bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systems Thinking: An approach for departmental transformation in the life sciences
Authors: Offerdahl Erika G. , Gangera Gita , Bronson Claire , Byers Steve , Davis William , DeMarais Alyce , Fitzhugh Ginger , Goedhart Christine , Linder Nalani , Liston Carrie , McFarland Jenny , Otto Joann , Pape-Lindstrom Pamela , Pollock Carol , Reiness Gary , Stavrianeas Stasinos , Wenderoth Mary Pat 
Published: April 2020

The Partnership for Undergraduate Life Sciences Education (PULSE) is a national organization that supports department‐level efforts to transform life sciences programs to align with the recommendations of Vision and Change (V&C). With support from the NSF, a team of PULSE fellows from the Pacific Northwest region created a program consisting of (1) a three‐day, team‐based workshop on how to apply systems‐thinking approaches to organizational change and (2) a mentored execution of a department‐level transformation plan. Over the past five years, faculty teams have participated from over 40% (63/148) of institutions in the NW region, including 27 community colleges, 15 liberal arts, and 11 masters granting, 9 doctoral granting and one professional‐degree granting institutions.Reported here are the short and long term outcomes of the first 45 institutional teams from years 1–3 of the project. A mixed‐methods approach was applied to (a) understand the ways in which NW PULSE supported departmental transformation, (b) identify strategies used by department and the relative efficacy of those strategies, and (c) determine emergent practices to inform departmental transformation efforts nationwide. Pre‐ and post‐surveys were administered prior to and immediately following the workshop and 6–7 months later. Long‐term effects of program participation were measured by a longitudinal survey. Fifty‐seven percent of the 138 individual participants responded to the survey, representing 87% (39 of 45) of institutions. An outlier sampling approach was subsequently used to interview faculty and administrators at 12 institutions to identify factors that contribute to departmental/institutional transformation.Results from the evaluation provide insight into potential “better practices” for supporting biology education reform. First, our data support the recommendation for systematic and inclusive engagement of faculty, especially faculty that represent the composition of the department and those that have decision‐making power or influence in the department. Further, while a critical mass of faculty is needed for transformation, our data suggest that effective transformation need not involve all department faculty members. Second, our data underscore the importance of providing a range of resources and support. Not surprisingly, there is no “one‐size‐fits‐all” approach because each institution has its own unique context. Finally, our data demonstrate the efficacy of applying systems thinking to department transformation efforts. These data are consistent with prior literature encouraging multiple levers across levels within the organization to catalyze change.
Simulations of Combination Therapy in Hepatocellular Carcinoma Using a Quantitative Systems Pharmacology Model
Authors: Sove Richard J. , Jafarnejad Mohammad , Wang Hanwen , Yarchoan Mark , Popel Aleksander S. 
Published: April 2020

Hepatocellular carcinoma (HCC) is a major health concern and despite efforts to screen at‐risk individuals, diagnosis often occurs at late stages when patients are no longer candidates for potentially curative therapies (i.e. surgical resection, ablation, or transplantation). For patients with advanced HCC, tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors may provide clinical benefit, but overall survival remains low. One strategy that has shown promise in on‐going clinical trials is to administer a combination of TKIs and immune checkpoint inhibitors. Despite the increased number of patients that respond to combination therapy compared to individual therapies, there is still a large fraction of patients who remain unresponsive. Therefore, to improve therapy outcomes for patients with HCC, there are two broad questions which need to be addressed. First, through which mechanisms are the therapies interacting in HCC, and secondly, why are they effective in only a subset of patients?To address these questions, we developed a mechanistic quantitative systems pharmacology (QSP) modeling platform for immuno‐oncology (IO) that can be used to predict the progression of HCC in response to molecular and immune therapies. This model integrates cancer growth, immune response, and intracellular signaling in four compartments (tumor, tumor‐draining lymph node, central and peripheral), and considers the interactions and transport of various immune cells (e.g. effector T cells, T regulatory cells and antigen presenting cells) as well as the growth of tumor cells which are partially dictated by interactions with immune cells in the tumor compartment. Additionally, the model includes the binding kinetics of immune checkpoint proteins. Further, pharmacokinetic models are used to model the uptake, transport and clearance of immune checkpoint inhibitors, and the antibodies in the model by bind the immune checkpoint proteins. In this work, the model was applied to an on‐going clinical trial (ClinicalTrials.gov Identifier: NCT03299946) of the combination of TKI, cabozantinib and immune checkpoint inhibitor, nivolumab.Overall, this work presents a modular platform for the development of QSP models in IO that integrate features at the molecular, cellular, tumor and whole patient scales. This framework can then be used to predict therapeutic response to the treatment of HCC, and is the first to predict the outcome of combination therapy for liver cancer. Additionally, it enables the analysis and interpretation of the complex interactions in HCC that may ultimately lead to the understanding of the drug interactions in cancer and enable the prediction of patient response to therapies, facilitating planning for patient cohorts and even individual patients.Support or Funding InformationSupported by NIH grant U01CA212007.
Bacterial Nanocellulose Membrane As Bolus in Radiotherapy: “Proof of Concept”
Authors: Chiozzini Giulia Cristina , Mendes Guilherme Paulão , Claro Amanda Maria , Amaral Creusa Sayuri Tahara , da Silva Barud Hernane , Amaral André Capaldo 
Published: April 2020

Bolus characterize materials with an electromagnetic radiation attenuation coefficient similar to biological tissue and which are positioned on the skin of patients during radiotherapy treatment. Such devices are responsible for the superficialization of the maximum dose of high energy photons and electrons, restricting its penetration and improving the coverage of the treatment isodose. The development of new materials, mainly from sustainable biotechnological routes, will contribute to increasing efficiency and expanding the use of these technologies. The objective of this research was to develop the “proof of concept” regarding the use of the bacterial nanocellulose membrane (BNCm) as a bolus for radiotherapy procedures. For this purpose, 1.4 cm thick BNCm were produced from static cultivation of the K. rhaeticus, purified and subjected to the physical‐chemical characterization process by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT‐IR). The samples were then subjected to the determination of the radiological density (RD), by computed tomography, and the radiation attenuation potential (%), after being irradiated with 6MV photons in a linear accelerator using ionization and phantom chamber at doses of 100 and 50 UM. The results were compared with data from the analyzes in a commercial bolus (CB) with same thickness. The physical‐chemical analysis demonstrated the constitution of a pure, highly hydrated, homogeneous and nanostructured network of cellulose fibers. The mean RD of BNCm was 1.1 and 5 Hounsfield units respectively, demonstrating high water (0HU) equivalence from BNCm. The values corresponding to the radiation attenuation at the dose of 100 MU were 5.1 ± 0.1% and 4.6 ± 0.2%, for CB and BNCm respectively. The values for the dose of 50 MU were 3.8 ± 0.1% and 3.0 ± 0.2%. In both doses, the attenuation of BNCm was similar to the CB. It stands out the superiority of the BNCm moldability and the possibility to change its composition to improve the radiation attenuation. The results support the concept of use the BNCm as an effective biotechnological device, align to the sustainability idea, as a bolus for radiotherapy treatment.Support or Funding InformationI.P.F.B. Indústria de Produtos Farm. e Biotecnológicos Ltda.
Finding molecular targets to reverse nerve degeneration associated with diabetic peripheral neuropathy (DPN)
Authors: Voithofer Gabrielle Elizabeth , Clark Jessica 
Published: April 2020

One of the most common comorbidities associated with diabetes mellitus is diabetic peripheral neuropathy (DPN), which is the progressive degeneration of peripheral nerves. The manner in which DPN develops and the underlying mechanisms of peripheral nerve degeneration are currently unknown. Our lab has characterized a glucose‐induced model of DPN in zebrafish (Danio rerio) in which we observe defasciculation/degeneration of motor axons, decreased myelination, and a decrease in ensheathment by perineurial glia. Currently, we are interested in characterizing the molecular pathways involved in the degeneration we observe. To accomplish this, we are testing dexamethasone, a FDA‐characterized small molecule drug, in an effort to decrease the degree of nerve degeneration present after DPN onset. Beginning 5 days post fertilization (dpf) experimental larvae were immersed in 120 mM
d‐glucose for 7 seven days to induce DPN. At 10 dpf, larvae were additionally incubated with 0.5% dimethyl sulfoxide (DMSO) and a 1:1000 dilution of dexamethasone. As a control, a group of larvae were exposed to the same conditions without the addition of the drug treatment. Tg(nkx2.2a:meGFP) fish were used to allow visualization of perineurial glia 12 dpf using EVOS fluorescent microscopy. The percentage of motor axons ensheathed by perineurial glia was measured and quantified using FIJI. An increase in motor axons ensheathed by perineurial glia was apparent, furthermore the number of perineurial cells surrounding the motor axons appeared to increase as well. This increase in perineurial glia is meaningful because these cells form the blood‐nerve‐barrier, have phagocytic capabilities, and have also been shown to provide guidance cues for axonal regrowth. Future work will focus on characterizing the pathways affected by dexamethasone to uncover the molecular mechanisms potentially responsible for facilitating nerve regeneration after DPN onset.Support or Funding InformationSupport was provided by the Henson School of Science and Technology at Salisbury University.
Rosmarinic Acid‐Induced Apoptosis and Cell Cycle Arrest in Triple‐Negative Breast Cancer Cells
Authors: Messeha Samia Shoukry , Zarmouh Najla Omar , Asiri Abrar Mohamed , Soliman Karam Farah 
Published: April 2020

Rosmarinic acid (RA) is one of the potent polyphenolic compounds in rosemary (Rosmarinus officinalis) extract. The compound has shown various bioactive properties, including, anti‐inflammatory, immunomodulatory, anti‐mutagenic, hepatoprotective, and neuroprotective, as well as having antioxidant and anti‐cancer activity. This study evaluated the effects and mechanisms of RA in two triple‐negative breast cancer (TNBC) cell lines; MDA‐MB‐231(MM‐231) and MDA‐MB‐468 (MM‐468); which were derived from a Caucasian and an African American woman, respectively. In this study, RA significantly and similarly inhibited cell viability and proliferation in both cell lines in a dose‐ and time‐dependent manner. The results obtained show that RA differentially affected the two cell lines in cell cycle arrest‐related apoptosis and in the alteration of the expression of many apoptosis‐involved genes. In MM‐231 cells, RA arrested the cells in the G0/G1 phase. In contrast, the data suggest that RA causes S‐phase arrest in MM‐468 cells and leads to a 2‐fold greater apoptotic effect than in MM‐231 cells. In MM‐231 cells, RA significantly upregulated the mRNA expression of three genes; harakiri (HRK), tumor necrosis factor receptor superfamily 25 (TNFRSF25), and BCL2 interacting protein 3 (BNIP3). In contrast, in MM‐468 cell line, the compound induced a significant transcription activation in five genes, including (TNF), baculoviral IAP repeat‐containing 3 (BIRC3), receptor‐interacting serine/threonine‐protein kinase 2 (RIPK2), BNIP3, and growth arrest and DNA damage‐inducible 45 alpha (GADD45A). Furthermore, RA repressed the expression of TNF receptor superfamily 11B (TNFRSF11B) in MM‐231 cells in comparison to the ligand TNF superfamily member 10 (TNFSF10) in MM‐468 cells. In conclusion, the data suggest that the polyphenol RA may have therapeutic potential for TNBC. However, RA should be further evaluated for in‐vivo studies and in non‐cancer cells.Support or Funding InformationU54 RCMI
Determination of hMATE1 Turnover Rate Using Quantitative Western Analysis
Authors: zhang xiaohong , Wright Stephen H 
Published: April 2020

Human MATE1 (Multidrug And Toxin Extrusion 1, hMATE1) is an electroneutral H+/organic cation (OC) exchanger mainly expressed in the apical membrane of renal proximal tubule cells. It plays a critical role in the final step of organic cation excretion of the kidney, and these OCs comprise about 40% of prescribed drugs. Understanding the transport turnover rate (TOR) has important consequences for investigation of the transport mechanism, and is critical for interpreting in vitro‐in vivo extrapolation (IVIVE) required for physiologically‐based pharmacokinetic (PBPK) modeling to predict the influence of transport on pharmacokinetics. In the present study, we purified MATE1 protein from CHO cells stably expressing V‐5 epitope tagged hMATE1 by cell surface biotinylation, and the amount of MATE1 protein was obtained by quantitative western analysis using standard curves based on the V‐5‐containing Multiple tag fusion protein (GenScript). Cell surface protein represented approximately 25% of total MATE1 protein expressed by the cell. The number of cell surface transporters was 29.2 fmol cm−2. (~50,000 transporters per cell). The kinetics of MATE1‐mediated uptake of 1‐methyl‐4‐phenylpyridinium (MPP), atenolol, and metformin were performed at pH 7.4 (room temperature) in these CHO cells following an ammonia pulse to produce an outwardly‐directed H+ gradient. Apparent Kt and Jmax values (±SE; n=4) were: MPP, 79.6 ± 10.9 μM and 284 ± 65 pmol cm−2 min−1; atenolol, 352 ± 67 μM and 398 ± 121 pmol cm−2 min−1; metformin, 629 ± 60 μM and 1,561± 153 pmol cm−2 min−1. TOR values (±SE, n=4) calculated using the number of transporters and Jmax values were: MPP, 180 ± 41 s−1; atenolol, 253 ± 77 s−1; and metformin, 993 ± 97 s−1. These values are consistent with TOR values determined for a variety of exchangers (NHEs), cotransporters (SGLTs, Lac permease) and uniporters (GLUTs, ENTs).ConclusionTORs of hMATE1 for a kinetically diverse set of substrates (MPP, atenolol, and metformin) determined using a quantitative Western blot technique, ranged from 100 to 1000 s−1, similar to TOR values of other Solute Carrier transport proteins. (supported by NIH grant 1R01GM129777)
Effect of Medium Chain Triglycerides Consumption on Running Performance in Long‐Distance Careers Recreational Runners
Authors: Castro-Sánchez Francisco Humberto , Ruiz-Ulloa Amayrani Vanessa , Ochoa-Acosta Dora Alicia , Urías-Lugo Diana Angelina , de Jesús Vergara-Jiménez Marcela 
Published: April 2020

ObjectiveThe purpose of the study was to determine the effect of medium chain triglycerides (MCT) consumption on running performance in long‐distance careers recreational runners.MethodologyA double‐blind placebo controlled crossover study was conducted with 10 recreationally runners. Participants underwent two 21‐kilometers training sessions in random sequence, once with a commercial hydrating sport drink consumption as placebo and once with the same sport drink plus 30g of MCT that were divided and given in four doses of the same amount once before start and the rest at kilometers number 5, 10 and 15. Due to the physical requirements of the tests, a rest period of 45 days was indicated between both evaluations. Anthropometric measurements through ISAK methodology and dietary assessment by 24 hours dietary recalls and food frequency questionnaires were evaluated before both training sessions to analyze that there were no changes in these variables. Participants were encouraged to not change their training sessions or modify their diets.Results50% of participants finished both training sessions. No differences in weight and body composition or dietary intake were observed during the rest period. Gastrointestinal upsets were reported by 66.6% of runners with MCT consumption and there no reports when they consumed placebo. There were no differences in running time when participants consumed MCT, in fact time was a bit higher when compared to placebo (132.6±22.1 vs 128.4±28.1 minutes; P=0.8). No difference were observed when partial times were compared.Conclusion30 g of MCT consumption divided in 4 doses does not improve velocity or running performance during 21‐kilometers training sessions in recreationally runners. MCT consumption was associated with gastrointestinal discomfort, thus possible could affect sport performance.
Abnormal Sarcoplasmic Reticulum/Mitochondria Ca2+ Microdomains Impairs Mitochondrial Ca2+ in Cardiomyocytes in Aging
Authors: Suarez Angelica E. , Cividini Federico , Suarez-Ramirez Jorge , Dillmann Wolfgang H. 
Published: April 2020

Mitochondrial (Mito) metabolism is regulated by free calcium concentration ([Ca2+]m) in the mitochondrial matrix. Cardiac function is impaired in aging and is associated with Mito disfunction. [Ca2+]m homeostasis depends on the Mito calcium uniporter complex and functional sarcoplasmic reticulum (SR)/Mito calcium microdomains. We hypothesized that Mito dysfunction could be the result of aging‐induced maladaptive changes in protein levels of key proteins of the SR/Mito microdomain resulting in deficient Mito Ca2+ uptake. Therefore, the objective of this work was to determine the protein levels of key members of the SR/Mito microdomain and analyze Mito Ca2+ handling as well as spatial SR‐Mito interaction using the proximity ligation assay. We measured protein levels by Western blot of MFN2, GRP75 and SERCA2a, in hearts of young (YH; 2–3 months) and old (OH; 19–22 months) mice. In addition, we analyzed Mito Ca2+ uptake, release and [Ca2+]m using Mitycam and Mito‐pericam. Our results showed that the SR‐Mito Ca2+ microdomain tethering proteins MFN2 and GRP75 were decreased in the OH by 55% and 60% respectively. SERCA2a, the key mediator of SR Ca2+ loading was also decreased by 41% in the OH. SR‐Mito interaction was dramatically diminished in OH. Consequently, Mito Ca2+ uptake and release as well as [Ca2+]m were significantly decreased. In vivo cardiac AAV‐based expression MFN2 improved SR‐Mito interaction. Adenoviral MFN2 expression in cardiomyocytes increased [Ca2+]m.In conclusion, SR/Mito interaction is impaired in the cardiomyocyte in aging. This results in abnormal Mito Ca2+ homeostasis and can be improved by expression of MFN2.Support or Funding InformationAuthors acknowledge funding from a Merit Grant from Veterans Affairs system I01BX003429. This work was supported by the National Institute on Aging, Grant T35 AG26757 (PI: Dilip V. Jeste, MD), and the Stein Institute for Research on Aging and the Center for Healthy Aging at the University of California, San Diego. Angelica Suarez was a 2018 UC San Diego MSTAR Student.
Exogenous Infusion of Epinephrine Augments Cardiac Output during Simulated Hemorrhage in Humans
Authors: Butterfield Brian P. , Shepherd John R. A. , Senefeld Jonathon W. , Wiggins Chad C. , Joyner Michael J. , Curry Timothy B. , Convertino Victor A. , Baker Sarah E. 
Published: April 2020

BackgroundLower body negative pressure (LBNP) simulates hemorrhage, evoking compensatory cardiovascular mechanisms of increased heart rate (HR) while stroke volume (SV) and cardiac output (CO) progressively decline, ultimately leading to presyncope. Previous work has shown that circulating levels of plasma epinephrine are elevated during LBNP; however, the role of early administration of epinephrine in compensatory cardiovascular mechanisms to simulated hemorrhage is not well understood.PurposeWe hypothesized that during simulated hemorrhage, a low‐dose exogenous infusion of epinephrine in humans would: 1) augment HR response, 2) attenuate the decline of SV and CO, and 3) prolong time to tolerance.MethodsNine healthy subjects (5M/4F, 35±9yrs, BMI 25±1 kg·m−2) participated in LBNP on two separate study days. Protocols on each day consisted of a 10‐minute pre‐infusion baseline, 15‐minute infusion period (randomized to saline or epinephrine, dose = 0.1 μg·kg−1·min−1, delivered through a peripherally inserted central catheter), 10‐minute post‐infusion baseline, and 5 minute stages of progressive LBNP with stepwise increases of 10–15 mmHg negative pressure until tolerance (systolic blood pressure less than 80 mmHg, bradycardia, or voluntary termination due to presyncopal symptoms). Heart rate (HR; electrocardiogram) and blood pressure (BP; radial arterial catheter) were recorded continuously. Cardiovascular function (HR, SV, CO, and systemic vascular resistance (SVR)) was determined using arterial waveform analysis. Data were analyzed via percent tolerance using repeated measures ANOVA with student method for pairwise comparisons.ResultsInfusion of exogenous epinephrine lowered MAP (p<0.01) and diastolic blood pressure (DBP; p<0.001), but raised systolic blood pressure (SBP; p=0.019) throughout all stages of LBNP. Epinephrine compared to saline augmented mean HR, SV and CO to the penultimate stage of LBNP (p≤0.01 for all cardiac measures) and concurrently reduced SVR (p=0.002). However, time to tolerance was not significantly different between epinephrine and saline conditions (1415 ± 79 vs. 1475 ± 150s, respectively; p=0.69).DiscussionOur findings suggest that during simulated hemorrhage exogenous epinephrine can augment cardiac function without increasing tolerance to progressive central hypovolemia. During the epinephrine infusion, benefits to cardiac function may have been limited by reduced vascular resistance.Support or Funding InformationThe United States Department of Defense W81XWH‐13‐2‐0038