Digital Commons Network^™

Associations Between Varied Susceptibilities To Pfatp4 Inhibitors And Genotypes In Ugandan Plasmodium Falciparum Isolates., Oriana Kreutzfeld, Stephanie A. Rasmussen, Aarti A. Ramanathan, Patrick K. Tumwebaze, Oswald Byaruhanga, Thomas Katairo, Victor Asua, Martin Okitwi, Stephen Orena, Jennifer Legac, Melissa D. Conrad, Samuel L. Nsobya, Ozkan Aydemir, Jeffrey Bailey, Maelle Duffey, Brett R. Bayles, Akhil B. Vaidya, Roland A. Cooper, Philip J. Rosenthal

Natural Sciences and Mathematics | Faculty Scholarship

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda, from 2016 to 2019. Median IC50s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many nonsynonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K …

A Structural Study Of The Cytoplasmic Chaperone Effect Of 14-3-3 Proteins On Ataxin-1, Seppe Leysen, Rebecca Jane Burnley, Elizabeth Rodriguez, Lech-Gustav Milroy, Lorenzo Soini, Carolyn J. Adamski, Larissa Nitschke, Rachel Davis, Tomas Obsil, Lucas Brunsveld, Tom Crabbe, Huda Yahya Zoghbi, Christian Ottmann, Jeremy Martin Davis

Faculty Publications

Expansion of the polyglutamine tract in the N terminus of Ataxin-1 is the main cause of the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1). However, the C-terminal part of the protein - including its AXH domain and a phosphorylation on residue serine 776 - also plays a crucial role in disease development. This phosphorylation event is known to be crucial for the interaction of Ataxin-1 with the 14-3-3 adaptor proteins and has been shown to indirectly contribute to Ataxin-1 stability. Here we show that 14-3-3 also has a direct anti-aggregation or "chaperone" effect on Ataxin-1. Furthermore, we provide structural and …

A Structural Study Of The Cytoplasmic Chaperone Effect Of 14-3-3 Proteins On Ataxin-1, Seppe Leysen, Rebecca Jane Burnley, Elizabeth Rodriguez, Lech-Gustav Milroy, Lorenzo Soini, Carolyn J Adamski, Larissa Nitschke, Rachel Davis, Tomas Obsil, Lucas Brunsveld, Tom Crabbe, Huda Yahya Zoghbi, Christian Ottmann, Jeremy Martin Davis

Faculty, Staff and Students Publications

Expansion of the polyglutamine tract in the N terminus of Ataxin-1 is the main cause of the neurodegenerative disease, spinocerebellar ataxia type 1 (SCA1). However, the C-terminal part of the protein - including its AXH domain and a phosphorylation on residue serine 776 - also plays a crucial role in disease development. This phosphorylation event is known to be crucial for the interaction of Ataxin-1 with the 14-3-3 adaptor proteins and has been shown to indirectly contribute to Ataxin-1 stability. Here we show that 14-3-3 also has a direct anti-aggregation or "chaperone" effect on Ataxin-1. Furthermore, we provide structural and …

Molecular Classification Improves Risk Assessment In Adult Bcr-Abl1-Negative B-All, Elisabeth Paietta, Kathryn G. Roberts, Victoria Wang, Zhaohui Gu, Georgina A N Buck, Deqing Pei, Cheng Cheng, Ross L. Levine, Omar Abdel-Wahab, Zhongshan Cheng, Gang Wu, Chunxu Qu, Lei Shi, Stanley Pounds, Cheryl L. Willman, Richard Harvey, Janis Racevskis, Jan Barinka, Yanming Zhang, Gordon W. Dewald, Rhett P. Ketterling, David Alejos, Hillard M. Lazarus, Selina M. Luger, Letizia Foroni, Bela Patel, Adele K. Fielding, Ari Melnick, David I. Marks, Anthony V. Moorman, Peter H. Wiernik, Jacob M. Rowe, Martin S. Tallman, Anthony H. Goldstone, Charles G. Mullighan, Mark R. Litzow

Pathology Research and Scholarship

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome …

Genetic Counseling As Preventive Intervention: Toward Individual Specification Of Transgenerational Autism Risk, Natasha Marrus, Tychele N Turner, Elizabeth Forsen, Drew Bolster, Alison Marvin, Andrew Whitehouse, Laura Klinger, Christina A Gurnett, J N Constantino

2020-Current year OA Pubs

BACKGROUND: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3-5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling.

METHODS: We assembled what is to our knowledge the largest collection of data on the …

Identification Of Micrornas And Gene Regulatory Networks In Cleft Lip Common In Humans And Mice, Hiroki Yoshioka, Aimin Li, Akiko Suzuki, Sai Shankar Ramakrishnan, Zhongming Zhao, Junichi Iwata

Faculty, Staff and Student Publications

The etiology of cleft lip with/without cleft palate (CL/P), one of the most frequent craniofacial birth defects worldwide, is complicated by contributions of both genetic and environmental factors. Understanding the etiology of these conditions is essential for developing preventive strategies. This study thus aims to identify regulatory networks of microRNAs (miRNAs), transcriptional factors (TFs) and non-TF genes associated with cleft lip (CL) that are conserved in humans and mice. Notably, we found that miR-27b, miR-133b, miR-205, miR-376b and miR-376c were involved in the regulation of CL-associated gene expression in both humans and mice. Among the candidate miRNAs, the overexpression of …

Exercise Intolerance In Older Adults With Heart Failure With Preserved Ejection Fraction: Jacc State-Of-The-Art Review, Ambarish Pandey, Sanjiv J Shah, Javed Butler, Dean L Kellogg, Gregory D Lewis, Daniel E Forman, Robert J Mentz, Barry A Borlaug, Marc A Simon, Julio A Chirinos, Roger A Fielding, Elena Volpi, Anthony J A Molina, Mark J Haykowsky, Flora Sam, Bret H Goodpaster, Alain G Bertoni, Jamie N Justice, James P White, Jingzhone Ding, Scott L Hummel, Nathan K Lebrasseur, George E Taffet, Iraklis I Pipinos, Dalane Kitzman

Faculty, Staff and Students Publications

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the …

Is Comprehensiveness Critical? Comparing Short And Long Format Cognitive Assessments In Preclinical Alzheimer Disease, Jason Hassenstab, Jessica Nicosia, Megan Larose, Andrew J Aschenbrenner, Brian A Gordon, Tammie L S Benzinger, Chengjie Xiong, John C Morris

2020-Current year OA Pubs

BACKGROUND: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a "sampling" of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers.

METHODS: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal …

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 …

Predicting The Effect Of Indirect Cell Kill In The Treatment Of Multiple Brain Metastases Via Single-Isocenter/Multitarget Volumetric Modulated Arc Therapy Stereotactic Radiosurgery, Allison N. Palmiero, Denise Fabian, Marcus E. Randall, William St. Clair, Damodar Pokhrel

Radiation Medicine Faculty Publications

PURPOSE: Due to spatial uncertainty, patient setup errors are of major concern for radiosurgery of multiple brain metastases (m-bm) when using single-isocenter/multitarget (SIMT) volumetric modulated arc therapy (VMAT) techniques. However, recent clinical outcome studies show high rates of tumor local control for SIMT-VMAT. In addition to direct cell kill (DCK), another possible explanation includes the effects of indirect cell kill (ICK) via devascularization for a single dose of 15 Gy or more and by inducing a radiation immune intratumor response. This study quantifies the role of indirect cell death in dosimetric errors as a function of spatial patient setup uncertainty …

Characterization Of Gut Microbiome And Metabolome In Helicobacter Pylori Patients In An Underprivileged Community In The United States, Brian White, John D Sterrett, Zoya Grigoryan, Lauren Lally, Jared D Heinze, Hyder Alikhan, Christopher A Lowry, Lark Perez, Joshua Desipio, Sangita Phadtare

College of Science & Mathematics Departmental Research

Background: Helicobacter pylori (H. pylori), a bacterium that infects approximately half of the world's population, is associated with various gastrointestinal diseases, including peptic ulcers, non-ulcer dyspepsia, gastric adenocarcinoma, and gastric lymphoma. As the burden of antibiotic resistance increases, the need for new adjunct therapies designed to facilitate H. pylori eradication and reduce negative distal outcomes associated with infection has become more pressing. Characterization of the interactions between H. pylori, the fecal microbiome, and fecal fatty acid metabolism, as well as the mechanisms underlying these interactions, may offer new therapeutic approaches. Aim: To characterize the gut microbiome and metabolome in H. …

Transcriptional Network Involving Erg And Ar Orchestrates Distal-Less Homeobox-1 Mediated Prostate Cancer Progression, Sakshi Goel, Vipul Bhatia, Sushmita Kundu, Tanay Biswas, Shannon Carskadon, Nilesh S. Gupta, Mohammad Asim, Colm Morrissey, Nallasivam Palanisamy, Bushra Ateeq

Urology Articles

Distal-less homeobox-1 (DLX1) is a well-established non-invasive biomarker for prostate cancer (PCa) diagnosis, however, its mechanistic underpinnings in disease pathobiology are not known. Here, we reveal the oncogenic role of DLX1 and show that abrogating its function leads to reduced tumorigenesis and metastases. We observed that ~60% of advanced-stage and metastatic patients display higher DLX1 levels. Moreover, ~96% of TMPRSS2-ERG fusion-positive and ~70% of androgen receptor (AR)-positive patients show elevated DLX1, associated with aggressive disease and poor survival. Mechanistically, ERG coordinates with enhancer-bound AR and FOXA1 to drive transcriptional upregulation of DLX1 in ERG-positive background. However, in ERG-negative context, AR/AR-V7 …

Brain White Matter Structure And Amyloid Deposition In Black And White Older Adults: The Aric-Pet Study, Keenan A Walker, Noah Silverstein, Yun Zhou, Timothy M Hughes, Clifford R Jack, David S Knopman, A Richey Sharrett, Dean F Wong, Thomas H Mosley, Rebecca F Gottesman

Open Access Publications

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross-sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion …

Dna-Encoded Chemistry Technology Yields Expedient Access To Sars-Cov-2m Pro Inhibitors, Srinivas Chamakuri, Shuo Lu, Melek Nihan Ucisik, Kurt M Bohren, Ying-Chu Chen, Huang-Chi Du, John C Faver, Ravikumar Jimmidi, Feng Li, Jian-Yuan Li, Pranavanand Nyshadham, Stephen S Palmer, Jeroen Pollet, Xuan Qin, Shannon E Ronca, Banumathi Sankaran, Kiran L Sharma, Zhi Tan, Leroy Versteeg, Zhifeng Yu, Martin M Matzuk, Timothy Palzkill, Damian W Young

Faculty, Staff and Students Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration–approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition …

Dna-Encoded Chemistry Technology Yields Expedient Access To Sars-Cov-2m Pro Inhibitors, Srinivas Chamakuri, Shuo Lu, Melek Nihan Ucisik, Kurt M Bohren, Ying-Chu Chen, Huang-Chi Du, John C Faver, Ravikumar Jimmidi, Feng Li, Jian-Yuan Li, Pranavanand Nyshadham, Stephen S Palmer, Jeroen Pollet, Xuan Qin, Shannon E Ronca, Banumathi Sankaran, Kiran L Sharma, Zhi Tan, Leroy Versteeg, Zhifeng Yu, Martin M Matzuk, Timothy Palzkill, Damian W Young

Faculty, Staff and Students Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration–approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition …

Relationship Between Food Insecurity And Smoking Status Among Women Living With And At Risk For Hiv In The Usa: A Cohort Study, Lila A. Sheira, Edward A. Frongillo Jr., Judith Hahn, Kartika Palar, Elise D. Riley, Tracey E. Wilson, Adebola Adedimeji, Daniel Merenstein, Mardge Cohen, Eryka L. Wentz, Adaora A. Adimora, Ighovwerha Ofotokun, Lisa Metsch, Janet M. Turan, Phyllis C. Tien, Sheri D. Weiser

Faculty Publications

Objectives People living with HIV (PLHIV) in the USA, particularly women, have a higher prevalence of food insecurity than the general population. Cigarette smoking among PLHIV is common (42%), and PLHIV are 6–13 times more likely to die from lung cancer than AIDS related causes. This study sought to investigate the associations between food security status and smoking status and severity among a cohort of predominantly low-income women of colour living with and without HIV in the USA.

Design Women enrolled in an ongoing longitudinal cohort study from 2013 to 2015.

Setting Nine participating sites across the USA.

Participants 2553 …

Quality Of Life Analyses In Patients With Multiple Myeloma: Results From The Selinexor (Kpt-330) Treatment Of Refractory Myeloma (Storm) Phase 2b Study, Gabriel Tremblay, Ravi Vij, Et Al.

2020-Current year OA Pubs

BACKGROUND: Selinexor is an oral, selective nuclear export inhibitor. STORM was a phase 2b, single-arm, open-label, multicenter trial of selinexor with low dose dexamethasone in patients with penta-exposed relapsed/refractory multiple myeloma (RRMM) that met its primary endpoint, with overall response of 26% (95% confidence interval [CI], 19 to 35%). Health-related quality of life (HRQoL) was a secondary endpoint measured using the Functional Assessment of Cancer Therapy - Multiple Myeloma (FACT-MM). This study examines impact of selinexor treatment on HRQoL of patients treated in STORM and reports two approaches to calculate minimal clinically important differences for the FACT-MM.

METHODS: FACT-MM data …

The Concurrence Of Dna Methylation And Demethylation Is Associated With Transcription Regulation, Jiejun Shi, Jianfeng Xu, Yiling Elaine Chen, Jason Sheng Li, Ya Cui, Lanlan Shen, Jingyi Jessica Li, Wei Li

Children’s Nutrition Research Center Staff Publications

The mammalian DNA methylome is formed by two antagonizing processes, methylation by DNA methyltransferases (DNMT) and demethylation by ten-eleven translocation (TET) dioxygenases. Although the dynamics of either methylation or demethylation have been intensively studied in the past decade, the direct effects of their interaction on gene expression remain elusive. Here, we quantify the concurrence of DNA methylation and demethylation by the percentage of unmethylated CpGs within a partially methylated read from bisulfite sequencing. After verifying 'methylation concurrence' by its strong association with the co-localization of DNMT and TET enzymes, we observe that methylation concurrence is strongly correlated with gene expression. …

Adar And Hnrnpc Deficiency Synergize In Activating Endogenous Dsrna-Induced Type I Ifn Responses, Anna-Maria Herzner, Zia Khan, Eric L Van Nostrand, Sara Chan, Trinna Cuellar, Ronald Chen, Ximo Pechuan-Jorge, Laszlo Komuves, Margaret Solon, Zora Modrusan, Benjamin Haley, Gene W Yeo, Timothy W Behrens, Matthew L Albert

Faculty, Staff and Students Publications

Cytosolic double-stranded RNA (dsRNA) initiates type I IFN responses. Endogenous retroelements, notably Alu elements, constitute a source of dsRNA. Adenosine-to-inosine (A-to-I) editing by ADAR induces mismatches in dsRNA and prevents recognition by MDA5 and autoinflammation. To identify additional endogenous dsRNA checkpoints, we conducted a candidate screen in THP-1 monocytes and found that hnRNPC and ADAR deficiency resulted in synergistic induction of MDA5-dependent IFN responses. RNA-seq analysis demonstrated dysregulation of Alu-containing introns in hnRNPC-deficient cells via utilization of unmasked cryptic splice sites, including introns containing ADAR-dependent A-to-I editing clusters. These putative MDA5 ligands showed reduced editing in the absence of ADAR, …

Fusion And Beyond: Satellite Cell Contributions To Loading-Induced Skeletal Muscle Adaptation, Kevin A. Murach, Christopher S. Fry, Esther E. Dupont-Versteegden, John J. Mccarthy, Charlotte A. Peterson

Center for Muscle Biology Faculty Publications

Satellite cells support adult skeletal muscle fiber adaptations to loading in numerous ways. The fusion of satellite cells, driven by cell-autonomous and/or extrinsic factors, contributes new myonuclei to muscle fibers, associates with load-induced hypertrophy, and may support focal membrane damage repair and long-term myonuclear transcriptional output. Recent studies have also revealed that satellite cells communicate within their niche to mediate muscle remodeling in response to resistance exercise, regulating the activity of numerous cell types through various mechanisms such as secretory signaling and cell–cell contact. Muscular adaptation to resistance and endurance activity can be initiated and sustained for a period of …

Msisensor-Ct: Microsatellite Instability Detection Using Cfdna Sequencing Data, Xinyin Han, Shuying Zhang, Daniel Cui Zhou, Dongliang Wang, Xiaoyu He, Danyang Yuan, Ruilin Li, Jiayin He, Xiaohong Duan, Michael C Wendl, Li Ding, Beifang Niu

2020-Current year OA Pubs

MOTIVATION: Microsatellite instability (MSI) is a promising biomarker for cancer prognosis and chemosensitivity. Techniques are rapidly evolving for the detection of MSI from tumor-normal paired or tumor-only sequencing data. However, tumor tissues are often insufficient, unavailable, or otherwise difficult to procure. Increasing clinical evidence indicates the enormous potential of plasma circulating cell-free DNA (cfNDA) technology as a noninvasive MSI detection approach.

RESULTS: We developed MSIsensor-ct, a bioinformatics tool based on a machine learning protocol, dedicated to detecting MSI status using cfDNA sequencing data with a potential stable MSIscore threshold of 20%. Evaluation of MSIsensor-ct on independent testing datasets with various …

Protection Levels Of N95-Level Respirator Substitutes Proposed During The Covid-19 Pandemic: Safety Concerns And Quantitative Evaluation Procedures, David Ballard, Alex Scott, Broc Burke, Jason Morris, Connie Gan, Jesse Hu, Udayabhanu Jammalamadaka, Sena Sayood, Stephen Liang, Bruno Maranhao, J. Tyler Bertroche, Nirah Shomer, Pamela Woodard, Kathleen Meacham, Et Al

Open Access Publications

OBJECTIVE: The COVID-19 pandemic has precipitated widespread shortages of filtering facepiece respirators (FFRs) and the creation and sharing of proposed substitutes (novel designs, repurposed materials) with limited testing against regulatory standards. We aimed to categorically test the efficacy and fit of potential N95 respirator substitutes using protocols that can be replicated in university laboratories.

SETTING: Academic medical centre with occupational health-supervised fit testing along with laboratory studies.

PARTICIPANTS: Seven adult volunteers who passed quantitative fit testing for small-sized (n=2) and regular-sized (n=5) commercial N95 respirators.

METHODS: Five open-source potential N95 respirator substitutes were evaluated and compared with commercial National Institute …

Uba2 Variants Underlie A Recognizable Syndrome With Variable Aplasia Cutis Congenita And Ectrodactyly, Rhonda E Schnur, Sairah Yousaf, James Liu, Wendy K Chung, Lindsay Rhodes, Michael Marble, Regina M Zambrano, Nara Sobreira, Parul Jayakar, Mary Ella Pierpont, Matthew J Schultz, Pavel N Pichurin, Rory J Olson, Gail E Graham, Matthew Osmond, Gustavo A Contreras-García, Karina A Campo-Neira, Camilo A Peñaloza-Mantilla, Mark Flage, Srikar Kuppa, Karina Navarro, Maria J Guillen Sacoto, Ingrid M Wentzensen, Maria I Scarano, Jane Juusola, Carlos E Prada, Robert B Hufnagel

Pediatrics Research and Scholarship

PURPOSE: The human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aimed to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease.

METHODS: Exome sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss of function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments.

RESULTS: Seven human UBA2 …

Loss Of Synergistic Transcriptional Feedback Loops Drives Diverse B-Cell Cancers, Jared M Andrews, Sarah C Pyfrom, Jennifer A Schmidt, Olivia I Koues, Rodney A Kowalewski, Nicholas R Grams, Jessica J Sun, Leigh R Berman, Eric J Duncavage, Yi-Shan Lee, Amanda F Cashen, Eugene M Oltz, Jacqueline E Payton

Open Access Publications

BACKGROUND: The most common B-cell cancers, chronic lymphocytic leukemia/lymphoma (CLL), follicular and diffuse large B-cell (FL, DLBCL) lymphomas, have distinct clinical courses, yet overlapping "cell-of-origin". Dynamic changes to the epigenome are essential regulators of B-cell differentiation. Therefore, we reasoned that these distinct cancers may be driven by shared mechanisms of disruption in transcriptional circuitry.

METHODS: We compared purified malignant B-cells from 52 patients with normal B-cell subsets (germinal center centrocytes and centroblasts, naïve and memory B-cells) from 36 donor tonsils using >325 high-resolution molecular profiling assays for histone modifications, open chromatin (ChIP-, FAIRE-seq), transcriptome (RNA-seq), transcription factor (TF) binding, and …

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 …

Alzheimer's Disease Alters Oligodendrocytic Glycolytic And Ketolytic Gene Expression, Erin R Saito, Justin B Miller, Oscar Harari, Carlos Cruchaga, Kathie A Mihindukulasuriya, John S K Kauwe, Benjamin T Bikman

2020-Current year OA Pubs

INTRODUCTION: Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain.

METHODS: RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, …

The Role Of Gip Receptor In The Cns For The Pathogenesis Of Obesity, Makoto Fukuda

Children’s Nutrition Research Center Staff Publications

Glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) is a hormone produced in the upper gut and secreted to the circulation in response to the ingestion of foods, especially fatty foods. Growing evidence supports the physiological and pharmacological relevance of GIP in obesity. In an obesity setting, inhibition of endogenous GIP or its receptor leads to decreased energy intake, increased energy expenditure, or both, eventually causing weight loss. Further, supraphysiological dosing of exogenous long-lasting GIP agonists alters energy balance and has a marked antiobesity effect. This remarkable yet paradoxical antiobesity effect is suggested to occur primarily via the …

Opportunities To Address Obesity Disparities Among High-Risk Latino Children And Adolescents, Erica G Soltero, Teresia M O'Connor, Deborah Thompson, Gabriel Q Shaibi

Children’s Nutrition Research Center Staff Publications

Purpose of review: This review highlights obesity-related disparities among Latino children and adolescents, discusses the social determinants of health (SDoH) that drive disparities, and presents case studies of strategies for reducing disparities and promoting health equity.

Recent findings: Recommended strategies for reducing obesity-related disparities include the use of culturally grounded programming, multi-sector collaborations, and technology. We present two exemplar studies that demonstrate that integrating cultural values and enhancing the overall cultural fit of prevention programs can increase engagement among high-risk Latino families. We also examine the use of multi-sector collaborations to build community capacity and address key SDoH that impact …

Theoretical Mediators Of Diabetes Risk And Quality Of Life Following A Diabetes Prevention Program For Latino Youth With Obesity, Erica G Soltero, Stephanie L Ayers, Marvyn A Avalos, Armando Peña, Allison N Williams, Micah L Olson, Yolanda P Konopken, Felipe G Castro, Kimberly J Arcoleo, Colleen S Keller, Donald L Patrick, Justin Jager, Gabriel Q Shaibi

Children’s Nutrition Research Center Staff Publications

Purpose: This study tested self-efficacy and social support for activity and dietary changes as mediators of changes in type 2 diabetes related outcomes following a lifestyle intervention among Latino youth.

Setting and intervention: Latino adolescents (14-16 years) with obesity (BMI% = 98.1 ± 1.4) were randomized to a 3-month intervention (n = 67) that fostered self-efficacy and social support through weekly, family-centered sessions or a comparison condition (n = 69).

Measures: Primary outcomes included insulin sensitivity and weight specific quality of life. Mediators included self-efficacy, friend, and family social support for health behaviors. Data was collected at baseline, 3-months, 6-months, …