bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rap 1a small GTPase alters extracellular matrix (ECM) deposition in response to TGF‐β1
Authors: Jeyaraj Selvi C , Unger Nicholas T , Stewart James A , Chotani Maqsood A 
Published: June 2021

Cardiac fibroblasts are essential to cardiac remodeling by regulating ECM production, maturation and degradation. TGF‐β, transforming growth factor beta, can regulate fibroblast differentiation and activation, and therefore tissue fibrosis. Rap1a, a Ras‐like GTPase, has been implicated in cell migration and attachment, however, its role in regulation of ECM has yet to be determined. In this study, we examined the impact of Rap1 deficiency on cardiac ECM remodeling.Analysis of left ventricular tissue sections from Rap1a deficient heterozygous or knockout (HET or KO) mice revealed significant decreases in total (picrosirius red‐PASR), soluble and insoluble collagen when compared to wild‐type (WT) controls (Table I). Isolated cardiac fibroblasts from heterozygous Rap1a mice showed a blunted collagen response to TGF‐β, suggesting an alteration in the normal pro‐fibrotic response to this cytokine. Genetic ablation of Rap1a shows an impact on regulation of ECM which may lead to alterations in cardiac remodeling and hypertrophic response.
Effect of melatonin and its combination with therapeutic exercise on Doxorubicin‐induced cardiac toxicity
Authors: Lkhagvasuren Tserentogtokh , Lee Seunghoon , Hong Jeong-Hwa , Hong Yonggeun 
Published: June 2021

Doxorubicin is one of the most widely used antitumor drugs in worldwide, but it has many other toxic effects to brain, kidney and heart. Importantly, it was demonstrated that it leads cardiac dysfunction. The aim of this study was to investigate the cardiac toxic‐protective effects of pineal hormone melatonin, exercise and combination of melatonin with exercise treatment on doxorubicin‐induced cardiac toxicity. Rats were divided 4 groups and all groups inflamed with doxorubicin (2.5mg/kg, 3 times per week) during two weeks. Rats were treated with melatonin (10mg/kg), exercise and melatonin combined with exercise. The results showed that all treated groups were decreased left ventricular thickness by result of sagittal section of H&E staining (P<0.05) and increased tibia/heart ratio (P<0.05) compared to control group. Furthermore, morphological changes and cardiomyocyte vacuolization were decreased by results of high magnification images. We suggest with these results that melatonin combined with exercise is a potential therapeutics against doxorubicin‐induced cardiac toxicity. We further aim to investigate a cellular and molecular mechanisms of against doxorubicin‐induced cardiac toxicity in the melatonin combined with exercise treatment.This work was supported by KRIBB Research Initiative Program (KGM03021112), Republic of Korea.
Conditional inactivation of the splicing regulator Tra2[beta] shifts myosin phosphatase isoforms and enhances smooth muscle sensitivity to cGMP‐mediated relaxation
Authors: Bhetwal Bhupal , Fu Kang , Mende Ylva , Perrino Brian , Wirth Brunhilde , Fisher Steven 
Published: June 2021

Based on patterns of expression, correlative physiologic studies, and in vitro mini‐gene splicing assays, we have proposed that 1) the tissue‐specific splicing of Myosin Phosphatase Targeting subunit (MYPT1) 3′ alternative exon (E23), by coding for isoforms that contain or lack a C‐terminal Leucine zipper (LZ) motif, determines smooth muscle sensitivity to NO/cGMP signaling and 2) that the tissue‐specific splicing of this exon is controlled by Transformer 2β (Tra2β). To test this model in vivo we crossed SM22Cre and Tra2β flox mice for conditional inactivation of Tra2β specifically in smooth muscle cells (cKO). Homozygous mice (Cre+//f/f) were non‐viable prior to birth. In mature heterozygous mice (Cre+//f/+) small intestinal smooth muscle there was a significant loss of MYPT1 E23 splicing (WT 82±5% vs cKO 25±7%,p<0.01) associated with the expected shift to the MYPT1 LZ+ isoform. The cKO muscles generated greater total force (AUC) under isometric conditions when activated ex vivo with Carbachol (1 μM) (cKO 105+25 vs WT 63+11; p<0.01, n=6), and were more sensitive to 8‐Br‐cGMP at all concentrations tested (50–300 μM; maximum inhibition of force production: cKO 68+2% vs WT 51+3%, p<0.01, n=3). We conclude that tissue‐specific splicing of MYPT1 E23 is highly sensitive to Tra2β gene dosage. The regulated splicing of MYPT1 E23, and likely other exons, tunes smooth muscle tissue‐specific contractile function and sensitivity to NO/cGMP signaling.This work was supported by NIH grants RO1 HL‐66171, RR08751
Loss of skeletal muscle oxidative phenotype and endurance in mild‐to‐moderate COPD
Authors: Slot Ilse , van den Borst Bram , Hellwig Valéry , Kelders Marco , Schols Annemie , Gosker Harry 
Published: June 2021

Loss of skeletal muscle oxidative phenotype (OXPHEN) and subsequent impaired muscle endurance are hallmarks of severe COPD, but less is known regarding these in mild‐to‐moderate COPD. We studied muscle OXPHEN in relation to muscle endurance in mild‐to‐moderate COPD patients (mean FEV1 58±16 %pred).Quadriceps biopsies were collected from 29 clinically stable mild‐to‐ moderate COPD patients and 15 controls to analyze fiber type distribution and gene expression levels of oxidative and glycolytic markers. Quadriceps strength and fatigability were determined by peak torque and temporal decline in torque respectively, during 30 maximal voluntary isokinetic leg extensions.Compared to controls, COPD patients had significantly lower fiber type I proportions, oxidative PGC1α and MyHC I mRNA levels, and higher glycolytic PFKM expression. Muscle strength was not different, but endurance was reduced in COPD and correlated with gene expression of PGC1α and MyHC I. A trend was observed with % type I fibers. No markers correlated with FEV1.To our knowledge this is the first time that loss of muscle OXPHEN associated with impaired muscle endurance is observed in patients with mild‐to‐moderate COPD. This supports the indication for and efficacy of lifestyle intervention targeting muscle function in less advanced COPD as previously proven in a RCT (Van Wetering et al. Thorax 2010).Performed within TI Pharma T1‐201.
Arterial PCO2 (PaCO2) can be accurately estimated using end‐tidal PCO2 (PETCO2) during rest and exercise in obese subjects
Authors: Bernhardt Vipa , Straub Allison M , Lavin Kaleen M , Lorenzo Santiago , Babb Tony G , Zavorsky Gerald S 
Published: June 2021

Obesity affects lung function, gas exchange and imposes mechanical ventilatory limitations during exercise that could disrupt the predictability of PaCO2 from PETCO2. 22 women (37 yrs, 50 BMI) and 16 men (40 yrs, 51 BMI) underwent a ramped cardiopulmonary exercise test to exhaustion. PETCO2 was recorded from expired gases simultaneously with arterial blood gases (radial arterial catheter) at rest, at minute 4 (submax) and at peak exercise. To estimate PaCO2 from PETCO2 and tidal volume (VT), the equation derived by Jones et al. (JAP 1979) was used: PJCO2 = 5.5 + 0.9PETCO2 – 2.1VT.Using independent t‐tests, no significant differences were found between men and women in PETCO2 or PaCO2 values at rest, submax or peak exercise, and were combined in further analyses. Paired t‐tests revealed that PETCO2 was not different from PaCO2 at rest (PETCO2 = 37.1 mmHg vs PaCO2 = 37.6 mmHg, p = 0.14). However, at submax and peak exercise PETCO2 was higher than PaCO2 (submax: 42.4 mmHg vs 40.0 mmHg, p < 0.001; peak: 39.9 mmHg vs 37.6 mmHg, p < 0.001). PJCO2 was not different from PaCO2 (submax: p = 0.65; peak: p = 0.07).Although obesity places a substantial load on the respiratory system, these obese individuals exhibited normal values in terms of CO2 clearance (i.e. PETCO2 – PaCO2). PJCO2 estimates corresponded more closely with PaCO2 than PETCO2 during exercise.Supported by HL096782, King Charitable Foundation Trust.
Effects of Spinal Cord Section on Inspiratory Pressure Generation During High Frequency Spinal Cord Stimulation (HF‐SCS)
Authors: Kowalski Krzysztof E , DiMarco Anthony F 
Published: June 2021

ObjectiveHF‐SCS is a novel and more physiologic method of inspiratory muscle activation which involves activation of spinal cord pathways. The specific pathways by which inspiratory motoneurons are activated by this method however are unknown. The aim of the present study was to evaluate the potential role of upper cervical inspiratory neurons on the observed responses.MethodsIn 6 anesthetized and spinalized (C1 level) dogs, HF‐SCS was applied at T2 level. Airway pressure generation (P) was monitored as an index of the degree of inspiratory muscle activation before and following sequential spinal sections at the C4 (to eliminate upper cervical propriospinal neurons) and subsequently the C8 level.ResultsDuring HF‐SCS, P at FRC was 68±6 cmH2O. Sequential bilateral dorsal columns (DC), lateral funiculi (LF) and complete section (CS) at C4, resulted in no significant changes in P (69±5, 67±5 and 65±7 cmH2O respectively, NS). While DC section at C8 resulted in no changes in P (63±5 cmH2O), LF section resulted in significant reduction in P to 18±3 cmH2O (p<0.05). Subsequent CS resulted in no further reduction in P (14±1 cmH2O, NS).ConclusionDuring upper thoracic HF‐SCS, activation of the phrenic motoneuron pools does not involve upper cervical propriospinal inputs. The phrenic motoneuron pools are activated via spinal pathways located bilaterally in the lateral funiculi.Support: NIH‐NINDS (R01NS064157).
Folate modulates adipocyte promoter methylation and lipid filling and release
Authors: Gouffon Julia S , Johnstone Megan , Zemel Michael B 
Published: June 2021

Nutritional inputs may modify gene promoter methylation and thereby affect adipocyte metabolism. We differentiated 3T3L1 adipocytes under low, standard and enhanced folate levels followed by maturation under similar treatments plus the methyl donor S‐adenosylmethionine (SAM) and methylation inhibitor, 5‐aza‐2‐deoxycitidine (2DC). Folate exposure during differentiation dose‐dependently decreased triglyceride accumulation, lipolysis and proliferation (p<0.001) while folate exposure during maturation dose‐dependently increased triglyceride accumulation and lipolysis (p<0.001). Adipocytes differentiated under low folate conditions showed increased mRNA levels of key metabolic genes after exposure to high folate conditions during maturation ; hormone sensitive lipase (Lipe, +54.25%), fatty acid synthase (Fasn, +288%), glucose transporter 4 (Glut4,+141%), leptin (Lep, +450%). Adipocyte genomic DNA was hybridized against Nimblegen whole genome CpG promoter arrays and RNA on Affymetrix Mouse arrays. Low folate exposure during maturation decreased promoter methylatation in Lipe and carboxylesterase (CES) with increased gene expression relative to standard conditions (1.17 & 4.14 FC respectively). Thus, adipocyte exposure to methyl donors during and following differentiation modulates lipid accumulation, and low folate during differentiation may promote lipid filling.Grant Funding Source : Internal Award
The reaction of HOCl and cyanocobalamin: corrin destruction and the liberation of cyanogen chloride
Authors: Maitra Dhiman , Byun Jaeman , Souza Carlos Eduardo A. , Banerjee Jashoman , Andreana Peter R. , Pennathur Subramaniam , Abu-Soud Husam M. 
Published: June 2021

Elevated hypochlorous acid (HOCl) has been associated with the development of several pathological conditions such as inflammation, heart disease, and cancer through its ability to modify different biomolecules. HOCl is a potent oxidant generated by the myeloperoxidase‐hydrogen peroxide‐chloride system. Recently, we have shown that higher levels of HOCl can cause heme destruction and free iron release from hemoglobin and erythrocytes. Our current finding extends this work and demonstrates the ability of HOCl to mediate the destruction of metal‐ion derivatives of tetrapyrrole macrocyclic rings, such as cyanocobalamin (Cobl), a common pharmacological form of vitamin B12. Cobl is a water‐soluble vitamin that plays an essential role as an enzyme cofactor and antioxidant, modulating nucleic acid metabolism and gene regulation. It is widely used as a therapeutic agent and supplement because of its efficacy and stability. In this report, we demonstrate that while Cobl can be an excellent antioxidant, exposure to high levels of HOCl can overcome the beneficial effects of Cobl and generate proinflammatory reaction products. Our rapid kinetic, HPLC and mass spectrometric analyses showed that HOCl can mediate corrin ring destruction and liberate cyanogen chloride through a mechanism that initially involves α‐axial ligand replacement in Cobl to form a chlorinated derivative, hydrolysis, and cleavage of the phosphonucleotide moiety. The susceptibility of Cobl to HOCl mediated degradation was compared with other vitamin B12 derivatives. Taken together, this is the first report of the generation of toxic molecular products through the interaction of Cobl with HOCl.Grant Funding Source : NIH
Predictors of Performance in Anatomical Sciences Courses: What Really Matters?
Authors: Lufler Rebecca S. 
Published: June 2021

The purpose of this study is to determine if factors previously related to learning in medical school courses predict performance in anatomical sciences courses. Data was collected from first‐year medical students at Tufts University School of Medicine (N= 119). A survey, Mental Rotations Test, and VARK learning preferences inventory were given to students at the beginning of year 1. Course scores were collected at the end of Year 1. Predictor variables included: gender, age, learning style, visual‐spatial ability, MCAT score, and undergraduate major. Outcome variables include final course scores in clinical anatomy (A), head and neck anatomy (HNA), neuroscience (N), and tissue and organ biology (TOB). Statistical analyses were performed using linear regression and standardized beta estimates (relative predictive value of each predictor) were calculated. MCAT scores were predictive of performance in all anatomical sciences courses (A β=0.28, p=0.002; HNA β =0.21, p=0.02; N β =0.31, p=0.001; TOB β =0.30, p=0.002). MRT scores were predictive of performance in HNA but no other courses (HNA β=0.21, p=0.04; A β=0.14, p=0.14; N β=0.04, p=0.7; TOB β=0.05, p=0.6). Other predictors were not significantly predictive of performance in any course. These results demonstrate that although previous studies relate the above predictors to performance in medical courses, only MCAT was consistently predictive of scores in the anatomical sciences.Grant Funding Source : None
Cholesterol Metabolism in Mycobacterium tuberculosis: Chewing Through the Fat
Authors: Nesbitt Natasha Monic , Dubnau Eugenie , Kisker Caroline , Lu Rui , Russell David G , Schäfer Christin , Sherman David R , Smith Issar , Thomas Suzanne T , VanderVen Brian C , Yang Xinxin , Sampson Nicole S 
Published: June 2021

New drugs with novel mechanisms of action are required to meet the severe threat to human health posed by the emergence of drug resistant strains of M. tuberculosis (M. tb). M. tb imports and metabolizes host cholesterol during infection, which is critical for the maintenance of M. tb infection. Both the igr operon and fadA5 are required for in vitro growth using cholesterol as a sole carbon source and for full virulence of M. tb in the mouse model of in vivo infection. We have elucidated the function of these genes, their corresponding enzymes and their role in cholesterol metabolism using a combination of transcriptional profiling, bioinformatics, enzymology, biochemistry and metabolic phenotype screening. The 2’propanoyl CoA side chain cleavage intermediate undergoes β‐oxidation catalyzed by FadE28/29, a heterotetrameric acyl CoA dehydrogenase, and Rv3542c/3541c, a heterotetrameric enoyl CoA hydratase; both are encoded by the igr operon. FadA5 is a thiolase that catalyzes side chain cleavage. Ultimately, drug discovery targeting these enzymes will provide inhibitors that attenuate M. tb growth and persistence in vivo.NIH (AI065251, AI092455, HL53306, S10RR021008 to NSS, A1044856, AI065987 to IS, DK007521 to NMN R01AI067027 to DGR) DOE‐GAANN to STT
MEASURING AND MODELING LIFE‐DEATH DECISIONS IN SINGLE CELLS
Authors: Sorger Peter K. , Lopez Carlos , Flusberg Deborah , Eydgahi Hoda , Bachman John , Sims Joshua , Chen William , Spencer Sabrina , Gaudet Suzanne 
Published: June 2021

At the level of single living cells, signal transduction involves remarkably complex biochemistry and great variability from one cell to the next. However, cells achieve exquisite control over fate decisions and subtle mutations that interfere with decision making cause disease. How can variability among genetically identical cells be reconciled with an apparent requirement for precise control over biochemical reactons, what is the impact of non‐genetic variability on the evolution of tumors and what are the implications for drug responses in patients?I will begin to address these issues with an emphasis extrinsic apoptosis induced by the TNF family member TRAIL. TRAIL is involved in natural immune surveillance of tumors and is also in development as a therapeutic agent. Some TRAIL‐treated human cells die within ~40 min, some only after 12 hr. and yet others live indefinitely. We have explored three explanations for these differences: (i) genetic or epigenetic variation (ii) the involvement of stochastic fluctuations (iii) transient but deterministic differences in cell state. I will illustrate how all three interact on different time scales to determine those aspects of cellular physiology that are highly invariant and those that are variable.I will also illustrate how studying such problems can be tackled by mathematical analysis of the underlying biochemistry. This involves a continuous interplay between (i) model generation, and variation (ii) calibration of models against experimental data and (iii) model verification through empirical testing of specific molecular hypotheses. I will describe a means to instantiate diverse biochemical hypotheses in networks of differential equations (using a new rules‐based meta‐language PySB) and to rigorously compare predictions to experimental data (via Bayesian parameter estimation). I will also describe strategies for collecting the necessary measurements from single‐cell studies and our attempts to push this into the mouse. I will advance the hypotheses that “systems‐based” approaches are nearing the point that it is possible to replace informal pathway pictures (which dominate molecular biology) with probabilistic mathematical constructs that assign rigorous “degrees of belief” to specific biochemical hypothesis. Finally, I hope to demonstrate that such approaches can be understood and used by a broad community of molecular biologists.
A Nationwide Qualitative Assessment of Third and Fourth Year Medical Students’ Views of Childhood Obesity
Authors: Cooke Natalie K. , Raad Alice A. , Alexander De'Ja S. , Lang Brittany A. , Wheeley Jennifer R. , Goodell L. Suzanne 
Published: June 2021

Medical professionals need to be prepared to both treat and prevent childhood obesity (CO) and therefore need to understand the multifactorial causes and consequences of CO. In order to qualitatively determine medical students’ views of CO, researchers conducted individual interviews with third and fourth year allopathic and osteopathic medical students across the nation. Researchers asked students to describe the term CO, explain the causes, consequences, prevention, and treatment of CO, and enumerate additional resources they might need to treat and prevent CO. Researchers asked students to give examples from their coursework and rotations. Transcript analysis revealed that students were not confident in educating patients to make dietary and lifestyle changes because this is not taught in medical school. Students who had more knowledge about CO were those who had or were pursuing an additional graduate degree, had volunteered with prevention programs, or had a personal interest in the subject. Many students felt that while they are learning about medical conditions and metabolic disorders, they are not learning the more practical knowledge they need to prevent and treat CO. Medical schools need to provide students both with information about CO and the more skills‐based knowledge to prevent and treat CO, whether through additional time allotted in medical school or through continuing education.Grant Funding Source : N/A
The GTPase ARFRP1 controls assembly of apoA1 to and lipidation of chylomicron in the Golgi of intestinal enterocyte
Authors: Jaschke Alexander , Chung Bomee , Hesse Deike , Kluge Reinhart , Heeren Joerg , Joost Hans-Georg , Schürmann Annette 
Published: June 2021

Intestinal lipid metabolism is comprised of multi‐steps of vesicle trafficking. ADP‐ribosylation factor‐related protein 1 (ARFRP1) regulates protein trafficking between intracellular organelles. To study the role of ARFRP1 in intestinal lipid metabolism, Arfrp1 was deleted in mouse intestine (Arfrp1vil−/−), or depleted by siRNA transfection in Caco‐2 cells. Lipid absorption and lipoprotein production were examined. Decreased lipid absorption was detected in oral fat tolerance test in Arfrp1vil−/− mice. However, the apolipoprotein (Apo) B48 and ApoA4 in the plasma were higher, whereas the level of ApoA1 was markedly lower. Fractionation of the plasma showed that the chylomicron fractions of Arfrp1vil−/− mice contain lower triglyceride level, indicating that the Arfrp1vil−/− enterocytes produce a large number of chylomicron particles that are smaller in size containing less fat. Caco‐2 cells demonstrated that the defect in Arfrp1 expression caused decreased lipid release, but normal lipid uptake. In conclusion, ARFRP1 plays important roles in chylomicron lipidation in the Golgi and the secretion of ApoA1 in the intestine.Grant Funding Source : Deutsche Forschungsgemeinschaft (Schu 750/5‐2; Schu 750/5‐3; GRK 1459; SFB958), Alexander von Humboldt Foundation
Although Equally Obese, High Fat Diet (HF)‐Fed Ovariectomized (O) Mice Respond with Greater Adipose Tissue (AT) Inflammation Than Sham‐Operated (S) Mice
Authors: Potter Victoria Jeanne Vieira , Strissel Katherine , Obin Martin S , Greenberg Andrew S 
Published: June 2021

How O and S mice differ in response to HF in regards to AT inflammation, insulin resistance (IR), and hepatic steatosis (HS) was investigated. O and S mice (11 wk, n=16) were fed normal chow diet (NC) for 12 wks and then either switched to HF or continued on NC for 14 wks. Mice were compared for total (MRI) and regional (fat pad weight) body fat, IR (HOMA), HS (mgTG), AT immune cell content (FACS) and AT gene expression (qPCR). Data were analyzed using t‐tests and presented as mean±SEM.O started heavier (33.5±0.8 vs. 27.4±0.8 g, p<0.05) with more body fat (34.6±1.5% vs. 17.6±1.9%, p<0.05) but S gained more rapidly on HF resulting in equally obese mice (48.6±1.0 g, 50.5% fat and 48.4±1.2 g, 47.7% fat for S and O on HF, p=0.24 (g), p=0.12 (% fat)). While neither NC group had HS (between groups, p=0.67), HS scores increased with HF (p<0.05 compared to NC) 2.8‐fold for S (136.3±26.4) and 2.6‐fold for O (127.5±22.5 mgTG/g) (between groups, p=0.81). On NC, O had higher HOMA‐IR (17.4±2.8 vs. 5.2±1.6, p<0.05) whereas both HF groups were IR (34.3±7.8 vs. 23.5±2.3 for O and S, p=0.23). HF increased AT T‐cells with O tending to have more than S (616±237 vs. 205±28 CD3+/10K events, p=0.097). O also had greater AT inflammatory gene expression (+2.1‐fold F480, +2.6‐fold CD11c, +7.3‐fold MCP1, +3.8‐fold IL12p40 compared to S, p<0.05).Postmenopausal women may be more sensitive to HF‐induced metabolic disturbances, an effect that is uncoupled from obesity.Grant Funding Source: NIDDK