bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic hypoxia‐induced upregulation of Ca2+‐activated Cl− channel in pulmonary arterial myocytes: a mechanism contributing to enhanced vasoreactivity
Authors: Sun Hui , Xia Yang , Paudel Omkar , Yang Xiao‐Ru , Sham James S. K. 
Published: June 2012

Key points
A prolonged reduced oxygen level in the lungs, as occurs in patients of many chronic lung diseases and in residents living at high altitude, causes pulmonary hypertension characterized by profound structural and functional changes in pulmonary vasculature.
Many of these changes are ascribed to alterations in Ca2+ homeostasis related to cation channels of pulmonary arterial smooth muscle cells.
Here we report the increase of an anion conductance called calcium‐activated chloride channel and the expression of the channel gene TMEM16A in pulmonary arterial smooth muscle cells isolated from rats exposed to 10% oxygen for 3–4 weeks.
The upregulation of the chloride channel contributes to the hyper‐responsiveness of pulmonary arteries to serotonin associated with pulmonary hypertension.
These results help us to appreciate the importance of anion channels in the pathophysiology of pulmonary hypertension, and may lead to alternative strategies for the treatment of the disease.
Abstract  Chronic hypoxic pulmonary hypertension (CHPH) is associated with altered expression and function of cation channels in pulmonary arterial smooth muscle cells (PASMCs), but little is known for anion channels. The Ca2+‐activated Cl− channel (CaCC), recently identified as TMEM16A, plays important roles in pulmonary vascular function. The present study sought to determine the effects of chronic hypoxia (CH) on the expression and function of CaCCs in PASMCs, and their contributions to the vascular hyperreactivity in CHPH. Male Wistar rats were exposed to room air or 10% O2 for 3–4 weeks to generate CHPH. CaCC current (ICl.Ca) elicited by caffeine‐induced Ca2+ release or by depolarization at a constant high [Ca2+]i (500 or 750 nm) was significantly larger in PASMCs of CH rats compared to controls. The enhanced ICl.Ca density in CH PASMCs was unrelated to changes in amplitude of Ca2+ release, Ca2+‐dependent activation, voltage‐dependent properties or calcineurin‐dependent modulation of CaCCs, but was associated with increased TMEM16A mRNA and protein expression. Maximal contraction induced by serotonin, an important mediator of CHPH, was potentiated in endothelium‐denuded pulmonary arteries of CH rats. The enhanced contractile response was prevented by the CaCC blockers niflumic acid and T16Ainh‐A01, or by the L‐type Ca2+ channel antagonist nifedipine. The effects of niflumic acid and nifedipine were non‐additive. Our results demonstrate for the first time that CH increases ICl.Ca density, which is attributable to an upregulation of TMEM16A expression in PASMCs. The augmented CaCC activity in PASMCs may potentiate membrane depolarization and L‐type channel activation in response to vasoconstrictors and enhance pulmonary vasoreactivity in CHPH.
Experience‐dependent expression of NPAS4 regulates plasticity in adult visual cortex
Authors: Maya‐Vetencourt José Fernando , Tiraboschi Ettore , Greco Dario , Restani Laura , Cerri Chiara , Auvinen Petri , Maffei Lamberto , Castrén Eero 
Published: June 2012

Key points
Transcription factors at the basis of plasticity in the adult visual system are unknown.
Enhanced levels of NPAS4 transcription factor parallel visual cortical plasticity in adult life.
Overexpression of NPAS4 restores plasticity in the adult visual cortex.
NPAS4 down‐regulation prevents the plastic outcome caused by fluoxetine (FLX) in adulthood.
NPAS4 regulates the expression of plasticity genes in the adult visual cortex.
Abstract  There is evidence that developmental‐like plasticity can be reactivated in the adult visual cortex. Although activity‐dependent transcription factors underlying the process of plasticity reactivation are currently unknown, recent studies point towards NPAS4 as a candidate gene for the occurrence of plasticity in the adult visual system. Here, we addressed whether NPAS4 is involved in the reinstatement of plasticity by using the monocular deprivation protocol and long‐term fluoxetine treatment as a pharmacological strategy that restores plasticity in adulthood. A combination of molecular assays for gene expression and epigenetic analysis, gene delivery by lentiviral infection, shRNA interference and electrophysiology as a functional read‐out, revealed a previously unknown role for the transcription factor NPAS4 in the regulation of adult visual cortical plasticity. We found that NPAS4 overexpression restores ocular dominance plasticity in adult naïve animals whereas NPAS4 down‐regulation prevents the plastic outcome caused by fluoxetine in adulthood. Our findings lead the way to the identification of novel therapeutic targets for pathological conditions where reorganization of neuronal networks would be beneficial in adult life.
Physical activity opposes coronary vascular dysfunction induced during high fat feeding in mice
Authors: Park Yoonjung , Booth Frank W. , Lee Sewon , Laye Mathew J. , Zhang Cuihua 
Published: June 2012

Key points
Sedentary and high‐fat diet lifestyles are associated with greater prevalence of obesity and type 2 diabetes in humans, both of which independently increase atherosclerosis.
High‐fat diet in sedentary individuals produces endothelial dysfunction in blood vessels as a first step toward coronary arteriosclerosis.
We observed preservation of coronary arteriolar vascular function when mice began voluntary running in wheels at the start of a high‐fat diet.
We further showed that mechanisms by which running opposed the detrimental effects of high‐fat diet on vascular function included maintenance of eNOS phosphorylation, leptin sensitivity, and redox balance in mouse coronary arterioles.
The results provide evidence for how physical activity is an effective therapy to oppose the development of atherosclerosis in the first place.
Abstract  The study's purpose was to investigate if physical activity initiated with the start of high‐fat feeding would oppose development of endothelial dysfunction, and if it does, then to determine some potential mechanisms. C57BL/6 female mice were randomly divided into three groups: (1) control low‐fat diet (LF‐SED; 15% of calories from fat), (2) high‐fat diet (HF‐SED; 45% of calories from fat), and (3) HF diet given access to a voluntary running wheel (HF‐RUN). Our hypothesis was that HF‐RUN would differ in multiple markers of endothelial dysfunction from HF‐SED after 10 weeks of 45%‐fat diet, but would not differ from LF‐SED. HF‐RUN differed from HF‐SED in nine determinations in which HF‐SED either had decreases in (1) acetylcholine (ACh)‐induced and flow‐induced vasodilatations in isolated, pressurized coronary arterioles, (2) heart phosphorylated endothelial nitric oxide synthase (p‐eNOS/eNOS) protein, (3) coronary arteriole leptin (ob) receptor protein, (4) phosphorylated signal transducer and activator of transcription 3 (p‐STAT3/STAT3) protein, and (5) coronary arteriole superoxide dismutase 1 protein; or had increases in (6) percentage body fat, (7) serum leptin, (8) coronary arteriole suppressor of cytokine signalling 3 (SOCS3) protein, and (9) coronary arteriole gp91phox protein. Higher endothelium‐dependent vasodilatation by ACh or leptin was abolished with incubation of NOS inhibitor NG‐nitro‐l‐arginine‐methyl ester (l‐NAME) in LF‐SED and HF‐RUN groups. Further, impaired ACh‐induced vasodilatation in HF‐SED was normalized by apocynin or TEMPOL to LF‐SED and HF‐RUN. These findings demonstrate multiple mechanisms (eNOS, leptin and redox balance) by which voluntary running opposes the development of impaired coronary arteriolar vasodilatation during simultaneous high‐fat feeding.
Morphological, neurochemical and electrophysiological features of parvalbumin‐expressing cells: a likely source of axo‐axonic inputs in the mouse spinal dorsal horn
Authors: Hughes D. I. , Sikander S. , Kinnon C. M. , Boyle K. A. , Watanabe M. , Callister R. J. , Graham B. A. 
Published: June 2012

Key points
Perception of normal bodily sensations relies on the precise regulation of sensory information entering the dorsal horn of the spinal cord.
Inhibitory, axoaxonic, synapses provide a mechanism for this regulation, but the source of these important inhibitory connections remains to be elucidated.
This study shows that a subpopulation of spinal interneurons that expresses parvalbumin and have specific morphological, connectivity and functional characteristics are a likely source of the inhibitory inputs that selectivity regulate non‐noxious tactile input in the spinal cord.
Our findings suggest that a loss of normal function in parvalbumin positive dorsal horn neurons may result in the development of tactile allodynia, where non‐painful stimuli gain the capacity to evoke the sensation of pain.
Abstract  Axo‐axonic synapses on the central terminals of primary afferent fibres modulate sensory input and are the anatomical correlate of presynaptic inhibition. Although several classes of primary afferents are under such inhibitory control, the origin of these presynaptic inputs in the dorsal horn is unknown. Here, we characterize the neurochemical, anatomical and electrophysiological properties of parvalbumin (PV)‐expressing cells in wild‐type and transgenic mice where enhanced green fluorescent protein (eGFP) is expressed under the PV promoter. We show that most PV cells have either islet or central cell‐like morphology, receive inputs from myelinated primary afferent fibres and are concentrated in laminae II inner and III. We also show that inhibitory PV terminals in lamina II inner selectively target the central terminals of myelinated afferents (∼80% of 935 PVeGFP boutons) and form axo‐axonic synapses (∼75% of 71 synapses from PV boutons). Targeted whole‐cell patch‐clamp recordings from PVeGFP positive cells in laminae II and III showed action potential discharge was restricted to the tonic firing and initial bursting patterns (67% and 33% respectively; n= 18), and virtually all express Ih subthreshold voltage‐gated currents (94%; n= 18). These neurons show higher rheobase current than non‐eGFP cells but respond with high frequency action potential discharge upon activation. Together, our findings show that PV neurons in laminae II and III are a likely source of inhibitory presynaptic input on to myelinated primary afferents. Consequently PV cells are ideally placed to play an important role in the development of central sensitization and tactile allodynia.
Validation of an Immunodiagnostic Assay for Detection of 13 Streptococcus pneumoniae Serotype-Specific Polysaccharides in Human Urine
Authors: Pride Michael W. , Huijts Susanne M. , Wu Kangjian , Souza Victor , Passador Sherry , Tinder Chunyan , Song Esther , Elfassy Arik , McNeil Lisa , Menton Ronald , French Roger , Callahan Janice , Webber Chris , Gruber William C. , Bonten Marc J. M. , Jansen Kathrin U. 
Published: June 2012

ABSTRACT

To improve the clinical diagnosis of pneumococcal infection in bacteremic and nonbacteremic community-acquired pneumonia (CAP), a Luminex technology-based multiplex
u
rinary
a
ntigen
d
etection (UAD) diagnostic assay was developed and validated. The UAD assay can simultaneously detect 13 different serotypes of
Streptococcus pneumoniae
by capturing serotype-specific
S. pneumoniae
polysaccharides (PnPSs) secreted in human urine. Assay specificity is achieved by capturing the polysaccharides with serotype-specific monoclonal antibodies (MAbs) on spectrally unique microspheres. Positivity for each serotype was based on positivity cutoff values calculated from a standard curve run on each assay plate together with positive- and negative-control urine samples. The assay is highly specific, since significant signals are detected only when each PnPS was paired with its homologous MAb-coated microspheres. Validation experiments demonstrated excellent accuracy and precision. The UAD assay and corresponding positivity cutoff values were clinically validated by assessing 776 urine specimens obtained from patients with X-ray-confirmed CAP. The UAD assay demonstrated 97% sensitivity and 100% specificity using samples obtained from patients with bacteremic, blood culture-positive CAP. Importantly, the UAD assay identified
Streptococcus pneumoniae
(13 serotypes) in a proportion of individuals with nonbacteremic CAP, a patient population for which the pneumococcal etiology of CAP was previously difficult to assess. Therefore, the UAD assay provides a specific, noninvasive, sensitive, and reproducible tool to support vaccine efficacy as well as epidemiological evaluation of pneumococcal disease, including CAP, in adults.
Abnormal Immune Responses in Persons with Previous Extrapulmonary Tuberculosis in anIn VitroModel That SimulatesIn VivoInfection with Mycobacterium tuberculosis
Authors: Fiske Christina T. , de Almeida Alexandre S. , Shintani Ayumi K. , Kalams Spyros A. , Sterling Timothy R. 
Published: June 2012

ABSTRACTPersons with previous extrapulmonary tuberculosis have reduced peripheral blood mononuclear cell cytokine production and CD4+lymphocytes compared to persons with previous pulmonary tuberculosis or latent tuberculosis infection, but specific defects related toMycobacterium tuberculosisinfection of macrophages have not been characterized. The objective of this study was to further characterize thein vitroimmune responses toM. tuberculosisinfection in HIV-seronegative persons with previous extrapulmonary tuberculosis. Peripheral blood mononuclear cells were isolated from HIV-seronegative persons with previous extrapulmonary tuberculosis (n= 11), previous pulmonary tuberculosis (n= 21), latentM. tuberculosisinfection (n= 19), and uninfected tuberculosis contacts (n= 20). Experimental conditions includedM. tuberculosis-infected macrophages cultured with and without monocyte-depleted peripheral blood mononuclear cells. Concentrations of interleukin 1β (IL-1β), IL-4, IL-6, CXCL8 (IL-8), IL-10, IL-12p70, IL-17, CCL2 (monocyte chemoattractant protein 1), tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) were measured by multiplex cytokine array. WhenM. tuberculosis-infected macrophages were cocultured with monocyte-depleted peripheral blood mononuclear cells, IFN-γ (P= 0.01), TNF-α (P= 0.04), IL-10 (P< 0.001), and IL-6 (P= 0.03) exhibited similar continua of responses, with uninfected persons producing the lowest levels, followed by extrapulmonary tuberculosis cases, pulmonary tuberculosis controls, and persons with latentM. tuberculosisinfection. A similar pattern was observed with CXCL8 (P= 0.04), IL-10 (P= 0.02), and CCL2 (P= 0.03) when monocyte-depleted peripheral blood mononuclear cells from the four groups were cultured alone. Persons with previous extrapulmonary tuberculosis had decreased production of several cytokines, both at rest and after stimulation withM. tuberculosis. Our results suggest that persons who develop extrapulmonary tuberculosis have a subtle global immune defect that affects their response toM. tuberculosisinfection.
Prosthetic Valve Endocarditis Due to Neisseria skkuensis, a Novel Neisseria Species
Authors: Park So Yeon , Kang Seung Ji , Joo Eun-Jeong , Ha Young Eun , Baek Jin Yang , Wi Yu Mi , Kang Cheol-In , Chung Doo Ryeon , Peck Kyong Ran , Lee Nam Young , Song Jae-Hoon 
Published: June 2012

ABSTRACT

We describe the first reported case of endocarditis due to
Neisseria skkuensis
. The organism from the blood cultures taken on admission day was identified initially as unidentified Gram-negative cocci by Vitek2. Finally, it was identified as
Neisseria skkuensis
by 16 rRNA gene sequence analysis.
Duration of Hospital Admission and the Need for Empirical Antipseudomonal Therapy
Authors: Daneman N. , Elligsen M. , Walker S. A. N. , Simor A. 
Published: June 2012

ABSTRACT

To reduce selective pressure for antimicrobial resistance, empirical use of antipseudomonal antibiotics is often reserved for patients with late-onset hospital-acquired infections. We examined the likelihood of isolating
Pseudomonas aeruginosa
as a function of time from hospital admission. We conducted a retrospective cohort study of all positive bacterial cultures in a tertiary-care hospital between March 2010 and November 2011. The primary outcome was the proportion of positive cultures yielding
P. aeruginosa
. Multivariable logistic regression was employed to assess the impact of time from admission on the likelihood of isolating
P. aeruginosa
, after adjusting for other important risk factors. A total of 7,668 positive cultures were obtained from 4,108 unique patients during the study interval, including 633 (8.3%) yielding
P. aeruginosa
. The probability of isolating
P. aeruginosa
increased linearly from 79/2,044 (3.9%) positive cultures obtained on admission to 153/664 (23%) in the 10th week of admission or beyond. The unadjusted odds ratio was 1.002/day (95% confidence interval [CI], 1.0016 to 1.0028;
P
< 0.0001); the adjusted odds ratio (aOR) was 1.0007/day (95% CI, 1.0001 to 1.0013;
P
= 0.02). Other important predictors of
P. aeruginosa
isolation included respiratory specimen type (aOR, 13.8; 95% CI, 9.1 to 21.1), recent hospital admission (aOR,1.8; 95% CI, 1.4 to 2.3), prior
P. aeruginosa
isolation during current admission (aOR, 4.9; 95% CI, 3.7 to 6.4), and prior antipseudomonal (aOR, 1.9; 95% CI, 1.4 to 2.5) or nonantipseudomonal (aOR, 1.8; 95% CI, 1.4 to 2.4) antibiotic exposure. It was determined that as time from admission increases, there is a linear increase in the likelihood of
P. aeruginosa
isolation. Any guidelines which distinguish early from late hospital-acquired infection must consider the implications of time point selection on the likelihood of inadequate
P. aeruginosa
empirical coverage.
Clustered Tuberculosis in a Low-Burden Country: Nationwide Genotyping through 15 Years
Authors: Kamper-Jørgensen Z. , Andersen A. B. , Kok-Jensen A. , Bygbjerg I. C. , Andersen P. H. , Thomsen V. O. , Kamper-Jørgensen M. , Lillebaek T. 
Published: June 2012

ABSTRACT

Molecular genotyping of
Mycobacterium tuberculosis
has proved to be a powerful tool in tuberculosis surveillance, epidemiology, and control. Based on results obtained through 15 years of nationwide IS
6110
restriction fragment length polymorphism (RFLP) genotyping of
M. tuberculosis
cases in Denmark, a country on the way toward tuberculosis elimination, we discuss
M. tuberculosis
transmission dynamics and point to areas for control interventions. Cases with 100% identical genotypes (RFLP patterns) were defined as clustered, and a cluster was defined as cases with an identical genotype. Of 4,601 included cases, corresponding to 76% of reported and 97% of culture-verified tuberculosis cases in the country, 56% were clustered, of which 69% were Danes. Generally, Danes were more often in large clusters (≥50 persons), older (mean age, 45 years), and male (male/female ratio, 2.5). Also, Danes had a higher cluster frequency within a 2-year observation window (60.8%), and higher clustering rate of new patterns over time, compared to immigrants. A dominant genotype, cluster 2, constituted 44% of all clustered and 35% of all genotyped cases. This cluster was primarily found among Danish males, 30 to 59 years of age, often socially marginalized, and with records of alcohol abuse. In Danes, cluster 2 alone was responsible for the high cluster frequency level. Immigrants had a higher incidence of clustered tuberculosis at a younger age (0 to 39 years). To achieve tuberculosis elimination in Denmark, high-risk transmission environments, like the cluster 2 enviornment in Danes, and specific transmission chains in immigrants in the capital area, e.g., homeless/socially marginalized Somalis/Greenlanders, often with alcohol abuse, must be targeted, including groups with a high risk of reactivation.
Hepatitis D Virus Isolates with Low Replication and Epithelial-Mesenchymal Transition-Inducing Activity Are Associated with Disease Remission
Authors: Shih Hsuan Hui , Sheen I-Jane , Su Chien-Wei , Peng Wei-Li , Lin Ling-Hui , Wu Jaw-Ching 
Published: June 2012

ABSTRACT

Clearance of hepatitis D virus (HDV) viremia leads to disease remission. Large hepatitis delta antigen (L-HDAg) has been reported to activate transforming growth factor β, which may induce epithelial-mesenchymal transition (EMT) and fibrogenesis. This study analyzed serum HDV RNA “quasispecies” in HDV-infected patients at two stages of infection: before and after alanine aminotransferase (ALT) elevations. Included in the study were four patients who went into remission after ALT elevation and three patients who did not go into remission and progressed to cirrhosis or hepatocellular carcinoma. Full-length HDV cDNA clones were obtained from the most abundant HDV RNA species at the pre- and post-ALT elevation stages. Using an
in vitro
model consisting of Huh-7 cells transfected with cloned HDV cDNAs, the pre- or post-ALT elevation dominant HDV RNA species were characterized for (i) their replication capacity by measuring HDV RNA and HDAg levels in transfected cells and (ii) their capacity to induce EMT by measuring the levels of the mesenchymal-cell-specific protein vimentin, the EMT regulators twist and snail, and the epithelial-cell-specific protein E-cadherin. Results show that in patients in remission, the post-ALT elevation dominant HDV RNA species had a lower replication capacity
in vitro
and lower EMT activity than their pre-ALT elevation counterparts. This was not true of patients who did not go into remission. The expression of L-HDAg, but not small HDAg, increased the expression of the EMT-related proteins. It is concluded that in chronically infected patients, HDV quasispecies with a low replication capacity and low EMT activity are associated with disease remission.
Hepatitis C Virus NS5A Disrupts STAT1 Phosphorylation and Suppresses Type I Interferon Signaling
Authors: Kumthip Kattareeya , Chusri Pattranuch , Jilg Nikolaus , Zhao Lei , Fusco Dahlene N. , Zhao Hong , Goto Kaku , Cheng Du , Schaefer Esperance A. , Zhang Leiliang , Pantip Chansom , Thongsawat Satawat , O'Brien Amornrat , Peng Lee F. , Maneekarn Niwat , Chung Raymond T. , Lin Wenyu 
Published: June 2012

ABSTRACT
Responses to alpha interferon (IFN-α)-based treatment are dependent on both host and viral factors and vary markedly among patients infected with different hepatitis C virus (HCV) genotypes (GTs). Patients infected with GT3 viruses consistently respond better to IFN treatment than do patients infected with GT1 viruses. The mechanisms underlying this difference are not well understood. In this study, we sought to determine the effects of HCV NS5A proteins from different genotypes on IFN signaling. We found that the overexpression of either GT1 or GT3 NS5A proteins significantly inhibited IFN-induced IFN-stimulated response element (ISRE) signaling, phosphorylated STAT1 (P-STAT1) levels, and IFN-stimulated gene (ISG) expression compared to controls. GT1 NS5A protein expression exhibited stronger inhibitory effects on IFN signaling than did GT3 NS5A protein expression. Furthermore, GT1 NS5A bound to STAT1 with a higher affinity than did GT3 NS5A. Domain mapping revealed that the C-terminal region of NS5A conferred these inhibitory effects on IFN signaling. The overexpression of HCV NS5A increased HCV replication levels in JFH1-infected cells through the further reduction of levels of P-STAT1, ISRE signaling, and downstream ISG responses. We demonstrated that the overexpression of GT1 NS5A proteins resulted in less IFN responsiveness than did the expression of GT3 NS5A proteins through stronger binding to STAT1. We confirmed that GT1 NS5A proteins exerted stronger IFN signaling inhibition than did GT3 NS5A proteins in an infectious recombinant JFH1 virus. The potent antiviral NS5A inhibitor BMS-790052 did not block NS5A-mediated IFN signaling suppression in an overexpression model, suggesting that NS5A's contributions to replication are independent of its subversive action on IFN. We propose a model in which the binding of the C-terminal region of NS5A to STAT1 leads to decreased levels of P-STAT1, ISRE signaling, and ISG transcription and, ultimately, to preferential GT1 resistance to IFN treatment.