Digital Commons Network^™

Circulating Serum Fatty Acid Synthase Is Elevated In Patients With Diabetes And Carotid Artery Stenosis And Is Ldl-Associated, Gayan S De Silva, Kshitij Desai, Malik Darwech, Uzma Naim, Xiaohua Jin, Sangeeta Adak, Nikolai Harroun, Luis A Sanchez, Clay F Semenkovich, Mohamed A Zayed

Open Access Publications

BACKGROUND AND AIMS: Diabetes is an independent risk factor for carotid artery stenosis (CAS). Fatty acid synthase (FAS), an essential de novo lipogenesis enzyme, has increased activity in the setting of diabetes that leads to altered lipid metabolism. Circulating FAS (cFAS) was recently observed in the blood of patients with hyperinsulinemia and cancer. We thought to evaluate the origin of cFAS and its role in diabetes-associated CAS.

METHODS: Patients with diabetes and no diabetes, undergoing carotid endarterectomy (CEA) for CAS, were prospectively enrolled for collection of plaque and fasting serum. FPLC was used to purify lipoprotein fractions, and ELISA was …

Quantification Of Image Texture In X-Ray Phase-Contrast-Enhanced Projection Images Of In Vivo Mouse Lungs Observed At Varied Inflation Pressures, Frank J Brooks, Sean P Gunsten, Sunil K Vasireddi, Steven L Brody, Mark A Anastasio

Open Access Publications

To date, there are very limited noninvasive, regional assays of in vivo lung microstructure near the alveolar level. It has been suggested that x-ray phase-contrast enhanced imaging reveals information about the air volume of the lung; however, the image texture information in these images remains underutilized. Projection images of in vivo mouse lungs were acquired via a tabletop, propagation-based, X-ray phase-contrast imaging system. Anesthetized mice were mechanically ventilated in an upright position. Consistent with previously published studies, a distinct image texture was observed uniquely within lung regions. Lung regions were automatically identified using supervised machine learning applied to summary measures …

Novel Cell Adhesion/Migration Pathways Are Predictive Markers Of Hdac Inhibitor Resistance In Cutaneous T Cell Lymphoma, Jared M Andrews, Jennifer A Schmidt, Kenneth R Carson, Amy C Musiek, Neha Mehta-Shah, Jacqueline E Payton

Open Access Publications

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.

METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks …

Host And Viral Mechanisms Of Congenital Zika Syndrome, Brooke Liang, José Paulo Guida, Maria Laura Costa Do Nascimento, Indira U Mysorekar

Open Access Publications

In 2015-2016, in the Americas, and especially in northeast Brazil, a significant number of cases of microcephaly and other congenital brain abnormalities were linked with an outbreak of Zika virus (ZIKV) infection in pregnant women. While maternal symptoms of ZIKV are generally mild and self-limiting, clinical presentation in fetuses and newborns infected is extensive and includes microcephaly, decreased cortical development, atrophy and hypoplasia of the cerebellum and cerebellar vermis, arthrogryposis, and polyhydramnios. The term congenital ZIKV syndrome (CZS) was introduced to describe the range of findings associated with maternal-fetal ZIKV transmission. ZIKV is primarily transmitted by

Precision Delivery Of Ras-Inhibiting Sirna To Kras Driven Cancer Via Peptide-Based Nanoparticles, Matthew S. Strand, Bradley A. Krasnick, Hua Pan, Xiuli Zhang, Ye Bi, Candace Brooks, Christopher Wetzel, Narendra Sankpal, Timothy Fleming, S Peter Goedegebuure, David G. Denardo, William E. Gillanders, William G. Hawkins, Samuel A. Wickline, Ryan C. Fields

Open Access Publications

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient …

Spinal V2b Neurons Reveal A Role For Ipsilateral Inhibition In Speed Control, Rebecca A. Callahan, Richard Roberts, Mohini Sengupta, Yukiko Kimura, Shin-Ichi Higashijima, Martha W. Bagnall

Open Access Publications

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting …

Situating Dissemination And Implementation Sciences Within And Across The Translational Research Spectrum, Aaron L Leppin, Jane E Mahoney, Kathleen R Stevens, Stephen J Bartels, Laura-Mae Baldwin, Rowena J Dolor, Enola K Proctor, Linda Scholl, Justin B Moore, Ana A Baumann, Catherine L Rohweder, Joan Luby, Paul Meissner

Open Access Publications

The efficient and effective movement of research into practice is acknowledged as crucial to improving population health and assuring return on investment in healthcare research. The National Center for Advancing Translational Science which sponsors Clinical and Translational Science Awards (CTSA) recognizes that dissemination and implementation (D&I) sciences have matured over the last 15 years and are central to its goals to shift academic health institutions to better align with this reality. In 2016, the CTSA Collaboration and Engagement Domain Task Force chartered a D&I Science Workgroup to explore the role of D&I sciences across the translational research spectrum. This special …

Low-Carbohydrate Diets For Gestational Diabetes, Sarah S Farabi, Teri L Hernandez

Open Access Publications

Nutrition therapy provides the foundation for treatment of gestational diabetes (GDM), and has historically been based on restricting carbohydrate (CHO) intake. In this paper, randomized controlled trials (RCTs) are reviewed to assess the effects of both low- and higher CHO nutrition approaches in GDM. The prevailing pattern across the evidence underscores that although CHO restriction improves glycemia at least in the short-term, similar outcomes could be achievable using less restrictive approaches that may not exacerbate IR. The quality of existing studies is limited, in part due to dietary non-adherence and confounding effects of treatment with insulin or oral medication. Recent …

Ml277 Specifically Enhances The Fully Activated Open State Of Kcnq1 By Modulating Vsd-Pore Coupling, Panpan Hou, Jingyi Shi, Kelli Mcfarland White, Yuan Gao, Jianmin Cui

Open Access Publications

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form I

Functional Outcome Of Adulthood Selective Dorsal Rhizotomy For Spastic Diplegia, T. S. Park, So Yeon Uhm, Deanna M. Walter, Nicole L. Meyer, Matthew B. Dobbs

Open Access Publications

Objective The medical evidence supporting the efficacy of selective dorsal rhizotomy (SDR) on children with spastic diplegia is strong. However, the outcome of SDR on adults with spastic diplegia remains undetermined. The aim is to study the effectiveness and morbidities of SDR performed on adults for the treatment of spastic diplegia. Methods Patients who received SDR in adulthood for the treatment of spastic diplegia were surveyed. The survey questionnaire addressed the living situation, education level, employment, health outcomes, postoperative changes of symptoms, changes in ambulatory function, adverse effects of SDR and orthopedic surgery after SDR. Results The study included 64 …

A Sparse Covarying Unit That Describes Healthy And Impaired Human Gut Microbiota Development, Arjun S Raman, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Sathish Subramanian, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of …

Effects Of Microbiota-Directed Foods In Gnotobiotic Animals And Undernourished Children, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Vanderlene L Kung, Jiye Cheng, Robert Y Chen, Sathish Subramanian, Carrie A Cowardin, Martin F Meier, David O'Donnell, Michael Talcott, Larry D Spears, Clay F Semenkovich, Christopher Sawyer, Richard D Head, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF …

A Stem-Cell-Derived Platform Enables Complete Cryptosporidium Development In Vitro And Genetic Tractability, Georgia Wilke, Lisa J Funkhouser-Jones, Yi Wang, Soumya Ravindran, Qiuling Wang, Wandy L Beatty, Megan T Baldridge, Kelli L Vandussen, Bang Shen, Mark S Kuhlenschmidt, Theresa B Kuhlenschmidt, William H Witola, Thaddeus S Stappenbeck, L. David Sibley

Open Access Publications

Despite being a frequent cause of severe diarrheal disease in infants and an opportunistic infection in immunocompromised patients, Cryptosporidium research has lagged due to a lack of facile experimental methods. Here, we describe a platform for complete life cycle development and long-term growth of C. parvum in vitro using "air-liquid interface" (ALI) cultures derived from intestinal epithelial stem cells. Transcriptomic profiling revealed that differentiating epithelial cells grown under ALI conditions undergo profound changes in metabolism and development that enable completion of the parasite life cycle in vitro. ALI cultures support parasite expansion > 100-fold and generate viable oocysts that are transmissible …

A Guinea Fowl Genome Assembly Provides New Evidence On Evolution Following Domestication And Selection In Galliformes, Alain Vignal, Simon Boitard, Noémie Thébault, Guiguigbaza-Kossigan Dayo, Valentine Yapi-Gnaore, Issaka Youssao Abdou Karim, Cécile Berthouly-Salazar, Nóra Pálinkás-Bodzsár, Daniel Guémené, Francoise Thibaud-Nissen, Wesley C Warren, Michèle Tixier-Boichard, Xavier Rognon

Open Access Publications

The helmeted guinea fowl Numida meleagris belongs to the order Galliformes. Its natural range includes a large part of sub-Saharan Africa, from Senegal to Eritrea and from Chad to South Africa. Archaeozoological and artistic evidence suggest domestication of this species may have occurred about 2,000 years BP in Mali and Sudan primarily as a food resource, although villagers also benefit from its capacity to give loud alarm calls in case of danger, of its ability to consume parasites such as ticks and to hunt snakes, thus suggesting its domestication may have resulted from a commensal association process. Today, it is …

The Future Is Open: Open-Source Tools For Behavioral Neuroscience Research, Samantha R White, Linda M Amarante, Alexxai V Kravitz, Mark Laubach

Open Access Publications

No abstract provided.

Neil Schechter Oral History.

Pediatric Palliative Care Oral History Project

Dr. Neil Schechter begins this interview by describing the state of the pediatric pain field during the late 1970s. As he was training, he "felt it was a bit wrong" to have the disciplines dealing with physical and emotional/mental well-being so divorced from one another, especially with unaddressed psychosocial care for pediatric patients and families during complex chronic conditions such as cancer and sickle cell. Dr. Schechter also recalls a prevalent fear in the medical community of addicting children to pain medication, which kept clinicians from treating children's pain at all. Dr. Schechter questioned why pain was so chronically undertreated …

Danai Papadatou Oral History.

Pediatric Palliative Care Oral History Project

Dr. Papadatou introduces her early beginnings in the field of pediatric palliative care and recalls several of influential figures in her life. These figures were "models of professionalism and humanity," and included her father, her professor, and a 30-year-old woman with ovarian cancer who "made it a point to teach [physicians], advocate [for patients], and prove wrong all the prognostics." Dr. Papadatou describes her international work in research, education, and her experience with organizing international events that incorporated some of the fields pioneers, such as Charles Corr, Elisabeth Kubler-Ross, Earl Grollman, Ida Martinson, Betty Davies, and many others. Dr. Papadatou …

Ann Armstrong-Dailey Oral History.

Pediatric Palliative Care Oral History Project

Ms. Ann Armstrong-Dailey begins her interview by describing some early pivotal moments in her life that led her to a career advocating for palliative care. She first describes the memory of her and her mother fleeing kamikaze pilots and German submarines in Pearl Harbor, Hawaii and how that was a formative moment in understanding the processing power and tenacity of children. She then describes the circumstances of her brother's death and the lack of support she received as a transformational moment that empowered her to "audaciously" seek out the global leaders of the world and ask them" why isn't there …

Unified Single-Cell Analysis Of Testis Gene Regulation And Pathology In Five Mouse Strains, Min Jung, Daniel Wells, Jannette Rusch, Suhaira Ahmad, Jonathan Marchini, Simon R. Myers, Donald F. Conrad

Open Access Publications

To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyze a novel 57,600 cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes

Intracellular Retention Of Mutant Lysyl Oxidase Leads To Aortic Dilation In Response To Increased Hemodynamic Stress, Vivian S Lee, Carmen M Halabi, Thomas J Broekelmann, Philip C Trackman, Nathan O Stitziel, Robert P Mecham

Open Access Publications

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and …

Bjc Today

BJC Today

No abstract provided.

Betty Davies Oral History.

Pediatric Palliative Care Oral History Project

Dr. Betty Davies begins with several stories about her first dying patients as a young professional and the gaps in both her education and the humanity about how death was handled in the hospital setting. Dr. Davies felt that cultivating dialogue about death, dying, and bereavement was a very important "human activity," that was being neglected. Early into her career, Dr. Davies connected with other likeminded professionals who supported her while she endeavored to give trainings and workshops. She then recalls her work in developing Canuck Place as well as her contributions to research, programs, and the international knowledge base …

Reactive Microglia And Il1Β/Il-1r1-Signaling Mediate Neuroprotection In Excitotoxin-Damaged Mouse Retina, Levi Todd, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh V Hoang, Warren A Campbell, Seth Blackshaw, Ning Quan, Andy J Fischer

Open Access Publications

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.

METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell …

Eosinophils Downregulate Lung Alloimmunity By Decreasing Tcr Signal Transduction, Oscar Okwudiri Onyema, Yizhan Guo, Bayan Mahgoub, Qing Wang, Amir Manafi, Zhongcheng Mei, Anirban Banerjee, Dongge Li, Mark H. Stoler, Melissa T. Zaidi, Adam G. Schrum, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, Alexander Sasha Krupnick

Open Access Publications

Despite the accepted notion that granulocytes play a universally destructive role in organ and tissue grafts, it has been recently described that eosinophils can facilitate immunosuppression-mediated acceptance of murine lung allografts. The mechanism of eosinophil-mediated tolerance, or their role in regulating alloimmune responses in the absence of immunosuppression, remains unknown. Using lung transplants in a fully MHC-mismatched BALB/c (H2d) to C57BL/6 (H2b) strain combination, we demonstrate that eosinophils downregulate T cell-mediated immune responses and play a tolerogenic role even in the absence of immunosuppression. We further show that such downregulation depends on PD-L1/PD-1-mediated synapse formation between eosinophils and T cells. …

Vesicular Glutamatergic Transmission In Noise-Induced Loss And Repair Of Cochlear Ribbon Synapses, Kyunghee X. Kim, Shelby Payne, Aizhen Yang-Hood, Song-Zhe Li, Bethany Davis, Jason Carlquist, Babak V-Ghaffari, Jay A. Gantz, Dorina Kallogjeri, James A.J. Fitzpatrick, Kevin K. Ohlemiller, Keiko Hirose, Mark A. Rutherford

Open Access Publications

Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3 (

Pi3k Inhibition Enhances The Anti-Tumor Effect Of Eribulin In Triple Negative Breast Cancer, Sandeep Rajput, Zhanfang Guo, Shunqiang Li, Cynthia X. Ma

Open Access Publications

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is commonly observed in triple negative breast cancer (TNBC), leading to activation of the phosphoinositide 3-kinase (PI3K) signaling to promote tumor cell growth and chemotherapy resistance. In this study, we investigated whether adding a pan-PI3K inhibitor could improve the cytotoxic effect of eribulin, a non-taxane microtubule inhibitor, in TNBC patient-derived xenograft models (PDX) with loss of PTEN, and the underlying molecular mechanisms. Three TNBC-PDX models (WHIM6, WHIM12 and WHIM21), all with loss of PTEN expression, were tested for their response to BKM120 and eribulin, alone or in combination

Immunomodulatory Role Of Non-Neuronal Cholinergic Signaling In Myocardial Injury, Cibele Rocha-Resende, Carla Weinheimer, Geetika Bajpai, Luigi Adamo, Scot J. Matkovich, Joel Schilling, Philip M. Barger, Kory J. Lavine, Douglas L. Mann

Open Access Publications

Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was …

Bjc Today

BJC Today

No abstract provided.

Expression Of Factor V By Resident Macrophages Boosts Host Defense In The Peritoneal Cavity, Nan Zhang, Rafael S. Czepielewski, Nicholas N. Jarjour, Emma C. Erlich, Ekaterina Esaulova, Brian T. Saunders, Steven P. Grover, Audrey C. Cleuren, George J. Broze, Brian T. Edelson, Nigel Mackman, Bernd H. Zinselmeyer, Gwendalyn J. Randolph

Open Access Publications

Macrophages resident in different organs express distinct genes, but understanding how this diversity fits into tissue-specific features is limited. Here, we show that selective expression of coagulation factor V (FV) by resident peritoneal macrophages in mice promotes bacterial clearance in the peritoneal cavity and serves to facilitate the well-known but poorly understood "macrophage disappearance reaction." Intravital imaging revealed that resident macrophages were nonadherent in peritoneal fluid during homeostasis. Bacterial entry into the peritoneum acutely induced macrophage adherence and associated bacterial phagocytosis. However, optimal control of bacterial expansion in the peritoneum also required expression of FV by the macrophages to form …

The Current State Of Animal Models And Genomic Approaches Towards Identifying And Validating Molecular Determinants Of Mycobacterium Tuberculosis Infection And Tuberculosis Disease, Allison N Bucsan, Smriti Mehra, Shabaana A Khader, Deepak Kaushal

2010-2019 OA Pubs

Animal models are important in understanding both the pathogenesis of and immunity to tuberculosis (TB). Unfortunately, we are beginning to understand that no animal model perfectly recapitulates the human TB syndrome, which encompasses numerous different stages. Furthermore, Mycobacterium tuberculosis infection is a very heterogeneous event at both the levels of pathogenesis and immunity. This review seeks to establish the current understanding of TB pathogenesis and immunity, as validated in the animal models of TB in active use today. We especially focus on the use of modern genomic approaches in these models to determine the mechanism and the role of specific …