Digital Commons Network^™

Uncovering The Complex Genetics Of Human Temperament, Igor Zwir, Javier Arnedo, Dragan M Svrakic, Sandor Rozsa, Maribel Martinez, C Robert Cloninger, Et Al

Open Access Publications

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified …

Cpx-351 (Cytarabine And Daunorubicin) Liposome For Injection Versus Conventional Cytarabine Plus Daunorubicin In Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia, Jeffrey E Lancet, Geoffrey L Uy, Et Al

Open Access Publications

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with …

Curriculum For Neurogastroenterology And Motility Training: A Report From The Joint Anms-Esnm Task Force, C P Gyawali, Et Al

Open Access Publications

Although neurogastroenterology and motility (NGM) disorders are some of the most frequent disorders encountered by practicing gastroenterologists, a structured competency-based training curriculum developed by NGM experts is lacking. The American Neurogastroenterology and Motility Society (ANMS) and the European Society of Neurogastroenterology and Motility (ESNM) jointly evaluated the components of NGM training in North America and Europe. Eleven training domains were identified within NGM, consisting of functional gastrointestinal disorders, visceral hypersensitivity and pain pathways, motor disorders within anatomic areas (esophagus, stomach, small bowel and colon, anorectum), mucosal disorders (gastro-esophageal reflux disease, other mucosal disorders), consequences of systemic disease, consequences of therapy …

Cardiovascular Consequences Of Katp Overactivity In Cantu Syndrome, Yan Huang, Conor Mcclenaghan, Theresa M Harter, Kristina Hinman, Carmen M Halabi, Scot J Matkovich, Haixia Zhang, G Schuyler Brown, Robert P Mecham, Sarah K England, Attila Kovacs, Maria S Remedi, Colin G Nichols

Open Access Publications

Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in …

Identification Of Enhanced Ifn-Γ Signaling In Polyarticular Juvenile Idiopathic Arthritis With Mass Cytometry, Allison A Throm, Halima Moncrieffe, Amir B Orandi, Jeanette T Pingel, Theresa L Geurs, Hannah L Miller, Allyssa L Daugherty, Olga N Malkova, Daniel J Lovell, Susan D Thompson, Alexei A Grom, Megan A Cooper, Stephen T Oh, Anthony R French

Open Access Publications

Polyarticular juvenile idiopathic arthritis (JIA) is among the most challenging of the JIA subtypes to treat. Even with current biologic therapies, the disease remains difficult to control in a substantial subset of patients, highlighting the need for new therapies. The aim of this study was to use the high dimensionality afforded by mass cytometry with phospho-specific antibodies to delineate signaling abnormalities in immune cells from treatment-naive polyarticular JIA patients. Peripheral blood mononuclear cells were isolated from 17 treatment-naive polyarticular JIA patients, 10 of the patients after achieving clinical remission, and 19 healthy controls. Samples were stimulated for 15 minutes with …

International Volunteerism And Urethral Stricture Disease: A Review, Jason K. Frankel, Gregory P. Murphy

Open Access Publications

Global health is an ever-expanding area of interest for many healthcare workers around the world. In recent years, it has become apparent that much of the global disease burden is surgical. Urologic disease is no exception-many international organizations send volunteers around the world to support Urologic services in countries that lack capacity and resources. Urethral stricture represents a unique opportunity for specialized surgical management that vastly improves long term morbidity. Here we review the prevalence, etiology, and management of urethral stricture from a global perspective while highlighting impact of international urologic volunteer efforts.

Site-1 Protease Deficiency Causes Human Skeletal Dysplasia Due To Defective Inter-Organelle Protein Trafficking, Yuji Kondo, Debabrata Patra, Et Al

Open Access Publications

Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We …

Epigenomics And Metabolomics Reveal The Mechanism Of The Apoa2-Saturated Fat Intake Interaction Affecting Obesity, Chao-Qiang Lai, Caren E Smith, Laurence D Parnell, Yu-Chi Lee, Dolores Corella, Paul Hopkins, Bertha A Hidalgo, Stella Aslibekyan, Michael A Province, Devin Absher, Donna K Arnett, Katherine L Tucker, Jose M Ordovas

Open Access Publications

Background: The putative functional variant -265T>C (rs5082) within the APOA2 promoter has shown consistent interactions with saturated fatty acid (SFA) intake to influence the risk of obesity.

Objective: The aim of this study was to implement an integrative approach to characterize the molecular basis of this interaction.

Design: We conducted an epigenome-wide scan on 80 participants carrying either the rs5082 CC or TT genotypes and consuming either a low-SFA (<22 g/d) or high-SFA diet (≥22 g/d), matched for age, sex, BMI, and diabetes status in the Boston Puerto Rican Health Study (BPRHS). We then validated the findings in selected participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study (n = 379) and the Framingham Heart Study (FHS) (n = 243). Transcription and metabolomics analyses were conducted to determine the relation between epigenetic status, APOA2 mRNA expression, and blood metabolites.

Results: In the BPRHS, we identified methylation site cg04436964 as exhibiting significant differences between CC and TT participants consuming a high-SFA diet, but not among those consuming low-SFA. Similar …

Maternal Diet And Morbidity Factors Associated With Low Birth Weight In Haiti: A Case-Control Study, Abdirahim Rashid, Thomas Park, Kenneth Macneal, Lora Iannotti, Will Ross

Open Access Publications

No abstract provided.

Cellular Trafficking Of Sn-2 Phosphatidylcholine Prodrugs Studied With Fluorescence Lifetime Imaging And Super-Resolution Microscopy, Dolonchampa Maji, Jin Lu, Pinaki Sarder, Anne H Schmieder, Grace Cui, Xiaoxia Yang, Dipanjan Pan, Matthew D Lew, Samuel Achilefu, Gregory M Lanza

Open Access Publications

While the

Hepatic Ketogenic Insufficiency Reprograms Hepatic Glycogen Metabolism And The Lipidome, D. André D'Avignon, Patrycja Puchalska, Baris Ercal, Yingju Chang, Shannon E. Martin, Mark J. Graham, Gary J. Patti, Xianlin Han, Peter A. Crawford

Open Access Publications

While several molecular targets are under consideration, mechanistic underpinnings of the transition from uncomplicated nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) remain unresolved. Here we apply multiscale chemical profiling technologies to mouse models of deranged hepatic ketogenesis to uncover potential NAFLD driver signatures. Use of stable-isotope tracers, quantitatively tracked by nuclear magnetic resonance (NMR) spectroscopy, supported previous observations that livers of wild-type mice maintained long term on a high-fat diet (HFD) exhibit a marked increase in hepatic energy charge. Fed-state ketogenesis rates increased nearly 3-fold in livers of HFD-fed mice, a greater proportionate increase than that observed for …

Decreasing Recurrent Bowel Obstructions, Improving Quality Of Life With Physiotherapy: Controlled Study, Amanda D Rice, Kimberley Patterson, Evette D Reed, Belinda F Wurn, Kristen Robles, Bernhard Klingenberg, Leonard B Weinstock, Janey S. A. Pratt, C. Richard King Iii, Lawrence J Wurn

Open Access Publications

AIM: To compare (1) quality of life and (2) rate of recurrent small bowel obstructions (SBO) for patients treated with novel manual physiotherapy

METHODS: One hundred and three subjects (age 19-89) with a history of recurrent adhesive SBO were treated with a manual physiotherapy called the Clear Passage Approach (CPA) which focused on decreasing adhesive crosslinking in abdominopelvic viscera. Pre- and post-therapy data measured recurring obstructions and quality of life, using a validated test sent 90 d after therapy. Results were compared to 136 untreated control subjects who underwent the same measurements for subjects who did not receive any therapy, …

Aberrant Atrx Protein Expression Is Associated With Poor Overall Survival In Nf1-Mpnst, Hsiang-Chih Lu, Vanessa Eulo, Anthony J. Apicelli, Melike Pekmezci, Yu Tao, Jingqin Luo, Angela C. Hirbe, Sonika Dahiya

Open Access Publications

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive soft tissue sarcomas that can occur sporadically or in the setting of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. These tumors carry a dismal overall survival. Previous work in our lab had identified ATRX chromatin remodeler (

Sall1 Functions As A Tumor Suppressor In Breast Cancer By Regulating Cancer Cell Senescence And Metastasis Through The Nurd Complex, Chunling Ma, Fang Wang, Bing Han, Xiaoli Zhong, Fusheng Si, Jian Ye, Eddy C Hsueh, Lynn Robbins, Susan M Kiefer, Yanping Zhang, Pamela Hunborg, Mark A Varvares, Michael Rauchman, Guangyong Peng

Open Access Publications

BACKGROUND: SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown.

METHODS: We analyzed SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor …

Subclones Dominate At Mds Progression Following Allogeneic Hematopoietic Cell Transplant, Meagan A Jacoby, Eric J Duncavage, Gue Su Chang, Christopher A Miller, Jin Shao, Kevin Elliott, Joshua Robinson, Robert S Fulton, Catrina C Fronick, Michelle O'Laughlin, Sharon E Heath, Iskra Pusic, John S Welch, Daniel C Link, John F Dipersio, Peter Westervelt, Timothy J Ley, Timothy A Graubert, Matthew J Walter

Open Access Publications

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. …

Physiological Mechanisms Of Sustained Fumagillin-Induced Weight Loss, Jie An, Michael L Patnode, Vanessa K Ridaura, Jeffrey I Gordon, Et Al

Open Access Publications

Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feeding. Here, we show that feeding of rats on a high-fat diet supplemented with fumagillin (HF/FG) suppresses the aggressive feeding observed in pair-fed controls (HF/PF) and alters expression of circadian genes relative to the HF/PF group. Multiple indices of reduced energy expenditure are observed in HF/FG but not HF/PF rats. HF/FG rats also exhibit changes in gut hormones linked to food intake, increased energy harvest by …

Largest Gwas Of Ptsd (N=20 070) Yields Genetic Overlap With Schizophrenia And Sex Differences In Heritability., L E Duncan, A Ratanatharathorn, A E Aiello, L M Almli, A B Amstadter, A E Ashley-Koch, D G Baker, J C Beckham, L J Bierut, J Bisson, B Bradley, C-Y Chen, S Dalvie, L A Farrer, S Galea, M E Garrett, J E Gelernter, G Guffanti, M A Hauser, E O Johnson, R C Kessler, N A Kimbrel, A King, N Koen, H R Kranzler, M W Logue, A X Maihofer, A R Martin, M W Miller, R A Morey, N R Nugent, J P Rice, S Ripke, A L Roberts, N L Saccone, J W Smoller, D J Stein, M B Stein, J A Sumner, M Uddin, R J Ursano, D E Wildman, R Yehuda, H Zhao, M J Daly, I Liberzon, K J Ressler, C M Nievergelt, K C Koenen

Open Access Publications

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h

Successful Surgical Repair And Perioperative Management Of 6-Month-Old With Total Anomalous Pulmonary Venous Return In A Developing Country: Considerations For The Treatment Of Pulmonary Hypertension, Lakshmi Gokanapudy, Kenneth Remy, Sathappan Karuppiah, Eneida Melgar Humala, Ibrahim Abdullah, Michael Ruppe, William Schechter, Robert Michler, Joseph Tobias

Open Access Publications

Total anomalous pulmonary venous return (TAPVR) is a rare congenital cardiac defect, accounting for 1.5-3% of cases of congenital heart disease. With prenatal ultrasonography, the majority of these patients are diagnosed in utero with definitive surgery performed during the neonatal period. However, as prenatal screening may not be available in developing countries, patients may present in later infancy. We present successful surgical repair of a 6-month-old infant with TAPVR who presented for medical care at 5 months of age in Lima, Peru. The late presentation of such infants and the limited resources available for the treatment of elevated pulmonary vascular …

Incorporating Reflection Boundary Conditions In The Neumann Series Radiative Transport Equation: Application To Photon Propagation And Reconstruction In Diffuse Optical Imaging, Abhinav K. Jha, Yansong Zhu, Simon Arridge, Dean F. Wong, Arman Rahmim

Open Access Publications

No abstract provided.

Resistance-Promoting Effects Of Ependymoma Treatment Revealed Through Genomic Analysis Of Multiple Recurrences In A Single Patient, Christopher A. Miller, Sonika Dahiya, Tiandao Li, Robert S. Fulton, Matthew D. Smyth, Gavin P. Dunn, Joshua B. Rubin, Elaine R. Mardis

Open Access Publications

No abstract provided.

Diltiazem Improves Contractile Properties Of Skeletal Muscle In Dysferlin‐Deficient Blaj Mice, But Does Not Reduce Contraction‐Induced Muscle Damage, Morium Begam, Alyssa F. Collier, Amber L. Mueller, Renuka Roche, Sujay S. Galen, Joseph A. Roche

Open Access Publications

No abstract provided.

Methylation-Based Enrichment Facilitates Low-Cost, Noninvasive Genomic Scale Sequencing Of Populations From Feces, Kenneth L. Chiou, Christina M. Bergey

Open Access Publications

No abstract provided.

Tidal And Diel Orchestration Of Behaviour And Gene Expression In An Intertidal Mollusc, Y. Schnytzer, N. Simon-Blecher, J. Li, H. Waldman Ben-Asher, M. Salmon-Divon, Y. Achituv, M. E. Hughes, O. Levy

Open Access Publications

No abstract provided.

A Method For Identifying Mouse Pancreatic Ducts, Chiemi Nakajima, Kenji Kamimoto, Katsuhiro Miyajima, Masahito Matsumoto, Yasushi Okazaki, Kazuo Kobayashi-Hattori, Makoto Shimizu, Takumi Yamane, Yuichi Oishi, Ken Iwatsuki

Open Access Publications

No abstract provided.

Phylogenetic Placement Of Exact Amplicon Sequences Improves Associations With Clinical Information, Stefan Janssen, Daniel Mcdonald, Antonio Gonzalez, Jose A. Navas-Molina, Lingjing Jiang, Zhenjiang Zech Xu, Kevin Winkler, Deborah M. Kado, Eric Orwoll, Mark Manary, Siavash Mirarab, Rob Knight

Open Access Publications

No abstract provided.

Lightweight Scmos-Based High-Density Diffuse Optical Tomography, Karla M. Bergonzi, Tracy M. Burns-Yocum, Jonathan R. Bumstead, Elise M. Buckley, Patrick C. Mannion, Christopher H. Tracey, Eli Mennerick, Silvina L. Ferradal, Hamid Dehghani, Adam T. Eggebrecht, Jospeh P. Culver

Open Access Publications

No abstract provided.

Ubiquitinated Cd36 Sustains Insulin-Stimulated Akt Activation By Stabilizing Insulin Receptor Substrate 1 In Myotubes, Shishuo Sun, Pengcheng Tan, Xiaoheng Huang, Wei Zhang, Chen Kong, Fangfang Ren, Xiong Su

Open Access Publications

No abstract provided.

Physiologic Impact Of Circulating Rbc Microparticles Upon Blood-Vascular Interactions, Ahmed S. Said, Stephen C. Rogers, Allan Doctor

Open Access Publications

No abstract provided.

Retinal De Novo Lipogenesis Coordinates Neurotrophic Signaling To Maintain Vision, Rithwick Rajagopal, Sheng Zhang, Xiaochao Wei, Teresa Doggett, Sangeeta Adak, Jennifer Enright, Vaishali Shah, Guoyu Ling, Shiming Chen, Jun Yoshino, Fong-Fu Hsu, Clay F. Semenkovich

Open Access Publications

No abstract provided.

Development Of A Questionnaire To Measure Impact And Outcomes Of Brachial Plexus Injury, Carol A. Mancuso, Steve K. Lee, Eliana B. Saltzman, Zina Model, Zoe A. Landers, Christopher J. Dy, Scott W. Wolfe

Open Access Publications

No abstract provided.