bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microstructural abnormality in white matter, regulatory T lymphocytes, and depressive symptoms after stroke
Authors: Yasuno Fumihiko , Taguchi Akihiko , Yamamoto Akihide , Kajimoto Katsufumi , Kazui Hiroaki , Kudo Takashi , Kikuchi‐Taura Akie , Sekiyama Atsuo , Kishimoto Toshifumi , Iida Hidehiro , Nagatsuka Kazuyuki 
Published: December 2014

AbstractBackgroundThe purpose of the present study was to investigate the existence of microstructure abnormalities in the white matter circuit in stroke patients and its relationship to depressive episodes. To target the prevention of depression, we also investigated the relationship between lymphocyte subsets and cerebral abnormalities in patients.MethodsParticipants included 18 patients with acute ischemic stroke and 22 healthy control subjects. Diffusion tensor imaging was performed. Whole‐brain voxel‐based analysis was used to compare fractional anisotropy (FA) between groups. Blood samples were obtained, and the lymphocyte subsets were evaluated using flow cytometry. Follow‐up examinations were conducted on 12 patients at 6 months.ResultsFA was decreased in the bilateral anterior limb of the internal capsule in stroke patients. At the 6‐month follow‐up examination, there was a significant increase in FA, which was associated with a lower depression scale score. Patients showed a decreased percentage of circulated regulatory T lymphocytes, and the degree of reduction was related to the decrease in the FA value in the internal capsule.ConclusionsFA reductions in the anterior limb of the internal capsule cause abnormality in the frontal‐subcortical circuits and confer a biological vulnerability, which in combination with environmental stressors results in the onset of depression. Our findings also demonstrated the possibility of preventing post‐stroke depression by targeting the role of regulatory T lymphocytes in brain tissue repair and regeneration after stroke.
The relationship between HIV and prevalence of disabilities in sub‐Saharan Africa: systematic review (FA)
Authors: Banks Lena Morgon , Zuurmond Maria , Ferrand Rashida , Kuper Hannah 
Published: December 2014

AbstractObjectiveTo systematically review evidence on the prevalence and risk of disabilities among children and adults living withHIVin sub‐Saharan Africa.MethodsArticles were identified from 1980 to June 2013 through searching seven electronic databases. Epidemiological studies conducted in sub‐Saharan Africa that explored the association betweenHIVstatus and general disability or specific impairments, with or without anHIV‐uninfected comparison group, were eligible for inclusion.ResultsOf 12 867 records initially identified, 61 papers were deemed eligible for inclusion. The prevalence of disability was high across age groups, impairment types and study locations. Furthermore, 73% of studies using anHIV‐ comparator found significantly lower levels of functioning in people living withHIV(PLHIV). By disability type, the results were as follows: (i) for studies measuring physical impairments (n = 14), median prevalence of limitations in mobility and motor function amongPLHIVwas 25.0% (95%CI: 21.8–28.2%). Five of eight comparator studies found significantly reduced functioning amongPLHIV; for arthritis, two of three studies which used anHIV‐ comparison group found significantly increased prevalence amongPLHIV; (ii) for sensory impairment studies (n = 17), median prevalence of visual impairment was 11.2% (95%CI: 9.5–13.1%) and hearing impairment was 24.1% (95%CI: 19.2–29.0%) inPLHIV. Significantly increased prevalence amongPLHIVwas found in one of four (vision) and three of three studies (hearing) with comparators; (iii) for cognitive impairment in adults (n = 30), median prevalence for dementia was 25.3% (95%CI: 22.0–28.6%) and 40.9% (95%CI: 37.7–44.1%) for general cognitive impairment. Across all types of cognitive impairment, twelve of fourteen studies found a significant detrimental effect ofHIVinfection; (iv) for developmental delay in children withHIV(n = 20), median prevalence of motor delay was 67.7% (95%CI: 62.2–73.2%). All nine studies that included a comparator found a significant difference betweenPLHIVand controls; for cognitive development and global delay, a significant detrimental effect ofHIVwas found in five of six and one of two studies, respectively. In the nine cohort studies comparing vertically infected and uninfected children, eight showed a significant gap in development over time in children withHIV. Finally, fifteen of thirty‐one (48%) studies found a statistically significant dose–response relationship between indicators of disease progression (CD4 orWHOstage) and disability.ConclusionsHIVis widespread in sub‐Saharan Africa and the evidence suggests that it is linked to disabilities, affecting a range of body structures and functions. More research is needed to better understand the implications ofHIV‐related disability for individuals, their families as well as those working in the fields of disability andHIVso that appropriate interventions can be developed.
THB1, a truncated hemoglobin, modulates nitric oxide levels and nitrate reductase activity
Authors: Sanz‐Luque Emanuel , Ocaña‐Calahorro Francisco , de Montaigu Amaury , Chamizo‐Ampudia Alejandro , Llamas Ángel , Galván Aurora , Fernández Emilio 
Published: December 2014

SummaryHemoglobins are ubiquitous proteins that sense, store and transport oxygen, but the physiological processes in which they are implicated is currently expanding. Recent examples of previously unknown hemoglobin functions, which include scavenging of the signaling molecule nitric oxide (NO), illustrate how the implication of hemoglobins in different cell signaling processes is only starting to be unraveled. The extent and diversity of the hemoglobin protein family suggest that hemoglobins have diverged and have potentially evolved specialized functions in certain organisms. A unique model organism to study this functional diversity at the cellular level is the green alga Chlamydomonas reinhardtii because, among other reasons, it contains an unusually high number of a particular type of hemoglobins known as truncated hemoglobins (THB1–THB12). Here, we reveal a cell signaling function for a truncated hemoglobin of Chlamydomonas that affects the nitrogen assimilation pathway by simultaneously modulating NO levels and nitrate reductase (NR) activity. First, we found that THB1 and THB2 expression is modulated by the nitrogen source and depends on NIT2, a transcription factor required for nitrate assimilation genes expression. Furthermore, THB1 is highly expressed in the presence of NO and is able to convert NO into nitrate in vitro. Finally, THB1 is maintained on its active and reduced form by NR, and in vivo lower expression of THB1 results in increased NR activity. Thus, THB1 plays a dual role in NO detoxification and in the modulation of NR activity. This mechanism can partly explain how NO inhibits NR post‐translationally.
Impaired sinoatrial node function and increased susceptibility to atrial fibrillation in mice lacking natriuretic peptide receptor C
Authors: Egom Emmanuel E. , Vella Kimberly , Hua Rui , Jansen Hailey J. , Moghtadaei Motahareh , Polina Iuliia , Bogachev Oleg , Hurnik Rhea , Mackasey Martin , Rafferty Sara , Ray Gibanananda , Rose Robert A. 
Published: December 2014

Key points
Natriuretic peptides (NPs) elicit their effects via multiple NP receptors (including NPR‐A, NPR‐B and NPR‐C, with NPR‐C being relatively poorly understood).
We have studied the effects of NPR‐C ablation on cardiac structure, function and arrhythmogenesis using NPR‐C knockout (NPR‐C−/−) mice.
NPR‐C−/− mice are characterized by sinoatrial node (SAN) dysfunction and a profound increase in susceptibility to atrial fibrillation.
Increased susceptibility to arrhythmias in NPR‐C−/− mice was associated with slowed electrical conduction in the SAN as well as the right and left atria due to enhanced collagen expression and deposition in the atria (structural remodelling), but without changes in action potential morphology (electrical remodelling) in isolated SAN or atrial myocytes.
This study demonstrates a critical protective role for NPR‐C in the heart.
AbstractNatriuretic peptides (NPs) are critical regulators of the cardiovascular system that are currently viewed as possible therapeutic targets for the treatment of heart disease. Recent work demonstrates potent NP effects on cardiac electrophysiology, including in the sinoatrial node (SAN) and atria. NPs elicit their effects via three NP receptors (NPR‐A, NPR‐B and NPR‐C). Among these receptors, NPR‐C is poorly understood. Accordingly, the goal of this study was to determine the effects of NPR‐C ablation on cardiac structure and arrhythmogenesis. Cardiac structure and function were assessed in wild‐type (NPR‐C+/+) and NPR‐C knockout (NPR‐C−/−) mice using echocardiography, intracardiac programmed stimulation, patch clamping, high‐resolution optical mapping, quantitative polymerase chain reaction and histology. These studies demonstrate that NPR‐C−/− mice display SAN dysfunction, as indicated by a prolongation (30%) of corrected SAN recovery time, as well as an increased susceptibility to atrial fibrillation (6% in NPR‐C+/+ vs. 47% in NPR‐C−/−). There were no differences in SAN or atrial action potential morphology in NPR‐C−/− mice; however, increased atrial arrhythmogenesis in NPR‐C−/− mice was associated with reductions in SAN (20%) and atrial (15%) conduction velocity, as well as increases in expression and deposition of collagen in the atrial myocardium. No differences were seen in ventricular arrhythmogenesis or fibrosis in NPR‐C−/− mice. This study demonstrates that loss of NPR‐C results in SAN dysfunction and increased susceptibility to atrial arrhythmias in association with structural remodelling and fibrosis in the atrial myocardium. These findings indicate a critical protective role for NPR‐C in the heart.
Indomethacin‐induced impairment of regional cerebrovascular reactivity: implications for respiratory control
Authors: Hoiland Ryan L. , Ainslie Philip N. , Wildfong Kevin W. , Smith Kurt J. , Bain Anthony R. , Willie Chris K. , Foster Glen , Monteleone Brad , Day Trevor A. 
Published: December 2014

Key points
Anterior and posterior cerebral circulations have differential reactivity to changes in arterial blood gases, but the implications for the chemoreflex control of breathing are unclear.
Indomethacin‐induced blunting of cerebrovascular flow responsiveness did not affect central or peripheral respiratory chemoreflex magnitude using steady‐state end‐tidal forcing techniques.
Posterior reactivity was related to hypoxic ventilatory decline, suggesting that CO2 washout from central chemoreceptors modulates hypoxic ventilatory dynamics.
Our data indicate that steady‐state end‐tidal forcing techniques reduce the arterial–venous gradients, attenuating the effect of brain blood flow on ventilatory responses.
Our study confirms the importance of measuring posterior cerebrovasculature when investigating the link between cerebral blood flow and the chemical control of breathing.
AbstractCerebrovascular reactivity impacts CO2–[H+] washout at the central chemoreceptors and hence has marked influence on the control of ventilation. To date, the integration of cerebral blood flow (CBF) and ventilation has been investigated exclusively with measures of anterior CBF, which has a differential reactivity from the vertebrobasilar system and perfuses the brainstem. We hypothesized that: (1) posterior versus anterior CBF would have a stronger relationship to central chemoreflex magnitude during hypercapnia, and (2) that higher posterior reactivity would lead to a greater hypoxic ventilatory decline (HVD). End‐tidal forcing was used to induce steady‐state hyperoxic (300 mmHg ) hypercapnia (+3, +6 and +9 mmHg ) and isocapnic hypoxia (45 mmHg ) before and following pharmacological blunting (indomethacin; INDO; 1.45 ± 0.17 mg kg−1) of resting CBF and reactivity. In 22 young healthy volunteers, ventilation, intra‐cranial arterial blood velocities and extra‐cranial blood flows were measured during these challenges. INDO‐induced blunting of cerebrovascular flow responsiveness (CVR) to CO2 was unrelated to variability in ventilatory sensitivity during hyperoxic hypercapnia. Further results in a sub‐group of volunteers (n = 9) revealed that elevations of via end‐tidal forcing reduce arterial–jugular venous gradients, attenuating the effect of CBF on chemoreflex responses. During isocapnic hypoxia, vertebral artery CVR was related to the magnitude of HVD (R2 = 0.27; P < 0.04; n = 16), suggesting that CO2–[H+] washout from central chemoreceptors modulates hypoxic ventilatory dynamics. No relationships were apparent with anterior CVR. As higher posterior, but not anterior, CVR was linked to HVD, our study highlights the importance of measuring flow in posterior vessels to investigate CBF and ventilatory integration.
Highly Purified Mycobacterial Phosphatidylinositol Mannosides Drive Cell-Mediated Responses and Activate NKT Cells in Cattle
Authors: Pirson Chris , Engel Regina , Jones Gareth J. , Holder Thomas , Holst Otto , Vordermeier H. Martin 
Published: December 2014

ABSTRACTMycobacterial lipids play an important role in the modulation of the immune response upon contact with the host. Using novel methods, we have isolated highly purified phosphatidylinositol mannoside (PIM) molecules (phosphatidylinositol dimannoside [PIM2], acylphosphatidylinositol dimannoside [AcPIM2], diacyl-phosphatidylinositol dimannoside [Ac2PIM2], acylphosphatidylinositol hexamannoside [AcPIM6], and diacylphosphatidylinositol hexamannoside [Ac2PIM6]) from virulentMycobacterium tuberculosisto assess their potential to stimulate peripheral blood mononuclear cell (PBMC) responses inMycobacterium bovis-infected cattle. Of these molecules, one (AcPIM6) induced significant levels of gamma interferon (IFN-γ) in bovine PBMCs. Three PIM molecules (AcPIM6, Ac2PIM2, and Ac2PIM6) were shown to drive significant proliferation in bovine PBMCs. AcPIM6was subsequently used to phenotype the proliferating cells by flow cytometry. This analysis demonstrated that AcPIM6was predominantly recognized by CD3+CD335+NKT cells. In conclusion, we have identified PIM lipid molecules that interact with bovine lymphocyte populations, and these lipids may be useful as future subunit vaccines or diagnostic reagents. Further, these data demonstrate, for the first time, lipid-specific NKT activation in cattle.
Complete Genome Sequence of the Autographa californica Multiple Nucleopolyhedrovirus Strain E2
Authors: Maghodia Ajay B. , Jarvis Donald L. , Geisler Christoph 
Published: December 2014

ABSTRACT

Many vectors that are commonly used in the baculovirus/insect cell system (BICS) are derived from the
Autographa californica
multiple nucleopolyhedrovirus (AcMNPV) strain E2. To facilitate work with these vectors, we sequenced the E2 genome, compared it to that of the AcMNPV C6 strain, and found that they are very similar overall.
Adaptation of Pandemic H2N2 Influenza A Viruses in Humans
Authors: Joseph Udayan , Linster Martin , Suzuki Yuka , Krauss Scott , Halpin Rebecca A. , Vijaykrishna Dhanasekaran , Fabrizio Thomas P. , Bestebroer Theo M. , Maurer-Stroh Sebastian , Webby Richard J. , Wentworth David E. , Fouchier Ron A. M. , Bahl Justin , Smith Gavin J. D. 
Published: December 2014

ABSTRACT
The 1957 A/H2N2 influenza virus caused an estimated 2 million fatalities during the pandemic. Since viruses of the H2 subtype continue to infect avian species and pigs, the threat of reintroduction into humans remains. To determine factors involved in the zoonotic origin of the 1957 pandemic, we performed analyses on genetic sequences of 175 newly sequenced human and avian H2N2 virus isolates and all publicly available influenza virus genomes.
MicroRNA-Mediated Transformation by the Kaposi's Sarcoma-Associated Herpesvirus Kaposin Locus
Authors: Forte Eleonora , Raja Archana N. , Shamulailatpam Priscilla , Manzano Mark , Schipma Matthew J. , Casey John L. , Gottwein Eva 
Published: December 2014

ABSTRACT
The human oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) expresses a set of ∼20 viral microRNAs (miRNAs). miR-K10a stands out among these miRNAs because its entire stem-loop precursor overlaps the coding sequence for the Kaposin (Kap) A/C proteins. The ectopic expression of KapA has been reported to lead to transformation of rodent fibroblasts. However, these experiments inadvertently also introduced miR-K10a, which raises the question whether the transforming activity of the locus could in fact be due to miR-K10a expression. To answer this question, we have uncoupled miR-K10a and KapA expression. Our experiments revealed that miR-K10a alone transformed cells with an efficiency similar to that when it was coexpressed with KapA. Maintenance of the transformed phenotype was conditional upon continued miR-K10a but not KapA protein expression, consistent with its dependence on miRNA-mediated changes in gene expression. Importantly, miR-K10a taps into an evolutionarily conserved network of miR-142-3p targets, several of which are expressed in 3T3 cells and are also known inhibitors of cellular transformation. In summary, our studies of miR-K10a serve as an example of an unsuspected function of an mRNA whose precursor is embedded within a coding transcript. In addition, our identification of conserved miR-K10a targets that limit transformation will point the way to a better understanding of the role of this miRNA in KSHV-associated tumors.

IMPORTANCE
Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus. The viral Kaposin locus has known oncogenic potential, which has previously been attributed to the encoded KapA protein. Here we show that the virally encoded miR-K10a miRNA, whose precursor overlaps the KapA-coding region, may account for the oncogenic properties of this locus. Our data suggest that miR-K10a mimics the cellular miRNA miR-142-3p and thereby represses several known inhibitors of oncogenic transformation. Our work demonstrates that functional properties attributed to a coding region may in fact be carried out by an embedded noncoding element and sheds light on the functions of viral miR-K10a.
Responding to symptoms suggestive of lung cancer: a qualitative interview study
Authors: Birt Linda , Hall Nicky , Emery Jon , Banks Jon , Mills Katie , Johnson Margaret , Hamilton Willie , Walter Fiona M 
Published: December 2014

BackgroundLate diagnosis of lung cancer can impact on survival rates. Patients delay seeking help for a number of reasons. This study explored symptom appraisal and help-seeking decisions among patients referred to specialist respiratory services with symptoms suggestive of lung cancer.MethodsIn-depth qualitative interviews with patients as soon as possible after referral, ideally before diagnosis and mainly within 10 weeks, explored factors impacting on their pathways prior to referral. Framework analysis, underpinned by the Model of Pathways to Treatment, was used to explore the data with particular focus on patients’ beliefs and experiences, disease factors and healthcare professional influences.Results35 patients were interviewed (aged 41–88 years, 15 women, 17 with lung cancer). All described similar presenting symptoms and triggers to seek help. Appraisal of symptoms was influenced by whether they had a lung comorbidity; seriousness of symptoms was interpreted within the context of previous illness experiences. Help-seeking was triggered when: symptoms failed to respond as expected; there was an increased awareness of symptoms of lung cancer; the public nature of a cough meant others were able to endorse help-seeking. Almost half visited the general practitioner (GP) two or more times before referral; during this period they reinterpreted initial symptoms and appraised new symptoms. The meaning given to symptoms changed over time and many became increasingly concerned they may have lung cancer. The GP played a role in ensuring timely further help-seeking but often there was little guidance on how to monitor symptoms or when to reconsult.ConclusionsPatients diagnosed with and without lung cancer had similar symptom pathways. Findings provide guidance for lung cancer awareness campaigns on the importance of social networks in endorsing patient help-seeking. The importance of appropriate advice, monitoring and safety-netting procedures by GPs for people presenting with symptoms suggestive of lung cancer is also highlighted.
The Selective Intravenous Inhibitor of the MET Tyrosine Kinase SAR125844 Inhibits Tumor Growth inMET-Amplified Cancer
Authors: Egile Coumaran , Kenigsberg Mireille , Delaisi Christine , Bégassat Françoise , Do-Vale Véronique , Mestadier Jessica , Bonche Fabrice , Bénard Tsiala , Nicolas Jean-Paul , Valence Sandrine , Lefranc Céline , Francesconi Elisa , Castell Christelle , Lefebvre Anne-Marie , Nemecek Conception , Calvet Loreley , Goulaouic Hélène 
Published: December 2014

AbstractActivation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose- and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET-amplified human gastric cancer models at tolerated doses without treatment-related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway–addicted tumors. Mol Cancer Ther; 14(2); 384–94. ©2014 AACR.