bluuebunny/crossref_metadata_2025_split huggingface dataset:
An interactive, case study computer module for teaching medical genetics using genomic sequence analysis tools.
Authors: Munzenmaier Diane H. , Worthey Elizabeth A. , Jacob Howard J. 
Published: June 2021

AimThe sequencing of the human genome has issued the promise of individualized medicine for the near future. Technology has accelerated to a point where it is clear that genomic sequence will be a basic component of medical care before today's medical students complete their residencies. This interactive computer laboratory has been designed to allow the student to be involved in practical and ethical decision making based on symptom presentation, family history, and genetic test results and to use genomic sequence tools to aid them in their diagnoses.MethodsCases are discussed in small groups as students use genetic test results and genome sequence as well as online tools and resources to diagnose, determine carrier status, and make decisions regarding treatment and testing of family members. Prenatal diagnosis, preimplantation genetic diagnosis, prophylactic screening, and ethics are also addressed. Genetic disorders represented in these case studies cover a wide range of types of genetic variation and presentation and increase in complexity through the module.ConclusionThis teaching module provides a link between genetics lectures and the clinic. Taught during the medical physiology course in the second semester of the first year, it attempts to integrate recently acquired knowledge in anatomy, biochemistry, neuroscience, physiology, and genetics with clinical genetics testing and diagnosis.
A fractal analysis of human fetal pituitary blood vessels
Authors: Chirculescu Andy Remus Marius , Staicu Cristian , Coculescu Mihai Gr , Chirculescu Mihaela , Morris John F. 
Published: June 2021

Fractal analysis allows a non‐Euclidian evaluation of the tissue‐blood vessels ratio and distribution. The fractal dimension varies from 1 to 2. Di Ieva et al have shown that fractal dimension is a good quantitator for microvasculature of normal (2007) and adenomatous (2008) pituitaries.We present here a fractal analysis study of pituitary vasculature in human fetuses of 9‐24 weeks obtained from terminations with ethical approval, performed on digital images taken from toluidine blue‐stained semithin sections and fluorescence microscopy after lectin binding or propidium iodide.Both light microscopy after toluidine blue and fluorescence microscopy are suitable for fractal analysis; fluorescence in red gave the best results. The fractal indices varied from 1.41 to 1.86, progressively decreasing from 9 to 24 weeks; the distribution of individual values varied following a logarithmic curve, thus demonstrating that in each case, there is a limit, over which the vessels fractal dimension does not increase; the ratio cells/blood vessels varies from 1.15 (9‐10 weeks) to 0.91 (18 to 24 weeks).These data show that fractal analysis is suitable for the study of dynamic changes in blood vessels in the human fetal pituitary, during ontogenesis, giving a quantitative image of its progressive development and time‐related evolution, complementary to the data derived from morphometric vascular density measurements.
Regulation of Embryonic Cardiac Wall Growth and Vascularization by FGF‐2
Authors: Nanka Ondrej , Petrovova Elena , Fikrle Michal , deAlmeida Angela , Sedmera David 
Published: June 2021

The aim of this study was to assess the effect of FGF‐2 signaling on growth of chick embryonic ventricular wall and its vascularization. In the first set of experiments, left ventricular wall of embryonic day 7 (E7) chick embryos was injected with either GFP‐expressing replication‐deficient adenovirus alone or in combination with adenoviral vector encoding human FGF‐2 gene. In the second set of experiments, FGF signaling was blocked in E8 embryos using FGFR1 receptor tyrosine kinase inhibitor SU 5402. Cell proliferation was measured in both cases using BrdU incorporation and immunohistochemistry on E9.Morphological examination of adenovirus‐injected hearts revealed no difference in normal myocardial architecture, but increased levels of myocyte proliferation in hearts injected with FGF‐2 adenovirus. There was no difference in capillary density or coronary artery anomalies. Blocking of FGF signaling with SU 5402 led to hemorrhages in the areas of developing vasculature in the tips of limbs and epicardium. However, the rate of myocyte proliferation was unchanged.We conclude that up‐regulation of FGF‐2 signaling has a positive effect on growth of the early fetal heart, while its inhibition impacts mainly vasculogenesis, pointing to functional redundancy in paracrine control of myocyte proliferation in the developing heart.Supported by MSMT VZ 0021620806, LC 06061, AS CR AVOZ50450515.Grant Funding SourceMSMT VZ 0021620806
Antitumoral effect of melatonin by G‐protein mediated toll‐like receptor (TLR) activation through autophagic cell death in gynecologic cancer cells
Authors: Hong Yonggeun , Won Jinyoung , Lee Youngjeon 
Published: June 2021

Toll‐like receptors(TLRs) induce innate immune responses that are essential for host defenses against invading microbial pathogens. Toll‐like receptor 4(TLR‐4) mediates many biological effects of lipopolysaccharide(LPS), which has antitumoral effects on tumor cells. However, the cellular mechanism of these antitumoral effects remains unknown. Here, we speculated that stimulation of TLR‐4 signaling by G‐protein activation plays important roles, which gives signal to stimulate of autophagic cell death in genecologic tumor, not to lead the activation of NF‐kB and inflammatory pathway. The role of TLR‐4 in the antitumoral effect of LPS was assessed in primary cultured cervical, endometrial and angioma cells. Cancer cells were transiently transfected with small G‐protein encoding plasmids, and then treated with LPS. Immunofluorescence microscopy, western blotting, and RT‐PCR were performed. LPS activated TLR‐4 and caused activation of autophagosome formation. However, when cells transfected with G‐protein, we observed inhibition of inflammatory cytokines pathway. These effects were induced by overexpression of G‐protein and lead cell death pathway such as apoptosis. These studies suggest that activation of G‐protein mediated TLR‐4 signaling induces autophagic cell death, not to lead necrotic cell death.Supported by KRF‐E00344, BioGreen21 Program (#20070401034006) of Rural Development Administration, South Korea.
Resveratrol and quercetin target microRNA 27a in their anti‐cancer effects in colon cancer cells
Authors: Del Follo Armando , Noratto Giuliana D. , Mertens‐Talcott Susanne 
Published: June 2021

The polyphenolics resveratrol and quercetin in combination previously were shown to exert synergistic anticarcinogenic effects. The objective was to investigate anticancer properties and underlying mechanisms of resveratrol and quercetin in combination in colorectal adenocarcinoma cells (HT‐29). Cell viability was determined after 24, 48, 72 and 96h, and IC50 values were 62, 24, 21 and 14 mg/L (combined concentration of resveratrol and quercetin in 1:1 ratio), respectively. Reactive oxygen species (ROS) increased up to 2.25‐fold at 5‐30mg/L and mRNA of the cell cycle regulator p53 and the apoptotic enzyme caspase‐3 were increased by up to 2‐fold and 2.5‐fold within a concentration range of 20‐60 mg/L after 24h, respectively. mRNA of zinc‐finger protein ZBTB10 a putative suppressor of the oncogenic specificity protein Sp‐1, was significantly increased by 3.5‐fold at 30 mg/L, coinciding with a significant decrease in Sp‐1mRNA levels. miRNA27a, which in previous studies was determined to be a downregulator of ZBTB10, was upregulated by 2.5‐fold, indicating the involvement of this miRNA in the down‐regulation of Sp1 protein and potentially the induction of apoptosis. In conclusion, the combination of resveratrol and quercetin was highly effective in the reduction of cell viability in colon cancer cells, employing apoptosis and the inhibition of microRNA27a as underlying mechanism.Grant Funding SourceTexas A&M University
Coconut oil enhancement of conjugated linoleic acid‐induced body fat loss and lipolysis in mice
Authors: Ippagunta SiriManasa , Barnes Kimberly M. 
Published: June 2021

Dietary conjugated linoleic acid (CLA) causes a body fat loss that is enhanced when mice are fed coconut oil (CO) compared to soy oil (SO). The objectives were to determine if CLA feeding altered adipose tissue lipolysis or the expression of perilipin. Male mice (n=80; 3 wk old) were fed 7% SO or CO diets for 6 wk then 0 or 0.5% CLA for 12 d. A body fat index was calculated: (retroperitoneal+epididymal (EPI) fat pads)*100/body weight. Lipolysis was determined by NEFA and glycerol release from EPI explants. The relative expression of perilipin and phosphorylated perilipin (P‐perilipin) were determined by western blotting. The body fat index was reduced by both CLA (P<0.05) and CO (P<0.001) but there was no interaction. NEFA release was increased by CLA in CO‐fed mice (2.94 vs 8.63 µmol/g; P<0.05) but not in SO‐fed mice (1.76 vs 2.26 µmol/g tissue). Glycerol release was not affected by CO or CLA. Total perilipin was not altered by diet but P‐perilipin tended to be increased by CLA in SO‐fed mice and decreased by CLA in CO‐fed mice (P=0.08). This may indicate that the CLA‐stimulated lipolysis in CO‐fed mice is on the decline since P‐perilipin is associated with increased lipase activity.Grant Funding SourceNone
Protective Effect of BG9928, an Adenosine Receptor Antagonist, against Cisplatin‐Induced Acute Renal Injury in Rats: Comparison with Furosemide
Authors: Whalley Eric , Gill Alan , Wortham Kathleen , Costa Don , Davis Wendell , Ticho Barry 
Published: June 2021

Cisplatin (CIS),is nephrotoxic due to renal vasoconstriction and decreased GFR, effects believed to involve of adenosine mediated activation of adenosine A1 receptors (A1Rs). We studied the effect of the A1R antagonist BG9928 (BG) and furosemide (FUR) in CIS‐induced acute renal injury in rats.BG was given p.o. at 1mg/kg bid from d0‐1 or d0‐6, FUR at 30 mg/kg p.o. d0‐5 to female SD rats (n=10) pretreated with CIS at 5 or 5.5 mg/kg i.v. Venous blood samples were taken for measurement of creatinine (CRE) and urea nitrogen (BUN) over 13 days.Data was similar for CIS at 5 and 5.5 mg/kg. CIS, 5 mg/kg gave significant elevations in CRE (3.7±0.41 mg/dL), BUN (146.2±18.3 mg/dL) (normal levels: 0.7 ± 0.26 mg/dL CRE & 16.9±2.8 mg/dL BUN) and reduction in body weight.BG d0‐1 or d0‐6 resulted in significant effects, including limiting accumulation of CRE and BUN to 60% of control, accelerating body weight gain and improved renal histopathology. FUR significantly elevated CRE(5.7±1.3 mg/dL), BUN (207±52 mg/dL) and reduced body weight. All FUR animals died on d7.These data support the involvement of A1Rs in CIS‐induced acute renal injury in rats. BG9928 may be useful in the prevention/treatment of renal failure induced by agents like CIS and in other conditions where activation of A1Rs by adenosine in the kidney occurs.
Design and development of novel non‐peptide agonists at natriuretic peptide receptor‐C
Authors: Hobbs Adrian J , Gane Paul , Lumsden Natalie , Nobles Muriel , Rebstock Anne‐Sophie , Simone Michela , Villar Inmaculada , Worthington Roberta , Xiao Fang , Ahluwalia Amrita , Selwood David 
Published: June 2021

Endothelium‐derived C‐type natriuretic peptide (CNP) possesses several cytoprotective functions that might be key in preventing cardiovascular disease (Ahluwalia & Hobbs [2005] Trends. Pharmacol. Sci., 26, 162). Since many of the vasoprotective effects of CNP are mediated via natriuretic peptide receptor (NPR)‐C, this receptor might represent a novel therapeutic target.Thus, we have undertaken a multi‐disciplinary drug development programme, incorporating computer modelling, chemical synthesis and cell‐based biological screens to generate novel small molecule mimetics of CNP (i.e. NPR‐C agonists). Using the NPR‐C crystal structure (He et al. [2001] Science, 293, 1657) as a starting point, we have (a) tested fragments of CNP to elucidate which amino acids make fundamental contact with NPR‐C; (b) modified the NPR‐C antagonist AP‐811, retaining the non‐peptide region and using pharmacophore searches to replace the peptide component; (c) manipulated the secondary conformation of CNP to replace key functional groups with spatially‐similar molecular structures.These strategies have led to the identification of a series of novel, selective, non‐peptide NPR‐C agonists that have sub‐micromolar potency to reverse vasoconstrictor‐induced Ca2+ flux in rat isolated vascular smooth muscle cells and relax rat isolated mesenteric arteries in vitro. Such molecules represent an excellent starting point from which to develop NPR‐C agonists for the potential treatment of cardiovascular disease.Supported by The Wellcome Trust
SCH 530348 Is a Novel Oral Antiplatelet Agent Selective for Protease‐Activated Receptor‐1 (PAR‐1) Receptor Subtype Without Partial Agonist Activity
Authors: Chintala Madhu , Kurowski Stan , Zhai Ying , Lachowicz Jean 
Published: June 2021

ObjectivesExisting antiplatelet therapies target the thromboxane A2 and P2Y12 ADP platelet activation pathways, but do not affect an important pathway triggered by binding of thrombin to the platelet PAR‐1 receptor. The present study evaluated SCH 530348, a novel thrombin receptor antagonist (TRA) selective for PAR‐1, on human platelet function.MethodsThe effect of SCH 530348 on platelet aggregation in human platelet‐rich plasma was assessed by optical aggregometry in the presence of various agonists. The effect of SCH 530348 on basal and PAR‐1 agonist peptide‐induced expression of P‐selectin, a marker of platelet activation, was also determined.ResultsSCH 530348 inhibited platelet aggregation induced by the PAR‐1 agonist peptide and α‐thrombin in a dose‐related manner, without affecting platelet aggregation in response to the PAR‐4 agonist peptide, ADP, collagen, and thromboxane mimetic. SCH 530348 effectively inhibited PAR‐1 agonist peptide‐induced P‐selectin expression, but did not affect the basal expression of P‐selectin.ConclusionsSCH 530348 selectively inhibits PAR‐1 on human platelets, with no partial agonist activity. SCH 530348 may incrementally reduce pathologic platelet activation not targeted by existing antiplatelet agents, and thus potentially further reduce the risk of ischemic events. This hypothesis is being tested in large clinical trials.
The immediate rise in leg blood flow during calf exercise is dependent on functional venous valves
Authors: Naadland Inger Helene , Wesche Jarlis , Sheriff Don , Toska Karin 
Published: June 2021

The importance of the muscle pump in exercise hyperemia is incompletely understood. We have recently shown that a large hydrostatic column induced by head up tilt (HUT) increases the effect of the leg muscle pump on muscle perfusion in healthy subjects. In this study we investigated the effect of a larger hydrostatic column on muscle perfusion in patients with insufficient venous valves.The transient and steady state rise in leg arterial blood flow (ultrasound Doppler) was investigated in 10 patients with venous insufficiency, both supine and 30º HUT.Within ~15 s of the start of exercise, the rise in femoral flow was not significantly different between supine (0.21 L/min) and HUT (0.24 L/min). After 80 s of exercise, femoral flow was stable at 0.20 L/min and 0.22 L/min above rest in supine and HUT respectively (not significantly different).These results indicate that there is no significant muscle pump effect on the immediate rise in muscle perfusion in patients with venous insufficiency.This is in contrast to the findings in healthy subjects, where the transient rise in femoral flow was considerably larger in the tilted than in the supine position. The reduced immediate rise in blood flow observed in the present study indicates that the larger transient rise in femoral flow in healthy subjects was indeed dependent on functional venous valves, and thus caused by a leg muscle pump effect.Research support: University of Oslo.
Serotonin depletion near end‐stage disease does not impair ventilation in a rat model of amyotrophic lateral sclerosis (ALS)
Authors: Nichols Nicole L. , Johnson Rebecca A. , Nashold Lisa J. , Mitchell Gordon S. 
Published: June 2021

In rodent models of ALS (SOD1G93A rat), ventilation is maintained until late in disease progression, despite a paucity of surviving respiratory motor neurons. Thus, surviving motor neurons compensate for motor neuron loss and preserve ventilation. We tested the hypothesis that 5‐HT is necessary for such compensatory plasticity by measuring ventilatory capacity following 5‐HT depletion near disease end stage in SOD1G93A rats. When SOD1G93A rats decreased body mass 15%, mutants (and wild type litter mates) were given para‐chlorophenylalanine (PCPA; 300 mg/kg IP) or vehicle injections (0.9% NaCl, 7.5 ml/kg IP) for 2 days. Ventilatory measurements were made during baseline, hypoxic (10.5% O2), hypercapnic (7% CO2) and hypoxic/hypercapnic (10.5% O2/7% CO2) conditions via whole‐body plethysmography (n=3‐5 per group). PCPA had no effect (or actually increased) minute ventilation and tidal volume in all conditions studied in both mutant and wild type rats. PCPA decreased breathing frequency (f) in wild type rats; although f was lower in untreated mutant rats (vs wild type), PCPA had no additional effect. Our data provide no evidence that 5‐HT depletion impairs the capacity to increase ventilation in end‐stage SOD1G93A rats. However, we cannot rule out a role for 5‐HT in the induction (vs maintenance) of compensatory plasticity in SOD1G93A rats.[Supported by NIH NSO57778.]
Abnormal Neurovascular Control During Exercise After Myocardial Infarction
Authors: Rondon Maria Urbana P. B. , Martinez Daniel G. , Nicolau Jose C , Lage Rony L , Laterza Mateus C. , Trombetta Ivani C. , Matos Luciana D.N.J. , Negrao Carlos E. 
Published: June 2021

ObjectiveWe hypothesized that muscle sympathetic nerve activity (MSNA) responses during exercise would be exacerbated whereas forearm blood flow responses would be reduced in patients post myocardial infarction (MI).MethodsWe studied 23 patients (52±2 yr; ejection fraction= 56±1%), 30‐days after MI and 8 age‐matched healthy controls (C, 46±1 yr), during handgrip exercise. MSNA was measured by microneurography, forearm blood flow by venous occlusion plethysmography, and blood pressure by oscillometric method.ResultsBaseline MSNA was higher (57±4 vs. 35±2 bursts/100HB, P=.006), and forearm vascular conductance (FVC) was lower (1.62±0.1 vs. 2.97±0.4 units, P<.002) in MI patients when compared with C. No significant difference in mean blood pressure between groups was found (90±5 vs. 86±2 mmHg, P=.61). MSNA bursts/100HB similarly increased during peak exercise in both groups (P<.001). However, the MSNA levels were significantly higher in MI patients than in C (66±4 vs. 47±3 bursts/100HB, P=.01). FVC significantly increased during exercise in C (2.60±0.3 vs. 4.13±0.6 units, P<.001), but not in MI patients in whom FVC was unchanged (1.48±0.1 vs. 1.53±0.2 units, P=.99).ConclusionSympathetic outflow is augmented and FVC is blunted during exercise in patients with MI. These findings highlight the abnormal neurovascular control during physiological maneuvers in patients with recent MI.
Mild skin surface cooling does not increase arterial stiffness in humans
Authors: Hess Kari L. , Wilson Thad E. , Gao Zhaohui , Sauder Charity L. , Ray Chester A. , Monahan Kevin D. 
Published: June 2021

To test the hypothesis that mild skin surface cooling acutely increases central arterial stiffness and alters timing and amplitude of central wave reflections we measured aortic pulse wave velocity (PWV), central augmentation index, and transit time of the reflected wave before and during 20 min of cooling (water perfused suit) in 12 adults (25 ?1 years old, mean ?SE). Cooling decreased skin temperature (Δ‐3.6 ±0.4° C; P<0.05) without effecting sublingual temperature. Arterial blood pressure increased during cooling (Δ10±1 and Δ8±1 mmHg for systolic and diastolic blood pressure, respectively; P<0.05). Arterial stiffness, measured as aortic PWV, was unchanged (6.1±0.2 vs. 6.6±0.3 m/s for baseline and cooling, respectively; P>0.40) by cooling. In contrast timing and amplitude of central wave reflections were modified by cooling as assessed by measures of augmentation index (6±2% vs. 14±4%; P<0.05) and transit time of the reflected wave (169±7 vs. 152±5 ms; P<0.05). None of these measures changed during a separate control trial. Collectively, these data indicate that mild skin surface cooling does not acutely increase central arterial stiffness (aortic PWV) although it does modify the timing and amplitude of central wave reflections. These latter responses likely result from cold induced splanchnic, renal, and cutaneous vasoconstriction.Support: NIH AG24420, HL77670, M01 RR10732
Topology of the C‐terminal Transmembrane Region of NBCe1‐A Differs from AE1
Authors: Zhu Quansheng , Kao Liyo , Liu Weixin , Newman Debra , Orozco Nicholas , Azimov Rustam , Pushkin Alexander , Abuladze Natalia , Kurtz Ira 
Published: June 2021

Sodium‐dependent bicarbonate cotransporter 1 (NBCe1) and sodium‐independent chloride/bicarbonate exchanger 1 (AE1) belong to the SLC4 transport family of membrane proteins that mediate bicarbonate transport. The extensively analyzed topology of AE1 highlights the structural and functional importance of the C‐terminal transmembrane region, which is considered to form the anion transport site. Residues in the C‐terminal transmembrane region of NBCe1‐A and AE1 are 40% homologous, however, no information is available on the topology of this region in NBCe1‐A. In this study, we performed introduced cysteine scanning mutagenesis coupled with sulfhydryl specific chemistry in the C‐terminal transmembrane region of NBCe1‐A. One hundred sixty cysteine mutations were individually introduced between Ala800 and Asp960 on a NBCe1‐A construct in which five cytoplasmic endogenous cysteines were changed to serine. These mutations completely covered the C‐terminal transmembrane region of NBCe1‐A, which includes the two proposed re‐entrant loops in AE1. The location of introduced cysteine residues were determined by whole cell labeling with two cysteine specific reagents: membrane permeant biotin maleimide (BM) and membrane impermeant MTS‐TAMRA. Of 160 introduced cysteine mutants, 31 were labeled with BM and 10 were labeled with MTS‐TAMRA. Our data demonstrate that topology of the C‐terminal transmembrane region of NBCe1‐A differs from AE1 in the following aspects: 1) NBCe1‐A lacks the two AE1 re‐entrant loops; 2) NBCe1‐A has 5 rather than 4 transmembrane helices (TM) in this region; 3) the average size of NBCe1‐A C‐terminal TMs is greater than AE1. On the basis of results, we propose a new topology model for the C‐terminal transmembrane region of NBCe1‐A.Supported by NIH