Digital Commons Network^™

Determining Subpopulation Methylation Profiles From Bisulfite Sequencing Data Of Heterogeneous Samples Using Dxm, Jerry Fong, Jacob R. Gardner, Jared M. Andrews, Amanda F. Cashen, Jacqueline E. Payton, Kilian Q. Weinberger, John R. Edwards

Open Access Publications

Epigenetic changes, such as aberrant DNA methylation, contribute to cancer clonal expansion and disease progression. However, identifying subpopulation-level changes in a heterogeneous sample remains challenging. Thus, we have developed a computational approach, DXM, to deconvolve the methylation profiles of major allelic subpopulations from the bisulfite sequencing data of a heterogeneous sample. DXM does not require prior knowledge of the number of subpopulations or types of cells to expect. We benchmark DXM's performance and demonstrate improvement over existing methods. We further experimentally validate DXM predicted allelic subpopulation-methylation profiles in four Diffuse Large B-Cell Lymphomas (DLBCLs). Lastly, as proof-of-concept, we apply DXM …

Breast Cancer Derived Gm-Csf Regulates Arginase 1 In Myeloid Cells To Promote An Immunosuppressive Microenvironment, Xinming Su, Yalin Xu, Gregory C Fox, Jingyu Xiang, Kristin A Kwakwa, Jennifer L Davis, Jad I Belle, Wen-Chih Lee, Wing H Wong, Francesca Fontana, Leonel Hernandez-Aya, Takayuki Kobayashi, Helen M Tomasson, Junyi Su, Suzanne J Bakewell, Sheila A Stewart, Christopher Egbulefu, Partha Karmakar, Melissa A Meyer, Deborah J Veis, David G Denardo, Gregory M Lanza, Samuel Achilefu, Katherine N Weilbaecher

Open Access Publications

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (Arg-1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular L-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor derived GM-CSF as the primary regulator of myeloid cell Arg-1 expression and local immune suppression through a gene knockout screen of breast tumor cell-produced factors. The induction of myeloid cell Arg-1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3, …

Insights Into The Expanding Phenotypic Spectrum Of Inherited Disorders Of Biogenic Amines, Oya Kuseyri Hübschmann, Toni S. Pearson, Et Al

Open Access Publications

No abstract provided.

A Pilot Study Of 3d Tissue‑Engineered Bone Marrow Culture As A Tool To Predict Patient Response To Therapy In Multiple Myeloma, Kinan Alhallak, Amanda Jeske, Pilar De La Puente, Jennifer Sun, Mark Fiala, Feda Azab, Barbara Muz, Ilyas Sahin, Ravi Vij, John F. Dipersio, Abdel Kareem Azab

Open Access Publications

No abstract provided.

Prevalence Of Elevated Serum Fatty Acid Synthase In Chronic Limb‑Threatening Ischemia, Shirli Tay, Gayan S. De Silva, Connor M. Engel, Nikolai Harroun, Amanda S. Penrose, Kshitij A. Desai, Yan Yan, Clay F. Semenkovich, Mohamed A. Zayed

Open Access Publications

No abstract provided.

Electroporation Safety Factor Of 300 Nanosecond And 10 Millisecond Defibrillation In Langendorff-Perfused Rabbit Hearts, Johanna U. Neuber, Andrei G. Pakhomov, Christian W. Zemlin

Open Access Publications

AIMS: Recently, a new defibrillation modality using nanosecond pulses was shown to be effective at much lower energies than conventional 10 millisecond monophasic shocks in ex vivo experiments. Here we compare the safety factors of 300 nanosecond and 10 millisecond shocks to assess the safety of nanosecond defibrillation.

METHODS AND RESULTS: The safety factor, i.e. the ratio of median effective doses (ED50) for electroporative damage and defibrillation, was assessed for nanosecond and conventional (millisecond) defibrillation shocks in Langendorff-perfused New Zealand white rabbit hearts. In order to allow for multiple shock applications in a single heart, a pair of needle electrodes …

Accelerated Functional Brain Aging In Pre-Clinical Familial Alzheimer’S Disease, Julie Gonneaud, Brian A. Gordon, Carlos Cruchaga, Tammie L. S. Benzinger, John C. Morris, Randall J. Bateman, Susan Brandon, Virginia Buckles, Tamara Donahue, Anne Fagan, Gigi Flynn, Erin Franklin, Cortaiga Gant, Julia Gray, Alexander Groves, Jason Hassenstab, Laura Hoechst-Swisher, David Holtzman, Russ Hornbeck, Gina Jerome, Celeste Karch, Denise Maue-Dreyfus, Eric Mcdade, Joanne Norton, Richard Perrin, Marc Raichle, Wendy Sigurdson, Peter Wang, Chengjie Xiong, Xiong Xu, Nigel J. Cairns, Erin Householder, Lisa Taylor Reinwald, Beau Ances, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Et Al

Open Access Publications

No abstract provided.

Application Of A Time-Series Deep Learning Model To Predict Cardiac Dysrhythmias In Electronic Health Records, Aixia Guo, Sakima Smith, Yosef M. Khan, James R. Langabeer Ii, Randi E. Foraker

Open Access Publications

BACKGROUND: Cardiac dysrhythmias (CD) affect millions of Americans in the United States (US), and are associated with considerable morbidity and mortality. New strategies to combat this growing problem are urgently needed.

OBJECTIVES: Predicting CD using electronic health record (EHR) data would allow for earlier diagnosis and treatment of the condition, thus improving overall cardiovascular outcomes. The Guideline Advantage (TGA) is an American Heart Association ambulatory quality clinical data registry of EHR data representing 70 clinics distributed throughout the US, and has been used to monitor outpatient prevention and disease management outcome measures across populations and for longitudinal research on the …

Tracheal Aspirate Rna Sequencing Identifies Distinct Immunological Features Of Covid-19 Ards, Aartik Sarma, Pratik Sinha, Et Al

Open Access Publications

No abstract provided.

Isolation Of Reconstructed Functional Ribonucleoprotein Complexes Of Machupo Virus, Jesse D. Pyle, Sean P.J. Whelan

Open Access Publications

Arenaviruses initiate infection by delivering a transcriptionally competent ribonucleoprotein (RNP) complex into the cytosol of host cells. The arenavirus RNP consists of the large (L) RNA-dependent RNA polymerase (RdRP) bound to a nucleoprotein (NP)-encapsidated genomic RNA (viral RNA [vRNA]) template. During transcription and replication, L must transiently displace RNA-bound NP to allow for template access into the RdRP active site. Concomitant with RNA replication, new subunits of NP must be added to the nascent complementary RNAs (cRNA) as they emerge from the product exit channel of L. Interactions between L and NP thus play a central role in arenavirus gene …

Comprehensive Characterization Of 536 Patient-Derived Xenograft Models Prioritizes Candidates For Targeted Treatment, Hua Sun, Song Cao, R. Jay Mashl, Chia-Kuei Mo, Sherri R. Davies, Tina M. Primeau, Jeremy Hoog, Jacqueline L. Mudd, Matthew A. Wyczalkowski, Reyka G. Jayasinghe, Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Yize Li, Kian-Huat Lim, Andrea Wang-Gillam, Brian A. Van Tine, Cynthia X. Ma, Katherine C. Fuh, John F. Dipersio, Julie Belmar, Jason Held, Rose Tipton, Yige Wu, Lijun Yao, Daniel Cui Zhou, Feng Chen, Shunqiang Li, Ramaswamy Govindan, Li Ding, Michael C. Wendl, Rebecca Aft, Julie K. Schwarz, Jose P. Zevallos, Sidharth V. Puram, Jingqin Luo, Ryan C. Fields, Et Al

Open Access Publications

No abstract provided.

Zika Virus Infection Of Pregnant Ifnar1-/- Mice Triggers Strain-Specific Differences In Fetal Outcomes, Ellie K. Bohm, Jennifer T. Vangorder-Braid, Anna S. Jaeger, Ryan V. Moriarty, John J. Baczenas, Natalie C. Bennett, Shelby L. O'Connor, Michael K. Fritsch, Nicole A. Fuhler, Kevin K. Noguchi, Matthew T. Aliota

Open Access Publications

Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed congenital Zika syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. During the 2015 to 2016 American outbreak of ZIKV, CZS rates varied by geographic location. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian-/American-lineage ZIKV strains in an established

Charge Syndrome Protein Chd7 Regulates Epigenomic Activation Of Enhancers In Granule Cell Precursors And Gyrification Of The Cerebellum, Naveen C. Reddy, Shahriyar P. Majidi, Lingchun Kong, Mati Nemera, Cole J. Ferguson, Michael Moore, Tassia M. Goncalves, Hai-Kun Liu, James A. J. Fitzpatrick, Guoyan Zhao, Tomoko Yamada, Azad Bonni, Harrison W. Gabel

Open Access Publications

No abstract provided.

Circulating Cd5l Is Associated With Cardiovascular Events And All-Cause Mortality In Individuals With Chronic Kidney Disease, Esmeralda Castelblanco, Maria R. Sarrias, Àngels Betriu, Berta Soldevila, Maria Barranco-Altirriba, Josep Franch-Nadal, Jose M. Valdivielso, Marcelino Bermudez-Lopez, Per-Henrik Groop, Elvira Fernández, Núria Alonso, Didac Mauricio

Open Access Publications

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age …

Lyve1+ Macrophages Of Murine Peritoneal Mesothelium Promote Omentum-Independent Ovarian Tumor Growth, Nan Zhang, Anastasiia Gainullina, Emma C. Erlich, Emily J. Onufer, Rafael S. Czepielewski, Beth A. Helmink, Brian T. Saunders, Jesse W. Williams, Bernd H. Zinselmeyer, Gwendalyn J. Randolph, Ki-Wook Kim, Et Al

Open Access Publications

Two resident macrophage subsets reside in peritoneal fluid. Macrophages also reside within mesothelial membranes lining the peritoneal cavity, but they remain poorly characterized. Here, we identified two macrophage populations (LYVE1hi MHC IIlo-hi CX3CR1gfplo/- and LYVE1lo/- MHC IIhi CX3CR1gfphi subsets) in the mesenteric and parietal mesothelial linings of the peritoneum. These macrophages resembled LYVE1+ macrophages within surface membranes of numerous organs. Fate-mapping approaches and analysis of newborn mice showed that LYVE1hi macrophages predominantly originated from embryonic-derived progenitors and were controlled by CSF1 made by Wt1+ stromal cells. Their gene expression profile closely overlapped with ovarian tumor-associated macrophages previously described in the …

Modeling Spinal Locomotor Circuits For Movements In Developing Zebrafish, Yann Roussel, Stephanie F. Gaudreau, Emily R. Kacer, Mohini Sengupta, Tuan V. Bui

Open Access Publications

Many spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of …

Is Left-Behind A Real Reason For Children's Social Cognition Deficit? An Fnirs Study On The Effect Of Social Interaction On Left-Behind Preschooler's Prefrontal Activation, Keya Ding, Chuanjiang Li, Huibin Jia, Mingming Zhang, Dongchuan Yu

Open Access Publications

The left-behind phenomenon, caused by parent out-migration, has become a common social issue and might lead to long-term and potential risks for children in rural areas of China. It is important to investigate the effect of social interaction on prefrontal activation of left-behind children in China because of possible effects of parent out-migration on children's social cognition. We recruited 81 rural Chinese preschoolers aged 52-76 months (mean = 64.98 ± 6.321 months) preschoolers with three different statuses of parental out-migration (including non-, partially, and completely left-behind children). Using functional Near-Infrared Spectroscopy (fNIRS), we compared behavior and brain activation and in …

Neuronal Activity In Dorsal Anterior Cingulate Cortex During Economic Choices Under Variable Action Costs, Xinying Cai, Camillo Padoa-Schioppa

Open Access Publications

The role of the dorsal anterior cingulate cortex (ACCd) in decision making has often been discussed but remains somewhat unclear. On the one hand, numerous studies implicated this area in decisions driven by effort or action cost. On the other hand, work on economic choices between goods (under fixed action costs) found that neurons in ACCd encoded only post-decision variables. To advance our understanding of the role played by this area in decision making, we trained monkeys to choose between different goods (juice types) offered in variable amounts and with different action costs. Importantly, the task design dissociated computation of …

Development And Assessment Of A Clinical Calculator For Estimating The Likelihood Of Recurrence And Survival Among Patients With Locally Advanced Rectal Cancer Treated With Chemotherapy, Radiotherapy, And Surgery, Martin R Weiser, William C. Chapman, Philip S. Bauer, Matthew G. Mutch, Parag J. Parikh, Et Al

Open Access Publications

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed.

Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score.

Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using …

Acaricidal Activity Of Foeniculum Vulgare Against Rhipicephalus Annulatus Is Mainly Dependent On Its Constituent From Trans-Anethone, Shawky M. Aboelhadid, Waleed M. Arafa, Abdel-Azeem S. Abdel-Baki, Atalay Sokmen, Saleh Al-Quraishy, Ahmed O. Hassan, Asmaa A. Kamel

Open Access Publications

Globally, the economic losses due to hard ticks infestation and the control of the associated diseases have been calculated at USD $13.9-18.7 billion per year. The economic impact is related to its direct damage to the skins, blood loss, anemia, severe immunological reactions and indirect losses that related to the effects of hemoparasites, cost of treatment for clinical cases and expenses incurred in the control of ticks. The current study evaluated the acaricidal activities of fennel Foeniculum vulgare essential oil and its main components; trans-anethole and fenchone; against R. annulatus. GC-MS analysis revealed that this oil contained 16 components representing …

The Kanyakla Study: Randomized Controlled Trial Of A Microclinic Social Network Intervention For Promoting Engagement And Retention In Hiv Care In Rural Western Kenya, Matthew D. Hickey, Elvin H. Geng, Et Al

Open Access Publications

BACKGROUND: Existing social relationships are a potential source of "social capital" that can enhance support for sustained retention in HIV care. A previous pilot study of a social network-based 'microclinic' intervention, including group health education and facilitated HIV status disclosure, reduced disengagement from HIV care. We conducted a pragmatic randomized trial to evaluate microclinic effectiveness.

METHODS: In nine rural health facilities in western Kenya, we randomized HIV-positive adults with a recent missed clinic visit to either participation in a microclinic or usual care (NCT02474992). We collected visit data at all clinics where participants accessed care and evaluated intervention effect on …

Live Imaging Reveals The Cellular Events Downstream Of Sarm1 Activation, Kwang Woo Ko, Laura Devault, Yo Sasaki, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

SARM1 is an inducible NAD

Intestinal Goblet Cells Sample And Deliver Lumenal Antigens By Regulated Endocytic Uptake And Transcytosis, Jenny K. Gustafsson, Jazmyne E. Davis, Tracy Rappai, Keely G. Mcdonald, Devesha H. Kulkarni, Kathryn A. Knoop, Simon P. Hogan, James A.J. Fitzpatrick, Wayne I. Lencer, Rodney D. Newberry

Open Access Publications

Intestinal goblet cells maintain the protective epithelial barrier through mucus secretion and yet sample lumenal substances for immune processing through formation of goblet cell associated antigen passages (GAPs). The cellular biology of GAPs and how these divergent processes are balanced and regulated by goblet cells remains unknown. Using high-resolution light and electron microscopy, we found that in mice, GAPs were formed by an acetylcholine (ACh)-dependent endocytic event remarkable for delivery of fluid-phase cargo retrograde into the trans-golgi network and across the cell by transcytosis - in addition to the expected transport of fluid-phase cargo by endosomes to multi-vesicular bodies and …

Practical Considerations For Quantitative Clinical Spect/Ct Imaging Of Alpha Particle Emitting Radioisotopes, Nadia Benabdallah, William Scheve, Nicholas Dunn, Delynn Silvestros, Paul Schelker, Diane Abou, Uday Jammalamadaka, Richard Laforest, Zekun Li, Jonathan Liu, David Ballard, Nichole Maughan, Hiram Gay, Brian Baumann, Robert Hobbs, Buck Rogers, Amir Iravani, Abhinav Jha, Farrokh Dehdashti, Daniel Thorek

Open Access Publications

No abstract provided.

Unfriendly Fire: How The Tobacco Industry Is Destroying The Future Of Our Children, Andrew Bush, Thomas Ferkol, Et Al.

2020-Current year OA Pubs

Tobacco has long been known to be one of the greatest causes of morbidity and mortality in the adults, but the effects on the foetus and young children, which are lifelong, have been less well appreciated. Developing from this are electronic nicotine delivery systems or vapes, promulgated as being less harmful than tobacco. Nicotine itself is toxic to the foetus, with permanent effects on lung structure and function. Most vapes contain nicotine, but they also contain many other compounds which are inhaled and for which there are no toxicity studies. They also contain known toxic substances, whose use is banned …

Assessment Of Antibiotic De-Escalation By Spectrum Score In Patients With Nosocomial Pneumonia: A Single-Center, Retrospective Cohort Study, Dan Ilges, David J. Ritchie, Tamara Krekel, Elizabeth A. Neuner, Nicholas Hampton, Marin H. Kollef, Scott Micek

Open Access Publications

Background: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) cause significant mortality. Guidelines recommend empiric broad-spectrum antibiotics followed by de-escalation (DE). This study sought to assess the impact of DE on treatment failure.

Methods: This single-center retrospective cohort study screened all adult patients with a discharge diagnosis code for pneumonia from 2016 to 2019. Patients were enrolled if they met predefined criteria for HAP/VAP ≥48 hours after admission. Date of pneumonia diagnosis was defined as day 0. Spectrum scores were calculated, and DE was defined as a score reduction on day 3 versus day 1. Patients with DE were compared to patients with …

Pet Study Of Sphingosine-1-Phosphate Receptor 1 Expression In Response To S. Aureus Infection, Hao Jiang, Jiwei Gu, Haiyang Zhao, Sumit Joshi, Joel Perlmutter, Robert Gropler, Robyn Klein, Tammie Benzinger, Zhude Tu

Open Access Publications

Sphingosine-1-phosphate receptor 1 (S1PR1) plays a crucial role in infectious diseases. Targeting S1PR1 provides protection against pathogens, such as influenza viruses. This study is aimed at investigating S1PR1 in response to bacterial infection by assessing S1PR1 expression in

Infectious Disease Providers’ Knowledge Of And Engagement In Quality Improvement, Kathleen R. Sheridan, Michael A. Lane, Thomas J. Kim, Joshua C. Eby

Open Access Publications

No abstract provided.

Comparison Of Response To Definitive Radiotherapy For Localized Prostate Cancer In Black And White Men: A Meta-Analysis, Ting Martin Ma, Jeff M. Michalski, Et Al

Open Access Publications

Importance: Black men have a 2-fold increased risk of dying from prostate cancer compared with White men. However, race-specific differences in response to initial treatment remain unknown.

Objective: To compare overall and treatment-specific outcomes of Black and White men with localized prostate cancer receiving definitive radiotherapy (RT).

Data Sources: A systematic search was performed of relevant published randomized clinical trials conducted by the NRG Oncology/Radiation Therapy Oncology Group between January 1, 1990, and December 31, 2010. This meta-analysis was performed from July 1, 2019, to July 1, 2021.

Study Selection: Randomized clinical trials of definitive RT for patients with localized …

A Proinflammatory Stimulus Disrupts Hippocampal Plasticity And Learning Via Microglial Activation And 25-Hydroxycholesterol, Yukitoshi Izumi, Anil G. Cashikar, Kathiresan Krishnan, Steven M. Paul, Douglas F. Covey, Steven J. Mennerick, Charles F. Zorumski

Open Access Publications

Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than