bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ca2+ signals mediated by bradykinin type 2 receptors in normal pancreatic stellate cells can be inhibited by specific Ca2+ channel blockade
Authors: Gryshchenko Oleksiy , Gerasimenko Julia V. , Gerasimenko Oleg V. , Petersen Ole H. 
Published: October 2015

Key points
Bradykinin may play a role in the autodigestive disease acute pancreatitis, but little is known about its pancreatic actions.
In this study, we have investigated bradykinin‐elicited Ca2+ signal generation in normal mouse pancreatic lobules.
We found complete separation of Ca2+ signalling between pancreatic acinar (PACs) and stellate cells (PSCs). Pathophysiologically relevant bradykinin concentrations consistently evoked Ca2+ signals, via B2 receptors, in PSCs but never in neighbouring PACs, whereas cholecystokinin, consistently evoking Ca2+ signals in PACs, never elicited Ca2+ signals in PSCs.
The bradykinin‐elicited Ca2+ signals were due to initial Ca2+ release from inositol trisphosphate‐sensitive stores followed by Ca2+ entry through Ca2+ release‐activated channels (CRACs). The Ca2+ entry phase was effectively inhibited by a CRAC blocker.
B2 receptor blockade reduced the extent of PAC necrosis evoked by pancreatitis‐promoting agents and we therefore conclude that bradykinin plays a role in acute pancreatitis via specific actions on PSCs.
AbstractNormal pancreatic stellate cells (PSCs) are regarded as quiescent, only to become activated in chronic pancreatitis and pancreatic cancer. However, we now report that these cells in their normal microenvironment are far from quiescent, but are capable of generating substantial Ca2+ signals. We have compared Ca2+ signalling in PSCs and their better studied neighbouring acinar cells (PACs) and found complete separation of Ca2+ signalling in even closely neighbouring PACs and PSCs. Bradykinin (BK), at concentrations corresponding to the slightly elevated plasma BK levels that have been shown to occur in the auto‐digestive disease acute pancreatitis in vivo, consistently elicited substantial Ca2+ signals in PSCs, but never in neighbouring PACs, whereas the physiological PAC stimulant cholecystokinin failed to evoke Ca2+ signals in PSCs. The BK‐induced Ca2+ signals were mediated by B2 receptors and B2 receptor blockade protected against PAC necrosis evoked by agents causing acute pancreatitis. The initial Ca2+ rise in PSCs was due to inositol trisphosphate receptor‐mediated release from internal stores, whereas the sustained phase depended on external Ca2+ entry through Ca2+ release‐activated Ca2+ (CRAC) channels. CRAC channel inhibitors, which have been shown to protect PACs against damage caused by agents inducing pancreatitis, therefore also inhibit Ca2+ signal generation in PSCs and this may be helpful in treating acute pancreatitis.
The Transition of Medical Students Through Residency: Effects on Physical Activity and Other Lifestyle-Related Behaviors
Authors: Pardo Alba , Mitjans Anna , Baranda Lucía , Salamero Manel , McKenna James , Arteman Antoni , Violán Mariona 
Published: October 2015

Background:Little is known about lifestyle choices and preventive healthcare-seeking behaviors during the transition from medical school graduation to residency training, a period characterized by increased rates of stress and lack of free time due to demanding working conditions. All of these issues are likely to affect physical activity (PA) level. This study explored the evolution of PA and other lifestyle behaviors during this transition.Methods:A cross-sectional study and a cohort study were conducted with medical students (2010) and physicians before and after the first year of residency (2013 and 2014). A self-administered questionnaire assessed PA, health and lifestyle behaviors.Results:From a sample of 420 medical students and 478 residents, 74% comply with current PA guidelines. PA decreased by 16% during residency. Low levels of PA were found among (i) females and in respondents who reported (ii) poor self-perceived health and (iii) unhealthy body weight (P < .05). Low PA level was also significantly associated with poor mental health in first-year residents.Conclusions:The transition has a negative effect on physicians’ PA level that may affect physicians’ own health and patient care. Medical programs should encourage residents to engage in PA to assure physicians’ personal and mental health.
Objectively Measured School Day Physical Activity Among Elementary Students in the United States and Finland
Authors: Yli-Piipari Sami , Kulmala Janne Santeri , Jaakkola Timo , Hakonen Harto , Fish Joseph Cole , Tammelin Tuija 
Published: October 2015

Background:Schools are in a unique position to ensure that all students meet the current physical activity (PA) recommendations. This study aimed to examine 1st to 3rd grade elementary students’ accelerometer measured school day PA in the United States (U.S.) and Finland.Methods:The sample consisted of 200 students (107 girls, 93 boys; ages 6 to 8) and their school day PA was monitored with hip-worn ActiGraph GT3X+ accelerometers across a 5-day school week and the thresholds 100 and 2296 count per minute were used to separate sedentary time, light PA, and moderate-to-vigorous PA (MVPA).Results:On an average school day, students were engaged in MVPA for 20.0 min in the U.S. and 24.1 min in Finland. Students’ school-day MVPA was 9 to 16 minutes higher during physical education (PE) days compared with non-PE days (U.S: 25.8 vs. 16.6 min/day; Finland: 36.3 vs. 20.1 min/day). Girls had less MVPA and more sedentary time compared with boys in both samples.Conclusion:This study highlights both the role of PE and other school day physical activities in meeting PA guidelines. Policy measures are needed to change the structure of the school day and enhance PA to ensure that students meet the PA recommendations.
Enhanced Trapping of HIV-1 by Human Cervicovaginal Mucus Is Associated with Lactobacillus crispatus-Dominant Microbiota
Authors: Nunn Kenetta L. , Wang Ying-Ying , Harit Dimple , Humphrys Michael S. , Ma Bing , Cone Richard , Ravel Jacques , Lai Samuel K. 
Published: October 2015

ABSTRACT

Cervicovaginal mucus (CVM) can provide a barrier that precludes HIV and other sexually transmitted virions from reaching target cells in the vaginal epithelium, thereby preventing or reducing infections. However, the barrier properties of CVM differ from woman to woman, and the causes of these variations are not yet well understood. Using high-resolution particle tracking of fluorescent HIV-1 pseudoviruses, we found that neither pH nor Nugent scores nor total lactic acid levels correlated significantly with virus trapping in unmodified CVM from diverse donors. Surprisingly, HIV-1 was generally trapped in CVM with relatively high concentrations of
d
-lactic acid and a
Lactobacillus crispatus
-dominant microbiota. In contrast, a substantial fraction of HIV-1 virions diffused rapidly through CVM with low concentrations of
d
-lactic acid that had a
Lactobacillus iners
-dominant microbiota or significant amounts of
Gardnerella vaginalis
, a bacterium associated with bacterial vaginosis. Our results demonstrate that the vaginal microbiota, including specific species of
Lactobacillus
, can alter the diffusional barrier properties of CVM against HIV and likely other sexually transmitted viruses and that these microbiota-associated changes may account in part for the elevated risks of HIV acquisition linked to bacterial vaginosis or intermediate vaginal microbiota.

IMPORTANCE
Variations in the vaginal microbiota, especially shifts away from
Lactobacillus
-dominant microbiota, are associated with differential risks of acquiring HIV or other sexually transmitted infections. However, emerging evidence suggests that
Lactobacillus iners
frequently colonizes women with recurring bacterial vaginosis, raising the possibility that
L. iners
may not be as protective as other
Lactobacillus
species. Our study was designed to improve understanding of how the cervicovaginal mucus barrier against HIV may vary between women along with the vaginal microbiota and led to the finding that the vaginal microbiota, including specific species of
Lactobacillus
, can directly alter the diffusional barrier properties of cervicovaginal mucus. This work advances our understanding of the complex barrier properties of mucus and highlights the differential protective ability of different species of
Lactobacillus
, with
Lactobacillus crispatus
and possibly other species playing a key role in protection against HIV and other sexually transmitted infections. These findings could lead to the development of novel strategies to protect women against HIV.
Identification of a Natural Viral RNA Motif That Optimizes Sensing of Viral RNA by RIG-I
Authors: Xu Jie , Mercado-López Xiomara , Grier Jennifer T. , Kim Won-keun , Chun Lauren F. , Irvine Edward B. , Del Toro Duany Yoandris , Kell Alison , Hur Sun , Gale Michael , Raj Arjun , López Carolina B. 
Published: October 2015

ABSTRACT

Stimulation of the antiviral response depends on the sensing of viral pathogen-associated molecular patterns (PAMPs) by specialized cellular proteins. During infection with RNA viruses, 5′-di- or -triphosphates accompanying specific single or double-stranded RNA motifs trigger signaling of intracellular RIG-I-like receptors (RLRs) and initiate the antiviral response. Although these molecular signatures are present during the replication of many viruses, it is unknown whether they are sufficient for strong activation of RLRs during infection. Immunostimulatory defective viral genomes (iDVGs) from Sendai virus (SeV) are among the most potent natural viral triggers of antiviral immunity. Here we describe an RNA motif (DVG
70-114
) that is essential for the potent immunostimulatory activity of 5′-triphosphate-containing SeV iDVGs. DVG
70-114
enhances viral sensing by the host cell independently of the long stretches of complementary RNA flanking the iDVGs, and it retains its stimulatory potential when transferred to otherwise inert viral RNA.
In vitro
analysis showed that DVG
70-114
augments the binding of RIG-I to viral RNA and promotes enhanced RIG-I polymerization, thereby facilitating the onset of the antiviral response. Together, our results define a new natural viral PAMP enhancer motif that promotes viral recognition by RLRs and confers potent immunostimulatory activity to viral RNA.

IMPORTANCE
A discrete group of molecular motifs, including 5′-triphosphates associated with double-stranded RNA, have been identified as essential for the triggering of antiviral immunity. Most RNA viruses expose these motifs during their replication; however, successful viruses normally evade immune recognition and replicate to high levels before detection, indicating that unknown factors drive antiviral immunity. DVGs from SeV are among the most potent natural viral stimuli of the antiviral response known to date. These studies define a new natural viral motif present in DVGs that maximizes viral recognition by the intracellular sensor RIG-I, allowing fast and strong antiviral responses even in the presence of viral-encoded immune antagonists. This motif can be harnessed to increase the immunostimulatory potential of otherwise inert viral RNAs and represents a novel immunostimulatory enhancer that could be used in the development of vaccine adjuvants and antivirals.
Trading Capsule for Increased Cytotoxin Production: Contribution to Virulence of a Newly Emerged Clade of
emm89
Streptococcus pyogenes
Authors: Zhu Luchang , Olsen Randall J. , Nasser Waleed , de la Riva Morales Ivan , Musser James M. 
Published: October 2015

ABSTRACT

Strains of
emm89
Streptococcus pyogenes
have become one of the major causes of invasive infections worldwide in the last 10 years. We recently sequenced the genome of 1,125
emm89
strains and identified three major phylogenetic groups, designated clade 1, clade 2, and the epidemic clade 3. Epidemic clade 3 strains, which now cause the great majority of infections, have two distinct genetic features compared to clade 1 and clade 2 strains. First, all clade 3 organisms have a variant 3
nga
promoter region pattern, which is associated with increased production of secreted cytolytic toxins SPN (
S. pyogenes
NADase) and SLO (streptolysin O). Second, all clade 3 strains lack the
hasABC
locus mediating hyaluronic acid capsule synthesis, whereas this locus is intact in clade 1 and clade 2 strains. We constructed isogenic mutant strains that produce different levels of SPN and SLO toxins and capsule (none, low, or high). Here we report that
emm89
strains with elevated toxin production are significantly more virulent than low-toxin producers. Importantly, we also show that capsule production is dispensable for virulence in strains that already produce high levels of SPN and SLO. Our results provide new understanding about the molecular mechanisms contributing to the rapid emergence and molecular pathogenesis of epidemic clade 3
emm89
S. pyogenes
.

IMPORTANCE
S. pyogenes
(group A streptococcus [GAS]) causes pharyngitis (“strep throat”), necrotizing fasciitis, and other human infections. Serious infections caused by
emm89
S. pyogenes
strains have recently increased in frequency in many countries. Based on whole-genome sequence analysis of 1,125 strains recovered from patients on two continents, we discovered that a new
emm89
clone, termed clade 3, has two distinct genetic features compared to its predecessors: (i) absence of the genes encoding antiphagocytic hyaluronic acid capsule virulence factor and (ii) increased production of the secreted cytolytic toxins SPN and SLO.
emm89
S. pyogenes
strains with the clade 3 phenotype (absence of capsule and high expression of SPN and SLO) are highly virulent in mice. These findings provide new understanding of how new virulent clones emerge and cause severe infections worldwide. This newfound knowledge of
S. pyogenes
virulence can be used to help understand future epidemics and conduct new translational research.
Plasmodium falciparum-Infected Erythrocyte Knob Density Is Linked to the PfEMP1 Variant Expressed
Authors: Subramani Ramesh , Quadt Katharina , Jeppesen Anine E. , Hempel Casper , Petersen Jens Emil Vang , Hassenkam Tue , Hviid Lars , Barfod Lea 
Published: October 2015

ABSTRACT

Members of the clonally variant
Plasmodium falciparum
erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the
P. falciparum
clone IT4, which expresses the PfEMP1 variants IT4VAR04, IT4VAR32b, and IT4VAR60. The knob density in each subline was then determined by atomic force microscopy (AFM) and scanning electron microscopy (SEM) and compared to PfEMP1 and knob-associated histidine-rich protein (KAHRP) expression. Selection for uniform expression of IT4VAR04 produced little change in knob density, compared to unselected IEs. In contrast, selection for IT4VAR32b expression increased knob density approximately 3-fold, whereas IEs selected for IT4VAR60 expression were essentially knobless. When IT4VAR60
+
IEs were subsequently selected to express IT4VAR04 or IT4VAR32b, they again displayed low and high knob densities, respectively. All sublines expressed KAHRP regardless of the PfEMP1 expressed. Our study documents for the first time that knob density is related to the PfEMP1 variant expressed. This may reflect topological requirements to ensure optimal adhesive properties of the IEs.

IMPORTANCE
Infections with
Plasmodium falciparum
malaria parasites are still responsible for many deaths, especially among children and pregnant women. New interventions are needed to reduce severe illness and deaths caused by this malaria parasite. Thus, a better understanding of the mechanisms behind the pathogenesis is essential. A main reason why
Plasmodium falciparum
malaria is more severe than disease caused by other malaria species is its ability to express variant antigens on the infected erythrocyte surface. These antigens are presented on membrane protrusions known as knobs. This study set out to investigate the interplay between different variant antigens on the surface of
P. falciparum
-infected erythrocytes and the density of the knobs on which the antigens are expressed. Such a direct analysis of this relationship has not been reported before but adds to the important understanding of the complexity of malaria antigen presentation.
Comparison of the Effects of Pretreatment with Repeated Electroacupuncture at Gv20 and St36 on Fatigue in Rats
Authors: Guo Kai , Zhu Jinyu , Quan Xin , Zhang Dawei , Chen Xiaoyong , Yang Chongfei , Li Xiaojie , Shi Jun , Hu Wendong , Zhu Qingsheng 
Published: October 2015

Objective To investigate and compare the effects of electroacupuncture (EA) pretreatment at GV20 and ST36 on fatigue in rats. Methods Rats were randomly allocated into 4 groups: control, fatigue, fatigue+GV20 and fatigue+ST36. The last two groups received EA pretreatment at GV20 or ST36 for 5 days before being maintained in cages filled with water to a height of 1.5 cm to establish an animal model of fatigue. We used the weight-loaded forced swimming test and open-field test and measured 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios and serum levels of blood urea nitrogen (BUN), lactic dehydrogenase (LDH) and testosterone as behavioural and biochemical markers of fatigue in the rats. Results Compared with controls, rats in the (untreated) fatigue group exhibited reduced weight-loaded swimming times and total movement/distance in the open-field test, plus higher BUN/LDH and lower testosterone levels. Both EA pretreatment at GV20 and ST36 increased swimming times, and reduced serum BUN/LDH. EA pretreatment at GV20 (but not ST36) increased serum testosterone. The 5-HIAA/5-HT ratios in four brain regions were decreased in the fatigue+GV20 group compared with the fatigue group (p<0.05). By contrast, 5-HIAA/5-HT ratios in striatum and hypothalamus (but not hippocampus or midbrain) were decreased in the fatigue+ST36 group compared with the fatigue group (p<0.05). Furthermore, only pretreatment at GV20 affected the results of the open-field test. Conclusions These results suggest that EA pretreatment had a positive effect on the prevention of fatigue. Pretreatment at GV20 had a greater anti-fatigue effect than pretreatment at ST36.
Accuracy and readability of cardiovascular entries on Wikipedia: are they reliable learning resources for medical students?
Authors: Azer Samy A , AlSwaidan Nourah M , Alshwairikh Lama A , AlShammari Jumana M 
Published: October 2015

ObjectiveTo evaluate accuracy of content and readability level of English Wikipedia articles on cardiovascular diseases, using quality and readability tools.MethodsWikipedia was searched on the 6 October 2013 for articles on cardiovascular diseases. Using a modified DISCERN (DISCERN is an instrument widely used in assessing online resources), articles were independently scored by three assessors. The readability was calculated using Flesch-Kincaid Grade Level. The inter-rater agreement between evaluators was calculated using the Fleiss κ scale.ResultsThis study was based on 47 English Wikipedia entries on cardiovascular diseases. The DISCERN scores had a median=33 (IQR=6). Four articles (8.5%) were of good quality (DISCERN score 40–50), 39 (83%) moderate (DISCERN 30–39) and 4 (8.5%) were poor (DISCERN 10–29). Although the entries covered the aetiology and the clinical picture, there were deficiencies in the pathophysiology of diseases, signs and symptoms, diagnostic approaches and treatment. The number of references varied from 1 to 127 references; 25.9±29.4 (mean±SD). Several problems were identified in the list of references and citations made in the articles. The readability of articles was 14.3±1.7 (mean±SD); consistent with the readability level for college students. In comparison, Harrison’s Principles of Internal Medicine 18th edition had more tables, less references and no significant difference in number of graphs, images, illustrations or readability level. The overall agreement between the evaluators was good (Fleiss κ 0.718 (95% CI 0.57 to 0.83).ConclusionsThe Wikipedia entries are not aimed at a medical audience and should not be used as a substitute to recommended medical resources. Course designers and students should be aware that Wikipedia entries on cardiovascular diseases lack accuracy, predominantly due to errors of omission. Further improvement of the Wikipedia content of cardiovascular entries would be needed before they could be considered a supplementary resource.
Educational recommendations for the conduct, content and format of EULAR musculoskeletal ultrasound Teaching the Teachers Courses
Authors: Iagnocco A , Terslev L , Backhaus M , Balint P , Bruyn G A W , Damjanov N , Filippucci E , Hammer H B , Jousse-Joulin S , Kane D , Koski J M , Mandl P , Möller I , Peetrons P , Schmidt W , Szkudlarek M , Vojinovic J , Wakefield R J , Hofer M , D'Agostino M A , Naredo E 
Published: October 2015

ObjectiveTo produce educational guidelines for the conduct, content and format of theoretical and practical teaching at EULAR musculoskeletal ultrasound (MSUS) Teaching the Teachers (TTT) Courses.MethodsA Delphi-based procedure with 24 recommendations covering five main areas (Duration and place of the course; Faculty members; Content of the course; Evaluation of the teaching skills; TTT competency assessment) was distributed among a group of experts involved in MSUS teaching, in addition to an advisory educational expert being present. Consensus for each recommendation was considered achieved when the percentage of agreement was >75%.Results21 of 24 invited participants responded to the first Delphi questionnaire (88% response rate). All 21 participants also responded to the second round. Agreement on 19 statements was obtained after two rounds.ConclusionsThis project has led to the development of guidelines for the conduct, content and format of teaching at the EULAR MSUS TTT Courses that are organised annually, with the aim of training future teachers of EULAR MSUS Courses, EULAR Endorsed MSUS Courses, as well as national and local MSUS Courses. The presented work gives indications on how to homogenise the teaching at the MSUS TTT Courses, thus resolving current discrepancies in the field.
On the Initial-Boundary-Value Problem for the Time-Fractional Diffusion Equation on the Real Positive Semiaxis
Authors: Goos D. , Reyero G. , Roscani S. , Santillan Marcus E. 
Published: October 2015

We consider the time-fractional derivative in the Caputo sense of orderα∈(0, 1). Taking into account the asymptotic behavior and the existence of bounds for the Mainardi and the Wright function inR+, two different initial-boundary-value problems for the time-fractional diffusion equation on the real positive semiaxis are solved. Moreover, the limit whenα↗1of the respective solutions is analyzed, recovering the solutions of the classical boundary-value problems whenα= 1, and the fractional diffusion equation becomes the heat equation.