro Quiroga, Patricia Weng, Raji Sreedharan, David Selewski, Keefe Davis, Mahmoud Kallash, Tetyana L Vasylyeva, Michelle Rheault, Aftab Chishti, Daniel Ranch, Scott E Wenderfer, Dmitry Samsonov, Donna J Claes, Oleh Akchurin, Dimitrios Goumenos, Maria Stangou, Judit Nagy, Tibor Kovacs, Enrico Fiaccadori, Antonio Amoroso, Cristina Barlassina, Daniele Cusi, Lucia Del Vecchio, Giovanni Giorgio Battaglia, Monica Bodria, Emanuela Boer, Luisa Bono, Giuliano Boscutti, Gianluca Caridi, Francesca Lugani, Gianmarco Ghiggeri, Rosanna Coppo, Licia Peruzzi, Vittoria Esposito, Ciro Esposito, Sandro Feriozzi, Rosaria Polci, Giovanni Frasca, Marco Galliani, Maurizio Garozzo, Adele Mitrotti, Loreto Gesualdo, Simona Granata, Gianluigi Zaza, Francesco Londrino, Riccardo Magistroni, Isabella Pisani, Andrea Magnano, Carmelita Marcantoni, Piergiorgio Messa, Renzo Mignani, Antonello Pani, Claudio Ponticelli, Dario Roccatello, Maurizio Salvadori, Erica Salvi, Domenico Santoro, Guido Gembillo, Silvana Savoldi, Donatella Spotti, Pasquale Zamboli, Claudia Izzi, Federico Alberici, Elisa Delbarba, Michał Florczak, Natalia Krata, Krzysztof Mucha, Leszek Pączek, Stanisław Niemczyk, Barbara Moszczuk, Malgorzata Pańczyk-Tomaszewska, Malgorzata Mizerska-Wasiak, Agnieszka Perkowska-Ptasińska, Teresa Bączkowska, Magdalena Durlik, Krzysztof Pawlaczyk, Przemyslaw Sikora, Marcin Zaniew, Dorota Kaminska, Magdalena Krajewska, Izabella Kuzmiuk-Glembin, Zbigniew Heleniak, Barbara Bullo-Piontecka, Tomasz Liberek, Alicja Dębska-Slizien, Tomasz Hryszko, Anna Materna-Kiryluk, Monika Miklaszewska, Maria Szczepańska, Katarzyna Dyga, Edyta Machura, Katarzyna Siniewicz-Luzeńczyk, Monika Pawlak-Bratkowska, Marcin Tkaczyk, Dariusz Runowski, Norbert Kwella, Dorota Drożdż, Ireneusz Habura, Florian Kronenberg, Larisa Prikhodina, David Van Heel, Bertrand Fontaine, Chris Cotsapas, Cisca Wijmenga, Andre Franke, Vito Annese, Peter K Gregersen, Sreeja Parameswaran, Matthew Weirauch, Leah Kottyan, John B Harley, Hitoshi Suzuki, Ichiei Narita, Shin Goto, Hajeong Lee, Dong Ki Kim, Yon Su Kim, Jin-Ho Park, Belong Cho, Murim Choi, Ans Van Wijk, Ana Huerta, Elisabet Ars, Jose Ballarin, Sigrid Lundberg, Bruno Vogt, Laila-Yasmin Mani, Yasar Caliskan, Jonathan Barratt, Thilini Abeygunaratne, Philip A Kalra, Daniel P Gale, Ulf Panzer, Thomas Rauen, Jürgen Floege, Pascal Schlosser, Arif B Ekici, Kai-Uwe Eckardt, Nan Chen, Jingyuan Xie, Richard P Lifton, Ruth J F Loos, Eimear E Kenny, Iuliana Ionita-Laza, Anna Köttgen, Bruce A Julian, Jan Novak, Francesco Scolari, Hong Zhang, Ali G Gharavi

Faculty, Staff and Students Publications

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum …

Pdcl2 Is Essential For Sperm Acrosome Formation And Male Fertility In Mice, Yoshitaka Fujihara, Kiyonori Kobayashi, Ferheen Abbasi, Tsutomu Endo, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round-headed spermatozoa.

OBJECTIVE: We generated Pdcl2 knockout mice to investigate the essential roles of PDCL2 in mammalian reproduction.

MATERIALS AND METHODS: We used reverse transcription-polymerase chain reaction to demonstrate that PDCL2 was expressed exclusively in the male reproductive tract in mice and humans. We created Pdcl2 knockout mice using the CRISPR-Cas9 system and analyzed their fertility. Pdcl2 null spermatozoa underwent further evaluation using computer-assisted sperm analysis, …

De Novo Variants In Cnot9 Cause A Neurodevelopmental Disorder With Or Without Epilepsy, Lydia Von Wintzingerode, Bruria Ben-Zeev, Claudia Cesario, Katie M Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V Kelley, Marie-Cécile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L Thompson, Marina Trivisano, Julia Hentschel, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann

Faculty, Staff and Students Publications

Purpose: The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.

Methods: Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.

Results: We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have …

Burden Of High-Risk Phenotype Of Heavy Alcohol Consumption Among Obese Us Population: Results From National Health And Nutrition Examination Survey, 1999–2020, Syed Ahsan Raza, Itunu O Sokale, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND: The phenotype of combined heavy alcohol consumption and obesity has the potential to pose as a considerable health burden in the U.S. No studies using nationally representative data in the U.S. have reported their secular joint prevalence trends. We estimated the prevalence and examined the joint trends of heavy alcohol use and obesity over time among adult U.S. men and women in different age groups and according to race/ethnicity.

METHODS: Using data from 10 cycles of the U.S. National Health and Nutrition Examination Survey (NHANES) from 1999 to 2020, we examined secular trends in the combined phenotype of heavy …

Remote Neuronal Activity Drives Glioma Progression Through Sema4f, Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm Mcdonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael R Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen

Faculty, Staff and Students Publications

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform …

Ywhae Loss Of Function Causes A Rare Neurodevelopmental Disease With Brain Abnormalities In Human And Mouse, Anne-Sophie Denommé-Pichon, Stephan C Collins, Ange-Line Bruel, Anna Mikhaleva, Christel Wagner, Valerie E Vancollie, Quentin Thomas, Martin Chevarin, Mathys Weber, Carlos E Prada, Alexis Overs, María Palomares-Bralo, Fernando Santos-Simarro, Marta Pacio-Míguez, Tiffany Busa, Eric Legius, Carlos A Bacino, Jill A Rosenfeld, Gwenaël Le Guyader, Matthieu Egloff, Xavier Le Guillou, Maria Antonietta Mencarelli, Alessandra Renieri, Salvatore Grosso, Jonathan Levy, Blandine Dozières, Isabelle Desguerre, Antonio Vitobello, Yannis Duffourd, Christopher J Lelliott, Christel Thauvin-Robinet, Christophe Philippe, Laurence Faivre, Binnaz Yalcin

Faculty, Staff and Students Publications

Purpose: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.

Methods: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae.

Results: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions < 1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans.

Conclusion: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.

Biallelic Variants In Cript Cause A Rothmund-Thomson-Like Syndrome With Increased Cellular Senescence, Luisa Averdunk, Maxim A Huetzen, Daniel Moreno-Andrés, Reinhard Kalb, Shane Mckee, Tzung-Chien Hsieh, Annette Seibt, Marten Schouwink, Seema Lalani, Eissa Ali Faqeih, Theresa Brunet, Peter Boor, Kornelia Neveling, Alexander Hoischen, Barbara Hildebrandt, Elisabeth Graf, Linchao Lu, Weidong Jin, Joerg Schaper, Jamal A Omer, Tanguy Demaret, Nicole Fleischer, Detlev Schindler, Peter Krawitz, Ertan Mayatepek, Dagmar Wieczorek, Lisa L Wang, Wolfram Antonin, Ron D Jachimowicz, Verena Von Felbert, Felix Distelmaier

Faculty, Staff and Students Publications

Purpose: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789).

Methods: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.

Results: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental …

Single-Cell Profiling Of Tumor Immune Microenvironment Reveals Immune Irresponsiveness In Gastric Signet-Ring Cell Carcinoma, Jing Chen, Kuai Liu, Yikai Luo, Muxing Kang, Jun Wang, Guofeng Chen, Jia Qi, Wenxuan Wu, Beidi Wang, Yaxuan Han, Le Shi, Kefan Wang, Xiaying Han, Xiaojing Ma, Wei Liu, Yuan Ding, Liangjing Wang, Han Liang, Lie Wang, Jian Chen

Faculty, Staff and Student Publications

Background & aims: Gastric cancer (GC) is a major cancer type characterized by high heterogeneity in both tumor cells and the tumor immune microenvironment (TIME). One intractable GC subtype is gastric signet-ring cell carcinoma (GSRCC), which is associated with poor prognosis. However, it remains unclear what the GSRCC TIME characteristics are and how these characteristics may contribute to clinical outcomes.

Methods: We enrolled 32 patients with advanced GC of diverse subtypes and profiled their TIME using an immune-targeted single-cell profiling strategy, including (1) immune-targeted single-cell RNA sequencing (n = 20 patients) and (2) protein expression profiling by a targeted antibody …

Co-Targeting Fasn And Mtor Suppresses Uveal Melanoma Growth, Anna Han, Dzmitry Mukha, Vivian Chua, Timothy J Purwin, Manoela Tiago, Bhavik Modasia, Usman Baqai, Jenna L Aumiller, Nelisa Bechtel, Emily Hunter, Meggie Danielson, Mizue Terai, Philip B Wedegaertner, Takami Sato, Solange Landreville, Michael A Davies, Stefan Kurtenbach, J William Harbour, Zachary T Schug, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent …

Atoh1 Drives The Heterogeneity Of The Pontine Nuclei Neurons And Promotes Their Differentiation, Sih-Rong Wu, Jessica C Butts, Matthew S Caudill, Jean-Pierre Revelli, Ryan S Dhindsa, Mark A Durham, Huda Y Zoghbi

Faculty, Staff and Students Publications

Pontine nuclei (PN) neurons mediate the communication between the cerebral cortex andthe cerebellum to refine skilled motor functions. Prior studies showed that PN neurons fall into two subtypes based on their anatomic location and region-specific connectivity, but the extent of their heterogeneity and its molecular drivers remain unknown. Atoh1 encodes a transcription factor that is expressed in the PN precursors. We previously showed that partial loss of Atoh1 function in mice results in delayed PN development and impaired motor learning. In this study, we performed single-cell RNA sequencing to elucidate the cell state–specific functions of Atoh1 during PN development and …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, …

Lateral Septum As A Melanocortin Downstream Site In Obesity Development, Yuanzhong Xu, Zhiying Jiang, Hongli Li, Jing Cai, Yanyan Jiang, Joshua Ortiz-Guzman, Yong Xu, Benjamin R Arenkiel, Qingchun Tong

Duncan NRI Faculty and Staff Publications

No abstract provided.

Hyperphosphorylation Of The Group A Streptococcal Control Of Virulence Regulator Increases Promoter Occupancy Specifically At Virulence Factor-Encoding Genes, Nicola Horstmann, Chau Nguyen Tran, Anthony R Flores, Samuel A Shelburne

Faculty, Staff and Student Publications

The control of virulence two-component gene regulatory system (CovRS) is critical to the pathogenesis of many medically important streptococci. In emm1 group A streptococci (GAS), CovR directly binds the promoters of numerous GAS virulence factor-encoding genes. Elimination of CovS phosphatase activity increases CovR phosphorylation (CovR~P) levels and abrogates GAS virulence. Given the emm type-specific diversity of CovRS function, in this study we used chromatin immunoprecipitation sequencing (ChIP-seq) to define global CovR DNA occupancy in the wild-type emm3 strain MGAS10870 (medium CovR~P) and its CovS phosphatase-negative derivative 10870-CovS-T284A (high CovR~P). In the wild-type emm3 strain, 89% of the previously identified emm1 …

Transcriptome- And Proteome-Wide Association Studies Nominate Determinants Of Kidney Function And Damage, Pascal Schlosser, Jingning Zhang, Hongbo Liu, Aditya L Surapaneni, Eugene P Rhee, Dan E Arking, Bing Yu, Eric Boerwinkle, Paul A Welling, Nilanjan Chatterjee, Katalin Susztak, Josef Coresh, Morgan E Grams

Faculty, Staff and Student Publications

BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.

RESULTS: Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are …

Small Molecule Rbi2 Disrupts Ribosome Biogenesis Through Pre-Rrna Depletion, Catherine E Scull, Guy Twa, Yinfeng Zhang, Naiheng J Yang, Robert N Hunter, Corinne E Augelli-Szafran, David A Schneider

Faculty, Staff and Student Publications

Cancer cells are especially sensitive to perturbations in ribosome biogenesis as they rely on finely tuned protein homeostasis to facilitate their rapid growth and proliferation. While ribosome synthesis and cancer have a well-established relationship, ribosome biogenesis has only recently drawn interest as a cancer therapeutic target. In this study, we exploited the relationship between ribosome biogenesis and cancer cell proliferation by using a potent ribosome biogenesis inhibitor, RBI2 (Ribosome Biogenesis Inhibitor 2), to perturb cancer cell growth and viability. We demonstrate herein that RBI2 significantly decreases cell viability in malignant melanoma cells and breast cancer cell lines. Treatment with RBI2 …

Drugging Evolution Of Antibiotic Resistance At A Regulatory Network Hub, Yin Zhai, John P Pribis, Sean W Dooling, Libertad Garcia-Villada, P J Minnick, Jun Xia, Jingjing Liu, Qian Mei, Devon M Fitzgerald, Christophe Herman, P J Hastings, Mauro Costa-Mattioli, Susan M Rosenberg

Faculty, Staff and Students Publications

Evolution of antibiotic resistance is a world health crisis, fueled by new mutations. Drugs to slow mutagenesis could, as cotherapies, prolong the shelf-life of antibiotics, yet evolution-slowing drugs and drug targets have been underexplored and ineffective. Here, we used a network-based strategy to identify drugs that block hubs of fluoroquinolone antibiotic-induced mutagenesis. We identify a U.S. Food and Drug Administration- and European Medicines Agency-approved drug, dequalinium chloride (DEQ), that inhibits activation of the

Nanoparticle-Enhanced Proton Beam Immunoradiotherapy Drives Immune Activation And Durable Tumor Rejection, Yun Hu, Sébastien Paris, Narayan Sahoo, Genevieve Bertolet, Qi Wang, Qianxia Wang, Hampartsoum B Barsoumian, Jordan Da Silva, Ailing Huang, Denaha J Doss, David P Pollock, Ethan Hsu, Nanez Selene, Claudia S Kettlun Leyton, Tiffany A Voss, Fatemeh Masrorpour, Shonik Ganjoo, Carola Leuschner, Jordan T Pietz, Nahum Puebla-Osorio, Saumil Gandhi, Quynh-Nhu Nguyen, Jing Wang, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of …

Parents’ Perspectives On The Utility Of Genomic Sequencing In The Neonatal Intensive Care Unit, Amy A. Lemke, Michelle L. Thompson, Emily C. Gimpel, Katelyn C. Mcnamara, Carla A. Rich, Candice R. Finnila, Meagan E. Cochran, James M.J. Lawlor, Kelly M. East, Kevin M. Bowling, Donald R. Latner, Susan M. Hiatt, Michelle D. Amaral, Whitley V. Kelley, Veronica Greve, David E. Gray, Stephanie A. Felker, Hannah Meddaugh, Ashley Cannon, Amanda Luedecke, Kelly E. Jackson, Laura G. Hendon, Hillary M. Janani, Marla Johnston, Lee Ann Merin, Sarah L. Deans, Carly Tuura, Trent Hughes

School of Medicine Faculty Publications

Background: It is critical to understand the wide-ranging clinical and non-clinical effects of genome sequencing (GS) for parents in the NICU context. We assessed parents’ experiences with GS as a first-line diagnostic tool for infants with suspected genetic conditions in the NICU. Methods: Parents of newborns (N = 62) suspected of having a genetic condition were recruited across five hospitals in the southeast United States as part of the SouthSeq study. Semi-structured interviews (N = 78) were conducted after parents received their child’s sequencing result (positive, negative, or variants of unknown significance). Thematic analysis was performed on all interviews. Results: …

Long-Term Outcomes And Molecular Correlates Of Sotorasib Efficacy In Patients With Pretreated Kras G12c-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis Of Codebreak 100, Grace K Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S Falchook, Antoine Italiano, Jürgen Wolf, Adrian G Sacher, Toshiaki Takahashi, Suresh S Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, David S Hong, Piro Lito, Qui Tran, Simon Jones, Abraham Anderson, Antreas Hindoyan, Wendy Snyder, Ferdinandos Skoulidis, Bob T Li

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

In the longest follow-up, to our knowledge, for a KRAS^G12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non–small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical …

Wdr5 Facilitates Recruitment Of N-Myc To Conserved Wdr5 Gene Targets In Neuroblastoma Cell Lines, Leigh A Bumpous, Kylie C Moe, Jing Wang, Logan A Carver, Alexandria G Williams, Alexander S Romer, Jesse D Scobee, Jack N Maxwell, Cheyenne A Jones, Dai H Chung, William P Tansey, Qi Liu, April M Weissmiller

Faculty, Staff and Student Publications

Collectively, the MYC family of oncoprotein transcription factors is overexpressed in more than half of all malignancies. The ability of MYC proteins to access chromatin is fundamental to their role in promoting oncogenic gene expression programs in cancer and this function depends on MYC-cofactor interactions. One such cofactor is the chromatin regulator WDR5, which in models of Burkitt lymphoma facilitates recruitment of the c-MYC protein to chromatin at genes associated with protein synthesis, allowing for tumor progression and maintenance. However, beyond Burkitt lymphoma, it is unknown whether these observations extend to other cancers or MYC family members, and whether WDR5 …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Tzu-Chiao Lu, Maria Brbić, Ye-Jin Park, Tyler Jackson, Jiaye Chen, Sai Saroja Kolluru, Yanyan Qi, Nadja Sandra Katheder, Xiaoyu Tracy Cai, Seungjae Lee, Yen-Chung Chen, Niccole Auld, Chung-Yi Liang, Sophia H Ding, Doug Welsch, Samuel D'Souza, Angela Oliveira Pisco, Robert C Jones, Jure Leskovec, Eric C Lai, Hugo J Bellen, Liqun Luo, Heinrich Jasper, Stephen R Quake, Hongjie Li

Duncan NRI Faculty and Staff Publications

Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterize 163 distinct cell types and perform an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further develop aging clock models to predict the fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find unique cell type-specific aging patterns. This atlas provides a …

Proteogenomic Landscape Of Gastric Adenocarcinoma Peritoneal Metastases, Shuangtao Zhao, Ruiping Wang, Shumei Song, Dapeng Hao, Guangchun Han, Xingzhi Song, Jianhua Zhang, Melissa Pool Pizzi, Namita Shanbhag, Andrew Futreal, Brian Badgwell, Kazuto Harada, George Calin, Jody Vykoukal, Chuan-Yih Yu, Hiroyuki Katayama, Samir M Hanash, Linghua Wang, Jaffer A Ajani

Faculty, Staff and Student Publications

Advanced gastric adenocarcinoma (GAC) often leads to peritoneal carcinomatosis (PC) and is associated with very poor outcome. Here we report the comprehensive proteogenomic study of ascites derived cells from a prospective GAC cohort (n = 26 patients with peritoneal carcinomatosis, PC). A total of 16,449 proteins were detected from whole cell extracts (TCEs). Unsupervised hierarchical clustering resulted in three distinct groups that reflected extent of enrichment in tumor cells. Integrated analysis revealed enriched biological pathways and notably, some druggable targets (cancer-testis antigens, kinases, and receptors) that could be exploited to develop effective therapies and/or tumor stratifications. Systematic comparison of expression …

Loss Of Ampkα2 Promotes Melanoma Tumor Growth And Brain Metastasis, Ping Yuan, Da Teng, Evelyn De Groot, Man Li, Sebastian Trousil, Che-Hung Shen, Jason Roszik, Michael A Davies, Y N Vashisht Gopal, Bin Zheng

Faculty, Staff and Student Publications

AMP-activated protein kinase (AMPK) is a critical cellular energy sensor at the interface of metabolism and cancer. However, the role of AMPK in carcinogenesis remains unclear. Here, through analysis of the TCGA melanoma dataset, we found that PRKAA2 gene that encodes the α2 subunit of AMPK is mutated in ∼9% of cutaneous melanomas, and these mutations tend to co-occur with NF1 mutations. Knockout of AMPKα2 promoted anchorage-independent growth of NF1-mutant melanoma cells, whereas ectopic expression of AMPKα2 inhibited their growth in soft agar assays. Moreover, loss of AMPKα2 accelerated tumor growth of NF1-mutant melanoma and enhanced their brain …

Poly(A)-Binding Protein Is An Ataxin-2 Chaperone That Regulates Biomolecular Condensates, Steven Boeynaems, Yanniv Dorone, Yanrong Zhuang, Victoria Shabardina, Guozhong Huang, Anca Marian, Garam Kim, Anushka Sanyal, Nesli-Ece Şen, Daniel Griffith, Roberto Docampo, Keren Lasker, Iñaki Ruiz-Trillo, Georg Auburger, Alex S Holehouse, Edor Kabashi, Yi Lin, Aaron D Gitler

Duncan NRI Faculty and Staff Publications

Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs) which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional …

Extracellular Rna Sensing Mediates Inflammation And Organ Injury In A Murine Model Of Polytrauma, Andrew O Suen, Fengqian Chen, Sheng Wang, Ziyi Li, Jing Zhu, Yang Yang, Olivia Conn, Kerri Lopez, Ping Cui, Laurence Wechsler, Alan Cross, Gary Fiskum, Rosemary Kozar, Peter Hu, Catriona Miller, Lin Zou, Brittney Williams, Wei Chao

Faculty, Staff and Student Publications

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma—bone fracture, muscle crush injury, and bowel ischemia—induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Yan Wang, Roger Lopez-Bellido, Xiaojiao Huo, Annemieke Kavelaars, Michael J Galko

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent …