bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Wisconsin Respiratory Symptom Survey‐21 to assess health‐related quality of life in college students during upper respiratory infections
Authors: Smith Tracey J. , Rigassio-Radler Diane , Touger-Decker Riva , Denmark Robert 
Published: June 2021

The Wisconsin Upper Respiratory Symptom Survey‐21 (WURSS‐21) assesses symptom severity and functional status during upper respiratory infections (URIs), which are important measures of health‐related quality of life (HRQL). To determine the reliability of the WURSS‐21 in college students; and, to explore which URI symptoms and functional impairments contributed to the total severity score. This descriptive study was part of a prospective, 12‐week trial in undergraduate students (n = 198, Framingham, MA). Incidence of URIs, and HRQL during URIs, was determined via the WURSS‐21 (items ranked on a 7‐point scale, 1 = very mild and 7 = severe). Cronbach's α was calculated for survey subscales (nasal symptoms, throat symptoms and functional tasks) using day 3 scores. Sixty‐one percent of subjects experienced ≥1 URI (167 total URIs; 1003 sick days; 993 complete surveys). Cronbach's α was ≥ 0.90, indicating good reliability. The median total WURSS‐ 21 score was 66 (range = 5–832); most items were ranked as mild to moderate. The most frequently reported symptoms were ‘runny nose’ and ‘tired’ (~71% of surveys); the most frequently impaired functional tasks were ‘breathe easily’ and ‘sleep well’ (57% and 49% of surveys, respectively). The WURSS‐21 reliably assessed HRQL during URIs in college students; and, both symptoms and impaired functional tasks contributed to total scores.Research Funded by Chr Hansen A/S
Role of HMGB1 in Doxorubicin‐induced myocardial apoptosis and its regulation pathway
Authors: Yao Yongwei , Zhang Guohui , Zhang Yingyu , Rui Tao 
Published: June 2021

The underlying mechanism by which Doxorubicin (DOX) causes cardiomyocyte apoptosis is not clear. The aim of present study is to investigate the role of high‐mobility group box 1 (HMGB1) in DOX‐induced myocardial apoptosis, and signal pathway involved in regulation of HMGB1 expression in cardiomyocytes with DOX.Methods and ResultsTreatment of cardiomyocytes and naive mice with the DOX resulted in an increased HMGB1 expression which was associated with increased myocardial cell apoptosis. Pharmacological (A‐box) or genetic blockade (TLR4 deficiency, TLR4−/−) of HMGB1 attenuated the DOX‐induced myocardial apoptosis and dysfunction. In addition, DOX resulted in an increment in the generation of peroxynitrite (ONOO‐) and an elevation in phosphorylation of c‐Jun N‐terminal kinase (JNK). Pretreatment of myocytes with FeTPPS, a peroxynitrite decomposition catalyst prevented DOX‐induced JNK phosphorylation, HMGB1 expression, myocardial apoptosis and cardiac dysfunction. Genetic (JNK−/−) or pharmacological (SP600125) inhibition of JNK ameliorated the DOX‐induced HMGB1 expression and diminished myocardial apoptosis and cardiac dysfunction.Conclusionthe results indicate that HMGB1 mediates the myocardial injury induced by DOX and ONOO‐/JNK is a key regulatory pathway of myocardial HMGB1 expression induced by DOX. (Supported by National Science Foundation of China# 81170210).
Sodium channel activator‐stimulated neuronal development involves BDNF‐TrkB signaling
Authors: Jabba Sairam V , Murray Thomas F 
Published: June 2021

N‐methyl D‐aspartate receptor (NMDAR) activation stimulates calcium influx and brain‐derived neurotrophic factor (BDNF) – TrkB signaling. This pathway is implicated in activity‐dependent neuronal development and synaptic plasticity. Voltage‐gated sodium channel (VGSC) activators promote neuronal development by increasing [Na+]i and upregulating NMDAR function. Here we tested the effect of the VGSC activator veratridine (VRT) on neurite outgrowth (NOG), synthesis and release of BDNF and TrkB activation in DIV1 cerebrocortical neurons. VRT enhanced NOG in a hormetic concentration‐response manner and this response was dependent on NMDAR and TrkB signaling. Inhibitors of NMDAR, TrkB, PI3K, and PLCγ inhibited VRT‐enhanced NOG. Acute treatment with VRT stimulated phosphorylation of TrkB and its downstream effectors Akt, mTOR, PLC, ERK1/2 and CREB. VRT increased BDNF synthesis and release in a concentration dependent manner; however, VRT stimulation of TrkB phosphorylation displayed a biphasic concentration‐response curve. VRT stimulation of BDNF synthesis required VGSCs and NMDARs. These data suggest that BDNF synthesis and release mediate VGSC activator‐enhanced NOG through activation of TrkB signaling.(NIH, R01NS053398)
Lipopolysaccharide impairs gap junction function and reduces rat kidney NRK‐52E cell proliferation
Authors: Wang Yanling , Wei Jing , Xia Zhengyuan , Hei Ziqing , Luo Chenfang 
Published: June 2021

Endotoxin lipopolysaccharide (LPS)‐induced shock is life‐threatening which is often associated with acute renal failure. Gap junctions (GJ) play critical roles in maintaining kidney functions by facilitating intercellular communication and tubular purinergic signaling. However, it is unknown whether or not LPS may cause acute kidney injury by impairing renal GJ functions. Renal tubular epithelial cells are one of the main parenchymal cells that are susceptible to injurious stimuli. We, therefore, employed normal rat renal tubular epithelial cell line (NRK‐52E) to investigate the impact of LPS on cell proliferation and GJ function. NRK‐52E cells were seeded at high and low density to promote or impede GJ formation, respectively, and to establish distinctive levels of intercellular communication We found that LPS dose‐dependently reduced cell proliferation rate and colony‐formation rate of high and low density NRK‐52E cells when LPS concentration was above 100 ng/mL, accompanied with reduced connexin43 protein expression and reduced fluorescent dye transmission between adjacent cells (all p<0.05 vs. control without LPS stimulation). The GJ inhibitor oleamide attenuated LPS‐induced reduction in colony‐formation rate of high density cells, but further decreased fluorescent transmission (all P<0.05 vs. LPS). In contrast, GJ agonist retinoic acid increased fluorescent dye transmission. It is concluded that impairment in GJ function may represent a mechanism whereby LPS induces kidney cell injury.Supported by NSFC grant (No. 81170449) and Guangdong Natural Science Foundation grant (S2011020002780).
Arteriolar remodeling limits maximal perfusion after percutaneous revascularization of a chronic stenosis in pigs with hibernating myocardium
Authors: Weil Brian Raymond , Page Brian J , Banas Michael D , Suzuki Gen , Canty John M 
Published: June 2021

Chronic myocardial ischemia results in remodeling of the coronary microcirculation in hibernating myocardium but the reversibility of these changes is unknown. Accordingly, we evaluated parameters of arteriolar structure and measured transmural myocardial perfusion during adenosine vasodilation before and up to one month after percutaneous coronary intervention (PCI) of a chronic LAD stenosis in swine (n=12). Regional function was depressed at rest (LAD wall thickening 38.6±4.0 vs. 92.2±7.5%, p<0.05). Immediately after PCI, subendocardial flow during adenosine vasodilation increased from 1.5±0.3 to 4.6±0.8 ml/min/g, but fell to 2.7±0.3 ml/min/g one month later without evidence of restenosis. Histological assessment of subendocardial resistance vessel remodeling is shown below:

Group
Subendocardial Arterioles

Lumen Area (μm2)
Density (arterioles/mm2)
WT/Lumen Diameter (%)

Hibernating (n=148)
721±67*
10.7±1.8*
37.3±1.5*

Revascularized (n=54)
659±88*
5.8±0.4
40.3±2.2*

Sham (n=54)
1184±173
6.2±0.3
28.7±1.3

Values are mean±SEM; n=total number of vessels analyzed; WT=wall thickness;
p<0.05 vs. Sham.

These data indicate that there is subendocardial microvascular remodeling in hibernating myocardium with an increase in arteriolar density compensating for a reduction in arteriolar lumen area. After revascularization, arteriolar density returns to normal but lumen area remains reduced and decreases maximal perfusion. These chronic microvascular structural changes could precipitate subendocardial ischemia in the absence of coronary restenosis. Supported by NIH HL61610.
CaR‐mediated vasodilatation: Role of endothelium TRPC channels
Authors: Albert Anthony Paul , Shi Jian , Mclough Jessica , Greenberg Harry , Preet Chadha , Greenwood Iain , Ho Vanessa 
Published: June 2021

There is increasing evidence that Ca2+‐sensing G‐protein‐coupled receptors (CaR) have an important role in modulating vascular activity; both CaR‐mediated contraction and dilation responses have been proposed. However, there is little information on mechanisms which govern CaR‐mediated responses. The aim of the present work was to investigate endothelium‐dependent actions of CaR stimulation on canonical transient receptor channels (TRPC) channel activity using patch clamp electrophysiology and functional studies. In cell‐attached patches from freshly isolated endothelium cells of the rabbit mesenteric artery, bath application of CaCl2 (1–10 mM), and the CaR mimics calindol and AC265347 activated two distinct TRPC channels with TRPC1 and TRPC3/6/7 subtype properties. TRPC channel activities were inhibited by the negative modulator of CaR, calhex, and the phospholipase C inhibitor U73122. Wire myograph studies showed that CaR stimulation relaxed methoxyamine‐contracted rabbit mesenteric arteries through an endothelium‐dependent mechanism. Immunocytochemistry revealed CaR expression in both vascular smooth muscle and endothelium cells. The present work indicates that endothelium‐dependent vasodilatations mediated by CaR are likely to involve activation of TRPC channels.The work was supported by the British Heart foundation.
Myoendothelial Contacts Within the Skeletal Muscle Arterial Network: A Potential Mediator for Divergent Control of Vascular Tone
Authors: Kirby Brett S , Bruhl Allison , Earley Scott 
Published: June 2021

Holes within the internal elastic lamina (IEL) of blood vessels, referred to as myoendothelial contacts (MECs), are sites of fenestration allowing for passage of diffusible vasoactive substances and interface of endothelial cell membrane projections with underlying vascular smooth muscle. Endothelial projections are sites of dynamic Ca2+ events leading to endothelial cell hyperpolarization‐mediated relaxation and the activity of these events increase as vessel diameter decreases. Given that arterioles are the primary site of vascular resistance within skeletal muscle, we tested the hypothesis that fenestration within the IEL would be greater in distal vs. proximal arteries of the skeletal muscle arterial network. Popliteal arteries, subsequent gastrocnemius feed arteries, and intramuscular 1A arterioles from the Sprague Dawley rat hindlimb were isolated, cut and fixed longitudinally, and imaged using confocal microscopy. Quantitative analysis revealed a larger MEC total area of 1A vs. feed and popliteal arteries (20.7% vs. 5.8% and 2.8%; N = 10 images/artery), due to a noticeably greater average size of MEC (39.6μm2 vs. 11.1μm2 and 7.6μm2). These initial observations highlight the superior MEC area of intramuscular arteries and are suggestive that the anatomical architecture for distinct vasodilatory signaling is present.Supported by RO1HL091905
Scleraxis works synergistically with Smads to regulate collagen gene expression
Authors: Bagchi Rushita , Czubryt Michael 
Published: June 2021

Elevated type I collagen expression in cardiac fibrosis impairs heart function. We have shown that the transcription factor scleraxis (Scx) is expressed by cardiac fibroblasts and myofibroblasts, and is sufficient to regulate human collagen Iα2 (COLIα2) expression. Here we studied the interaction of Scx with the fibrotic Smad signaling pathway. We identified Scx binding sites (E‐boxes) within the COLIα2 proximal gene promoter, examined promoter occupancy by Scx using ChIP assay, and measured promoter activation by Scx and/or Smads via luciferase gene reporter assays. Scx augmented TGF‐β1 transactivation of the promoter. Scx and Smad3 synergistically up‐regulated COLIα2 promoter transactivation. Mutation of the promoter Smad binding element significantly reduced transactivation by Scx. A similar effect of E‐box mutations on Smad3‐mediated activation was also observed, suggesting that cross‐talk in these pathways is required for maximal gene activity. Scx expression was up‐regulated by Smad3 and down‐regulated by Smad7, further supporting cross‐pathway signaling. A dominant negative Scx mutant completely abrogated COLIα2 gene expression by TGF‐β1. Our results indicate that Scx and Smads synergistically co‐regulate collagen gene expression, and that interference with this interaction may represent a novel avenue for anti‐fibrotic therapy development.Supported by CIHR and MHRC.
Enhanced Proliferation and Cardiogenic Differentiation of Cardiac Progenitor Cells Treated with a Naturally Derived Cardiac Extracellular Matrix
Authors: French Kristin M , DeQuach Jessica A , Christman Karen L , Davis Michael E 
Published: June 2021

Adverse remodeling of the myocardium after myocardial infarction speeds progression to heart failure. Some of the major shortcomings in cell therapy are the growth and differentiation of implanted cells. In patients, cells are injected to an area comprised mostly of noncontractile collagen, far different from their native microenvironment. This study aims to determine whether a naturally derived porcine cardiac extracellular matrix (cECM) enhances proliferation and differentiation in cardiac progenitor cells (CPCs).CPCs were isolated via magnetic sorting of c‐kit+ cells in cardiac tissue homogenates and were grown on plates coated with either cECM or collagen I (COL). Greater serum‐induced proliferation was seen on cECM as compared to COL (3.17 vs. 1.99‐fold) as measured by Coulter counting at 2 days. Further, a trend toward increased expression of cardiac markers (Nkx2.5 and GATA4) was seen at this early time point. At 7 days, protein levels of Nkx2.5 and GATA4 were increased. Finally, fibroblastic markers were decreased at 7 days, while the environment of the cells had become oxidative, compatible with reports of redox regulation during differentiation.Our data demonstrate that a naturally derived matrix may provide enhanced proliferation and cardiogenic differentiation of CPCs compared to collagen and thus may be a suitable vehicle to deliver cells in vivo. This study was supported by internal funding.
Age‐dependent alterations to the cardiac extracellular matrix in heart failure: differences between ventricular and atrial remodeling
Authors: Horn Margaux Anne , Graham Helen , Bode Elizabeth , Dibb Katharine , Trafford Andrew 
Published: June 2021

Structural remodeling of the ventricles and the atria are features of both myocardial disease and aging and the extracellular matrix (ECM) plays a pertinent role in this process. This study sought to determine if aging exacerbates structural remodeling of the myocardium in heart failure (HF).HF was induced in young (18 months) and old (>8 years) sheep by ventricular tachypacing. Echocardiography was performed consciously and collagen content assessed histologically. Matrix metalloproteinases (MMPs) were quantified by gelatin zymography whereas tissue inhibitor of metalloproteinases (TIMPs) were assessed by immunoblotting.HF led to left ventricular (LV) dilatation and reduced contractility in both young and old animals, although changes were more pronounced in old. In contrast, HF increased left atrial (LA) diameter to a similar extent in both groups. Age‐associated changes to LV ECM remodeling occurred in HF with collagen accumulation in young and depletion in old. In the LA however, fibrosis was present with HF in both young and old animals. LV MMP‐2 activity was elevated in young HF but to no greater extent in old HF, however TIMP levels were reduced only in aged HF. In the LA, MMP‐2:TIMP ratio was elevated in both young and old HF.This study demonstrates that age‐dependent alterations to LV ECM remodeling occur in HF, but HF‐induced remodeling of the LA is largely unaffected by age.Funded by BHF and EU “Normacor”.
In Vivo Application of Dynamic Hyaluronic Acid Material for Myocardial Infarction Therapy
Authors: Young Jennifer L , Schaefer Jacquelyn , Tuler Jeremy , Schup-Magoffin Pamela , Braden Rebecca , Christman Karen L , Engler Adam J 
Published: June 2021

Tissue‐specific elasticity arises from developmental changes, e.g. ~10‐fold myocardial stiffening from E3 to E10 in the chick embryo. We have shown that pre‐cardiac mesodermal cells plated on top of a thiolated hyaluronic acid (HA) hydrogel engineered to mimic this time‐dependent stiffening improves cardiomyocyte maturation compared to cells on static matrices. Here we determined cell‐matrix interactions using in vivo injections and in vitro encapsulation assays. Prior to assembly, HA was injected subcutaneously or intramyocardially into rats. Histological analysis showed minimal infiltration of host cells and capsule formation around the matrix. Hematological analysis showed no significant systemic immune response was elicited in pre‐ vs. post‐injection animals for all time points. Atomic force microscopy of subcutaneously injected gels showed increasing hydrogel stiffness over time similar to that previously found in vitro. Improved pre‐cardiac and embryonic stem cell distribution and viability was observed when cells were encapsulated with HA and immobilized thiolated protein. These data indicate the presentation of developmentally appropriate matrix stiffness may improve cell differentiation for use in future studies for treating heart failure post‐myocardial infarction.Funding: AHA (0865150F to A.J.E.), NIH (1DP02OD006460 to A.J.E.), ARCS (to J.L.Y.), AHA (10PRE4160143 to J.L.Y.)
Insulin regulates hSGLT2 expression via PKA and PKC activation
Authors: Ghezzi Chiara , Wright Ernest M 
Published: June 2021

Recent evidence suggest that in the rat proximal tubule SGLT2 (Sodium dependent Glucose Transporter 2) is phosphorylated. To test if human SGLT2 is regulated by posphorylation we analyze the effect of PKA and PKC activation on HEK‐293T cells expressing hSGLT2 using patch clamp and radio tracer uptake. PKA activation was induced by incubation of cells in 8‐bromoadenosine 3′‐5′‐cyclic monophosphate (Br‐cAMP) and sn‐1,2‐dioctanoylglycerol (DOG) was use as activator of PKC. After 1 h incubation in Br‐cAMP we observed a 2.5 fold increase in [14 C]α‐MDG uptake confirmed by a similar increase in glucose induced current. Incubation in DOG resulted in a 50 % increase in [14C]α‐MDG uptake and glucose induced current. In both cases increase is caused by an increase in Imax and not in the change in glucose affinity. These effects were completely suppressed by mutation of the SGLT2 phosphorylation site (S625A). In order to determine the initial event triggering the phosphorylation, we measured the effect of insulin on [14C]α‐MDG uptake. Incubating cells expressing hSGLT2 wt or S625A mutant with 400 pM insulin induced a 3 fold increase in glucose transport in wild type hSGLT2 but not in the mutant. In conclusion our results indicate that insulin via PKA and PKC activation regulates hSGLT2 expression in a fast time scale by an increasing trafficking of hSGLT2 to the plasma membrane.NIH grant DK077133 and SNSF grant PBZHP3‐135919.
Evaluation of salt appetite in brain specific 11β hydroxysteroid dehydrogenase type 2 knockout (11βHSD2−/−) mice
Authors: Evans Louise Christine , Holmes Megan , Mullins John , Bailey Matthew 
Published: June 2021

Male brain specific 11βHSD2−/− mice and floxed controls were individually housed in metabolic cages and basal water turnover assessed over 4 days. In separate studies mice were given access to 2 bottles containing water and 1.5% NaCl and salt preference measured over 7 days. The role mineralocorticoid receptor (MR) in salt appetite was evaluated using spironolactone s.c.Basal water and sodium turnover and plasma sodium concentrations were not altered by the deletion of 11βHSD2 in the brain. When given access to NaCl brain specific 11βHSD2−/− mice displayed a significant salt preference, 70% of total fluid intake was accounted for by NaCl. Salt appetite was significantly reduced by MR blockade. Sodium was not retained in the null mice; increased salt intake resulted in significant natriuresis and polyuria.Deletion of 11βHSD2 in the brain, which is specifically expressed in the nucleus of the solitary tract (NTS) in mice, resulted in an increased salt appetite. Activation of MR is implicated since spironolactone significantly reduced NaCl intake. These data are the first demonstration of salt appetite occurring in the absence of sodium depletion and with normal renal function. They suggest that activation of MR on 11βHSD2 positive neurons in the NTS increases salt appetite. Funded by the British Heart Foundation.
Preliminary investigation of skeletal muscle signal recognition particle receptor beta in response to aging in the rat
Authors: Receno Candace N , Doyle Robert P , DeRuisseau Lara R , DeRuisseau Keith C 
Published: June 2021

The signal recognition particle receptor (SRPR) interacts with the signal recognition particle (SRP), which targets and transports nacent polypeptides destined for secretion or expression on the cell membrane. The SRP is likely important for normal muscle functioning since individuals with autoantibody production against the SRP can develop myopathy. The SRPR contains two subunits; one of which is the beta subunit that is integrated within the membrane of the endoplasmic reticulum (ER). We became interested in SRPR beta after an initial proteomic screening indicated altered expression of the protein in aged muscle. The objective of the current experiment was to further examine skeletal muscle SRPR beta protein expression in response to aging. We harvested extensor digitorum longus muscles from 8, 28, and 36‐ month old male Fisher 344xBrown Norway F1 hybrid rats (n = 4/group). Protein expression of SRPR beta was assessed using Western blot and was approximately 60% lower in the 36‐month old rats compared to younger animals (8‐month old group = 0.20 ± 0.04, 28‐month old group = 0.21 ± 0.05, 36‐month old group = 0.09 ± 0.03; values are mean ± SEM). This preliminary investigation is the first to examine SRPR protein expression in aging skeletal muscle and the findings suggest changes in SRPR beta may be associated with skeletal muscle alterations that occur in old age.Supported by NIH 5R03AG032033 (KCD).