bluuebunny/crossref_metadata_2025_split huggingface dataset:
Equilibrium analysis between the venous return surface and cardiac output curve enables us to predict hemodynamic impact of percutaneous cardiopulmonary support (PCPS)
Authors: Tanaka Atsushi , Sunagawa Kenji 
Published: June 2021

BackgroundPCPS is a vital tool in managing cardiogenic shock with respiratory failure. It remains difficult, however, to quantitatively predict the hemodynamic impact of PCPS. Theoretical analysis: We developed a circulatory equilibrium model in which cardiac output (CO) and venous pressures (right and left atrial pressures(PRA and PLA)) are determined as the intersection between the venous return (VR) surface and integrated CO curve. PCPS shifts the VR surface downward to the same extent of PCPS assisted flow (ΔCO). In contrast, PCPS increases left ventricular afterload pressure by R*ΔCO (R: arterial resistance) independent of ventricular ejection. Thus, PCPS lowers the equilibrium pulmonary CO and venous pressures. Using this model, we predicted CO and venous pressures under various levels of PCPS.Methods and ResultsIn 5 anesthetized dogs (15–20 kg), we inserted PCPS and isolated carotid sinuses with bilateral vagotomy. We measured hemodynamics (CO, PLA, PRA, and aortic pressure) under various levels of PCPS support. Predicted COs and PLA correlated well with those measured (y=0.91x+6.9, r2=0.91, n=17, y=1.03x‐0.5, r2=0.93, n=17), whereas marginally correlated in PRA (y=0.69x+1.08, r2=0.73, n=17).ConclusionWe could predict the impact of PCPS on CO and venous pressures. The proposed framework would be useful in managing patients with severely compromised hemodynamics.
The Context‐dependent Effect of Transforming Growth Factor Beta on Valve Interstitial Cell Growth in Vitro
Authors: Li Chen (Maggie) Xi , Rosenthal Alan , Gotlieb Avrum I. 
Published: June 2021

BackgroundValve interstitial cells (VICs) are the most prevalent cell type in heart valves. We showed that in the early stages of VIC wound repair transforming growth factor beta (TGF‐β) promotes VIC proliferation and repair (A. Liu et al. Am J Pathol 2008; 173:1275–1285). However, the effect of TGF‐β on VIC growth independent of injury is poorly understood.Materials and MethodsWe used normal subconfluent VIC monolayer cultures to test the hypothesis that TGF‐β enhances VIC proliferation. Control and TGF‐β treated VICs were plated at low density. Cell number and proliferation (bromodeoxyuridine) were quantified. Cell morphology was observed and the extent of VIC adhesion to the substratum was quantified using a trypsin adhesion assay.ResultsTGF‐β significantly decreased cell number and altered cell morphology as cells were mostly rhomboid‐shaped as opposed to spindle‐shaped. Cell proliferation was significantly inhibited and treated cells showed significantly more adhesion to the substratum, which may contribute to the observed growth inhibition.ConclusionThe effect of TGF‐β on VIC growth is context dependent, allowing it to play a dual role by preventing excessive heart valve growth in normal adult conditions and promoting cell proliferation in the early stages of repair, as we reported previously.Supported by a grant from the Heart and Stroke Foundation of Ontario (grant NA6204).
Association of N‐cadherin and beta‐catenin with activation of valve interstitial cells
Authors: Xu Songyi , Gotlieb Avrum 
Published: June 2021

BackgroundValve interstitial cells (VICs), the most prevalent cells in the heart valve, become activated upon injury and disease. Cell‐cell adhesion proteins N‐cadherin and β‐catenin should be present in VICs and the latter may translocate to the nucleus upon disruption of cell‐cell contacts to regulate gene expression. We hypothesize that absence or disruption of cell‐cell contacts increases cytosolic β‐catenin and VIC activation.MethodsPorcine VIC cultures were maintained in standard media in 10% fetal bovine serum for 7 to 10 days. Subconfluent, confluent, and wounded monolayers were fixed and stained with antibodies against β‐catenin and N‐cadherin, and α‐SMA to demonstrate VIC activation. Immunofluorescently stained VICs were viewed under a scanning confocal microscope.ResultsComparing single, islands, confluent monolayers, and wound edge VICs, we found diffuse, stress fiber and diffuse, reduced, and stress fiber α‐SMA staining respectively. Single VICs and VICs that migrated into the wound showed N‐cadherin and β‐catenin staining in the cytoplasm and lamellapodia with some cells showing nuclear or perinuclear staining for β‐catenin. Cellular islands and confluent monolayers showed co‐localized staining of N‐cadherin and β‐catenin at cell‐cell contacts with weak diffuse cytoplasmic staining.ConclusionN‐cadherin and β‐catenin at cell‐cell contacts may regulate VIC activation.Supported by a grant from the Heart and Stroke Foundation of Ontario (grant NA6204).
hESC‐Derived Definitive Endoderm Induces Cardiomyogenesis in Human Embryonic Stem Cells.
Authors: Van Orman Jordan R , Tayeb Karim Si , Duncan Stephen A , Lough John 
Published: June 2021

This laboratory previously reported that chick anterolateral endoderm (AL endoderm) potently induces cardiac myogenesis in mouse embryoid bodies. The requirement to microdissect AL endoderm from gastrulation‐stage embryos precludes the utilization of this tissue to identify cardiomyogenic factors. To overcome these limitations we have assessed whether human definitive endoderm (hDE) cells can mimic AL endoderm. Results indicate that while hDE does not share the cardiomyogenic potency of AL endoderm, both hDE cells and medium conditioned by them significantly enrich cardiac myogenesis in pluripotent hESCs as indicated by rhythmic beating and immunohistochemical/qPCR monitoring of marker gene expression. This response appears to be cardiomyocyte‐specific, since endothelial cell markers are unaffected. The cardiomyogenic effect of hDE is further enhanced when pluripotent hESCs are pre‐induced to mes‐endoderm. These findings demonstrate that, like chick AL endoderm, hDE induces cardiomyogenesis in pluripotent cells, and even more effectively in cells at early stages of mesoderm differentiation (mes‐endoderm). Because this approach is tractable and scalable it should facilitate the identification of novel hDE‐secreted factors, for inclusion in defined cardiomyogenic cocktails to generate homogeneous populations of human cardiomyocytes for use in experimental cell therapy.Grant Funding Source: NIH
Does quadriceps strength modify the association between patella alta and structural features of osteoarthritis on MRI? The MOST Study
Authors: Stefanik Joshua , Zhu Yanyan , Zumwalt Ann , Gross K. Doug , Clancy Margaret , Lynch John , Frey‐Law Laura , Lewis Cora , Roemer Frank , Guermazi Ali , Powers Christopher , Felson David 
Published: June 2021

Patella alta (PA), a high riding patella, is associated with cartilage damage and bone marrow lesions (BMLs) in the lateral patellofemoral joint (PFJ). Quadriceps strength has been shown to decrease cartilage loss in the lateral PFJ. In subjects with PA, the patella is not stabilized by the trochlea; we hypothesized that stronger quadriceps, a dynamic stabilizer, would lead to less PFJ cartilage damage and BMLs, especially in those with PA. We measured the Insall‐Salvati ratio (ISR) [patellar tendon length/patellar length] in 896 knees from a cohort of persons aged 50–79 years. Knees in the highest quartile of ISR were considered to have PA. Quadriceps strength was measured using an isokinetic dynamometer. Lateral PFJ cartilage damage and BMLs were graded on MRI and dichotomized into presence or absence. Using separate logistic regression models, we determined the association between sex specific tertiles of quadriceps strength and cartilage damage and BMLs, among those with and without PA, adjusting for age, sex, and BMI. Among those with PA, subjects in the highest strength tertile were 0.73 (0.4, 1.3) and 0.65 (0.35, 1.2) times less likely to have cartilage damage and BMLs compared to those in the lowest strength tertile. Similar results were seen in subjects without PA. Our results suggest that quadriceps strength may protect against cartilage loss and BMLs but is no more protective for those with than those without PA.Grant Funding Source: NIH/Arthritis Foundation
Redesigning the Learning Environment for the Millennial Student
Authors: Kvavik Robert B. 
Published: June 2021

Redesigning the learning environment for the next generation of students in the health sciences requires space that is flexible, adaptable, and able to support ever‐changing technologies and new learning paradigms. Students benefit from a hands‐on, laboratory‐rich environment where students learn by doing. Students need immediate access to real data and small group workspaces, where IT is highly integrated into all aspects of the learning space.The presentation outlines ways in which the design of facilities can enable more research and engagement opportunities into the curriculum. Also addressed are success metrics to assess the effectiveness of new learning environments. Expected outcomes are greater ability in problem solving, critical thinking, data analysis and interpretation, laboratory skills, teamwork and communication, and quantitative reasoning.
Structural Analysis of Heterotrimeric G Proteins and G Protein‐Coupled Receptor Kinases
Authors: Tesmer John J. G. 
Published: June 2021

Heterotrimeric G proteins and G protein‐coupled receptor kinases (GRKs) are two relatively small families of enzymes that are turned on via direct interactions with active G protein‐coupled receptors (GPCRs), a large and diverse family of integral membrane proteins. Through these interactions, an amazing variety of environmental cues can induce profound changes in G protein‐regulated processes, such as glucose metabolism and regulation of the actin cytoskeleton, as well as GRK‐regulated processes, such as receptor down‐regulation and MAP kinase activation. Crystal structures of G proteins in complex with their effector targets have revealed many insights into the molecular mechanisms by which heterotrimeric G proteins directly regulate the generation of second messengers (1–4). Structural analysis of GRKs has further demonstrated how heterotrimeric G proteins interact with GRK2 (5, 6), and, most recently, how GRKs are allosterically activated by GPCRs. Based on the available structural data, we propose that heterotrimeric G proteins and GRKs recognize active GPCRs using a similar mechanism.Support was provided by NIH grants HL071818 and HL086865.
Transcriptional Regulatory Mechanisms in Animal Cells
Authors: Roeder Robert G. 
Published: June 2021

Transcriptional regulation by gene‐ and cell‐specific DNA‐binding factors underlies key events in development and in cell growth, differentiation and transformation. Whereas animal cells contain thousands of these factors, their stimulatory or inhibitory effects on the general transcription machinery (RNA polymerases and cognate initiation factors) on specific target genes depend upon complex arrays of cofactors (coactivators and corepressors) that add additional layers of regulation. These cofactors include both chromatin remodeling/histone modifying factors (including various histone acetyltransferases and methyltransferases) and factors (such as the 30‐subunit Mediator complex and the TAF subunits of TFIID) that facilitate more direct communication between promoter‐bound regulatory factors and the general transcription machinery. Most recently, the laboratory has employed biochemically defined cell‐free systems reconstituted with recombinant chromatin templates and purified factors (containing over 90 distinct polypeptides) to identify and to analyze both independent and cooperative functions of diverse types of cofactors, as well as underlying mechanisms.The function of Mediator, TFIID/TAFs, and selected cell‐specific coactivators and histone modifying factors will be discussed in relation to gene activation by specific transcription factors.
Pectin inhibits invasiveness of breast and prostate cancer cells by down‐regulation of urokinase plasminogen activator (uPA) secretion
Authors: Wojnowski Rachael , Jiang Jiahua , Jedinak Andrej , Sliva Daniel 
Published: June 2021

Breast and prostate cancers are the most prevalent cancers among women and men in the United States. Pectin is a heteropolysaccharide found mainly in citrus fruits. In the present study, we evaluated the effect of pectin on highly invasive breast [MDA‐MB‐231] and prostate [PC3] cancer cells. We have found that pectin significantly reduced the migration of these cells, however, had no effect on proliferation. Interestingly, when pectin was combined with ProstaCaid & BreastDefend, breast and prostate dietary supplements respectively, it markedly further enhanced inhibition of invasive behavior of breast and prostate cancer cells. These effects were mediated through the down‐regulation of urokinase plasminogen activator (uPA) secretion. Further microarray analysis demonstrated that this treatment affected expression of cell‐cycle regulatory genes e.g. cyclinA2, CDC28, MCM2, TPD1, PCNA and CDKN1A which was confirmed by Western blot analysis. Our data suggests potential use of pectin with ProstaCaid or BreastDefend for the prevention and treatment of breast and prostate cancers, respectively.Grant Funding Source: Unknown
De novo lipogenesis in Type 1 diabetes pre‐ and post‐islet transplant
Authors: Lambert Jennifer Elizabeth , Ryan Edmond A. , Thomson Alan B.R. , Clandinin Michael T. 
Published: June 2021

Type 1 diabetes (T1D) patients have elevated cardiovascular disease (CVD) risk yet normal blood lipids, suggesting altered lipid metabolism. Islet transplant (ITx) may cure T1D in some people, but immunosuppressive drugs may be hyperlipidemic. The objective was to investigate lipogenesis in T1D and ITx patients using stable isotopes. People with T1D (T1D; 4F/3M), post‐ITx patients (ITx; 3F/5M) and healthy subjects (Control; 4F/2M) participated. Fasting blood samples (0h and 24h) were analyzed for triglyceride (TG). Deuterium‐labeled water was given and stable isotope analysis performed on VLDL TG estimated hepatic synthesis of total and individual fatty acids (FA). Plasma TG was not different between Control (0.84±0.24), T1D (0.95±0.22), or ITx (0.75±0.31). Compared to Control, T1D showed a trend for greater total FA synthesis, of particularly 14:0, 16:0, and 18:0. ITx had reduced total FA synthesis (p<0.01), particularly 14:0, 16:0, 18:0, and 18:1 (p<0.01 for all) compared to T1D. Total FA synthesis was significantly related to plasma TG in ITx only (p<0.05). Synthesis of 16:0 was correlated with plasma TG level in Control and T1D (p<0.05) but not ITx. T1D may have greater hepatic FA synthesis, contributing to CVD risk. In this ITx group, immunosuppression did not raise plasma TG levels and did not have deleterious effects on hepatic FA synthesis.Grant Funding Source: Canadian Institutes of Health Research
Online nutrition education for practicing physicians (NEPP)
Authors: Kohlmeier Martin , Adams Kelly , Powell Margo , Zeisel Steven 
Published: June 2021

Nutritional interventions can greatly reduce disease burden and mortality throughout the world. Physicians' lack of knowledge and practical skills limits the potential of this simple therapeutic tool. We are generating online instructional modules that give physicians the critical knowledge and skills for nutritional disease prevention and treatment of conditions known to respond to dietary measures.The presentation is modeled after our widely used Nutrition in Medicine curriculum, using interactions, case studies, and quizzes. The modules describe assessment procedures and therapeutic prescriptions in detail, translating guidelines into actionable practice. The instructional design is tightly focused on assured retention with adaptive remediation. Interactive case studies and skill‐building exercises reinforce the instruction. These interactions serve an additional innovative function of competency assessment by replacing traditional exam questions. Self‐contained, brief units build the instructional paradigm. Designed for busy practitioners, individual modules take only 5–15 minutes to complete. The goal is to prepare learners to immediately use the newly learned skills with their patients.A constantly growing number of modules is available online (nutritioninmedicine.org) without charge for all physicians in training.Supported by a grant from the National Cancer Institute.
Non‐Electronic, Non‐Computerized Educational Games for Youth from Music to Nutrition
Authors: Wong Siew Sun , Wong Siew Ngan 
Published: June 2021

ObjectivePresent evaluations of educational game concepts and actual games developed for multiethnic youth aged 4 to 18.MethodsWe applied a set of game concepts to develop music and nutrition educational games. These games were well‐received in classrooms, funfairs, 4‐H and Family Consumer Science conferences. Based on observations and feedback about the most popular games, we created a list of game features that were highly favored by youth. A qualitative pilot study to measure the impact of these games is being conducted in Utah to measure improvement in knowledge, diet, physical activity, and behavior among 8–18 years old youth.ResultsThese music or nutrition educational games were tested among >1000 youth in Utah and Malaysia. We found that in general, youth are most attracted to games with sound, next, point increments. Other features that increase engagement are competition yet each player has a fair chance of winning something back, doable tasks that do not require extensive thinking or strenuous physical activity, incentives rewarded by points system, quick turnover, and use of oversize game pieces. One unique feature of these games is that they do not involve screen time but encourage face‐to‐face social interaction, thus balancing the increasingly popular high‐tech learning environment.ConclusionsThese best practices may enrich efforts in educational game development for multiethnic youth.
Sleep duration and risk of obesity among Filipino women
Authors: Borja Judith B. , Adair Linda S. 
Published: June 2021

Recent studies have shown a negative association between sleep duration and obesity. We examined this relationship using data on 2002 non‐pregnant women aged 35–68 from the Cebu Longitudinal Health and Nutrition Survey, a community‐based prospective study in Metro Cebu, Philippines. Sleep duration (total hours sleep) was calculated from the women's 24‐hr activity diaries (reported for a typical weekday). Obesity measures include body mass index (BMI; in kg/m2)) and waist circumference (in cm). Linear regression models adjusted for age, energy intake, parity, activity levels, and other confounders show a negative association between sleep duration and BMI [beta (95% CI) −0.26 (−0.38 to −0.14)] and waist circumference[beta (95% CI) −0.57 (−0.88 to −0.27)]. Getting more than 6 hours of sleep protected against the risk of overweight (BMI=>25) [Odds ratio (95% CI) −0.68 (0.55 to 0.84)]. These findings are consistent with those of other studies, and provide valuable insights particularly for older women given that 39% of these women are aged >=50. Among older adults, this sleep‐obesity association gains relevance as sleep duration gets shorter and losing weight becomes more difficult with age.NIH Grant No. 5R03TW008133‐02
Mechanisms of 1α, 25‐Dihydroxyvitamin D regulation of hypoxia‐inducible factor‐1α in breast epithelial cells
Authors: Jiang Yan , Harris Jessica , Teegarden Dorothy 
Published: June 2021

The purpose of this study was to investigate 1α, 25‐dihydroxyvitamin (1,25(OH)2D) regulation of hypoxia inducible factor‐1α (HIF‐1α), an angiogenic transcriptional regulator, in untransformed MCF10A (10A) and H‐ras transfected MCF10A (10A‐ras) breast epithelial cells, a model of cancer progression. In 10A cells, 1,25(OH)2D increased HIF‐1α mRNA abundance (64% ± 19 greater than vehicle control, p=0.01) and protein level (137% ± 30, p<0.001) at 12 hr. In contrast, 1,25(OH)2D treatment did not alter HIF‐1α mRNA abundance in 10A‐ras although, similar to 10A cells, the protein level was increased at 12 hrs (108% ± 38, p=0.05). A transcriptional inhibitor prevented the 1,25(OH)2D‐mediated increase in HIF‐1α protein expression in 10A but not in 10A‐ras cells. In contrast, inhibition of proteasomal degradation prevented the 1,25(OH)2D‐induced HIF‐1α protein level in 10A‐ras but not in 10A cells. Knock‐down of VDR (siRNA) prevented 1,25(OH)2D‐mediated induction of HIF‐1α protein in 10A but not in 10A‐ras cells and VDR was associated with a putative VDR response element on HIF‐1α gene promoter in 10A cells (chromatin IP assay). These results support that 1,25(OH)2D regulates HIF‐1α protein level in 10A cells via transcriptional regulation in contrast to through proteosomal degradation in 10A‐ras cells, suggesting a differential mechanism in the two cell types.Grant Funding Source: Supported by NIH CA128770
Redox modulation as a mechanistic feature of biological effects of cysteine and glutathione mixed disulfide conjugates of Allium thiosulfinates
Authors: ZHANG GUODONG , PARKIN KIRK L 
Published: June 2021

The objective of this work was to determine if phase II enzyme induction and inhibition of nitric oxide (NO) evolution by cysteine and glutathione mixed disulfide conjugates of Allium thiosulfinates (CySSR/GSSR) were linked to redox homeostasis in cultured cells. The CySSR/GSSR species induced quinone reductase (QR) through the Nrf2 pathway in Hepa 1c1c7 cells, and inhibited iNOS expression and NO evolution in LPS‐activated macrophages. CySSR/GSSR also modulated intracellular redox status by boosting intracellular GSH levels. The effects of the CySSR and GSSR species were progressively attenuated by the addition of exogenous thiol agents that influenced redox status in a dose‐dependent manner in both intracellular and extracellular spaces. Thus, the biological activities of CySSR/GSSR appear to be dependent on both extracellular and intracellular redox status. The effects of CySSR, but not GSSR, treatments resulted in an increase in extracellular thiol levels. Evidence was obtained for a mechanism involving cellular uptake of CySSR by L transporter, disulfide bond reduction by thioredoxin reductase (TRxR) and the export of cysteine and RSH into the medium by multiple drug resistance protein. This study adds to the evidence that Allium organosulfur compounds and metabolic derivatives exert a range of biological effects through a redox‐modulatory mechansism.Supported by USDA‐NRI‐CGP.
Men and not women showed cholesterol lowering after 12 weeks of supplementation with secoisolariciresinol diglucoside
Authors: Ye Zhong , Kong Kai Ling , Wu Xianai , Lee Sun Ok , Williamson‐Hughes Patricia , Hendrich Suzanne 
Published: June 2021

We hypothesized that secoisolariciresinol diglucoside (SDG, Beneflax™) derived from flaxseed, would lower serum cholesterol in hypercholesterolemic humans and that the effect would be correlated with serum lignan metabolites. 90 subjects ingested 0 mg (18 male, 12 female), 150 mg (19 male, 11 female), or 300 mg SDG (, 20 male, 10 female) total daily dose for 12 w in a randomized, placebo‐controlled double‐blind trial. At 0 and 12 weeks, serum secoisolariciresinol (SECO), enterodiol (ED), and enterolactone (EL) were measured by LC/MS. Fasting serum cholesterol, glucose, and HbA1c were measured at −2, 0, 4, 8 and 12 wks. Decrease of total cholesterol (TC) and LDL‐cholesterol (LDL‐C) from baseline were significant in men ingesting either dose of SDG. Plasma glucose was not changed from baseline by any treatment. The decrease of TC and LDL‐C from baseline was significantly greater in men than in women ingesting 300 mg SDG/d. Serum SECO, EL and ED were significantly increased in subjects ingesting either dose of lignans. LDL‐C was negatively correlated with serum ED (r = − 0.50, P = 0.03); and LDL decrease from baseline was positively correlated with serum SECO (r = 0.59, P = 0.01) in subjects ingesting 150 mg SDG/d. In conclusion, SDG decreased serum TC and LDL‐C in men but not in women and this function was related to the bioavailability of lignan metabolites. Research funded by Archer Daniels Midland.Grant Funding Source: Archer Daniels Midland