bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lassa Virus Cell Entry via Dystroglycan Involves an Unusual Pathway of Macropinocytosis
Authors: Oppliger Joel , Torriani Giulia , Herrador Antonio , Kunz Stefan 
Published: May 2016

ABSTRACT
The pathogenic Old World arenavirus Lassa virus (LASV) causes a severe hemorrhagic fever with a high rate of mortality in humans. Several LASV receptors, including dystroglycan (DG), TAM receptor tyrosine kinases, and C-type lectins, have been identified, suggesting complex receptor use. Upon receptor binding, LASV enters the host cell via an unknown clathrin- and dynamin-independent pathway that delivers the virus to late endosomes, where fusion occurs. Here we investigated the mechanisms underlying LASV endocytosis in human cells in the context of productive arenavirus infection, using recombinant lymphocytic choriomeningitis virus (rLCMV) expressing the LASV glycoprotein (rLCMV-LASVGP). We found that rLCMV-LASVGP entered human epithelial cells via DG using a macropinocytosis-related pathway independently of alternative receptors. Dystroglycan-mediated entry of rLCMV-LASVGP required sodium hydrogen exchangers, actin, and the GTPase Cdc42 and its downstream targets, p21-activating kinase-1 (PAK1) and Wiskott-Aldrich syndrome protein (N-Wasp). Unlike other viruses that enter cells via macropinocytosis, rLCMV-LASVGP entry did not induce overt changes in cellular morphology and hardly affected actin dynamics or fluid uptake. Screening of kinase inhibitors identified protein kinase C, phosphoinositide 3-kinase, and the receptor tyrosine kinase human hepatocyte growth factor receptor (HGFR) to be regulators of rLCMV-LASVGP entry. The HGFR inhibitor EMD 1214063, a candidate anticancer drug, showed antiviral activity against rLCMV-LASVGP at the level of entry. When combined with ribavirin, which is currently used to treat human arenavirus infection, EMD 1214063 showed additive antiviral effects. In sum, our study reveals that DG can link LASV to an unusual pathway of macropinocytosis that causes only minimal perturbation of the host cell and identifies cellular kinases to be possible novel targets for therapeutic intervention.

IMPORTANCE
Lassa virus (LASV) causes several hundred thousand infections per year in Western Africa, with the mortality rate among hospitalized patients being high. The current lack of a vaccine and the limited therapeutic options at hand make the development of new drugs against LASV a high priority. In the present study, we uncover that LASV entry into human cells via its major receptor, dystroglycan, involves an unusual pathway of macropinocytosis and define a set of cellular factors implicated in the regulation of LASV entry. A screen of kinase inhibitors revealed HGFR to be a possible candidate target for antiviral drugs against LASV. An HGFR candidate inhibitor currently being evaluated for cancer treatment showed potent antiviral activity and additive drug effects with ribavirin, which is used in the clinic to treat human LASV infection. In sum, our study reveals novel fundamental aspects of the LASV-host cell interaction and highlights a possible candidate drug target for therapeutic intervention.
Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses
Authors: Whelan Jillian N. , Tran Kim C. , van Rossum Damian B. , Teng Michael N. 
Published: May 2016

ABSTRACT
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children worldwide. The RSV nonstructural protein 2 (NS2) is a multifunctional protein that primarily acts to antagonize the innate immune system by targeting STAT2 for proteasomal degradation. We investigated the structural determinants of NS2 important for interaction with the host ubiquitin system to degrade STAT2 during infection. We found that NS2 expression enhances ubiquitination of host proteins. Bioinformatics analysis provided a platform for identification of specific residues that limit NS2-induced ubiquitination. Combinations of multiple mutations displayed an additive effect on reducing NS2-induced ubiquitination. Using a reverse genetics system, we generated recombinant RSV (rRSV) containing NS2 ubiquitin mutations, which maintained their effect on ubiquitin expression during infection. Interestingly, STAT2 degradation activity was ablated in the NS2 ubiquitin mutant rRSV. In addition, NS2 ubiquitin mutations decreased rRSV replication, indicating a correlation between NS2's ubiquitin function and antagonism of innate immune signaling to enhance viral replication. Our approach of targeting NS2 residues required for NS2 inhibition of immune responses provides a mechanism for attenuating RSV for vaccine development.

IMPORTANCE
RSV has been circulating globally for more than 60 years, causing severe respiratory disease in pediatric, elderly, and immunocompromised populations. Production of a safe, effective vaccine against RSV is a public health priority. The NS2 protein is an effective target for prevention and treatment of RSV due to its antagonistic activity against the innate immune system. However, NS2-deleted RSV vaccine candidates rendered RSV overattenuated or poorly immunogenic. Alternatively, we can modify essential NS2 structural features to marginally limit viral growth while maintaining immune responses, providing the necessary balance between antigenicity and safety required for an effective vaccine. We coupled bioinformatics analysis with reverse genetics to introduce mutations into RSV's negative-sense genome. In this way we constructed rRSV NS2 ubiquitin mutants that limited NS2's ability to antagonize the innate immune system, thereby attenuating rRSV growth and increasing innate immune responses.
CD69 Deficiency Enhances the Host Response to Vaccinia Virus Infection through Altered NK Cell Homeostasis
Authors: Notario Laura , Alari-Pahissa Elisenda , de Molina Antonio , Lauzurica Pilar 
Published: May 2016

ABSTRACTDuring the host response to viral infection, the transmembrane CD69 protein is highly upregulated in all immune cells. We have studied the role of CD69 in the murine immune response to vaccinia virus (VACV) infection, and we report that the absence of CD69 enhances protection against VACV at both short and long times postinfection in immunocompetent and immunodeficient mice. Natural killer (NK) cells were implicated in the increased infection control, since the differences were greatly diminished when NK cells were depleted. This role of NK cells was not based on an altered NK cell reactivity, since CD69 did not affect the NK cell activation threshold in response to major histocompatibility complex class I NK cell targets or protein kinase C activation. Instead, NK cell numbers were increased in the spleen and peritoneum of CD69-deficient infected mice. That was not just secondary to better infection control in CD69-deficient mice, since NK cell numbers in the spleens and the blood of uninfected CD69−/−mice were already augmented. CD69-deficient NK cells from infected mice did not have an altered proliferation capacity. However, a lower spontaneous cell death rate was observed for CD69−/−lymphocytes. Thus, our results suggest that CD69 limits the innate immune response to VACV infection at least in part through cell homeostatic survival.IMPORTANCEWe show that increased natural killer (NK) cell numbers augment the host response and survival after infection with vaccinia virus. This phenotype is found in the absence of CD69 in immunocompetent and immunodeficient hosts. As part of the innate immune system, NK lymphocytes are activated and participate in the defense against infection. Several studies have focused on the contribution of NK cells to protection against infection with vaccinia virus. In this study, it was demonstrated that the augmented early NK cell response in the absence of CD69 is responsible for the increased protection seen during infection with vaccinia virus even at late times of infection. This work indicates that the CD69 molecule may be a target of therapy to augment the response to poxvirus infection.
Screening for malnutrition in patients with gastro-entero-pancreatic neuroendocrine tumours: a cross-sectional study
Authors: Qureshi Sheharyar A , Burch Nicola , Druce Maralyn , Hattersley John G , Khan Saboor , Gopalakrishnan Kishore , Darby Catherine , Wong John L H , Davies Louise , Fletcher Simon , Shatwell William , Sothi Sharmila , Randeva Harpal S , Dimitriadis Georgios K , Weickert Martin O 
Published: May 2016

ObjectivesTo investigate whether screening for malnutrition using the validated malnutrition universal screening tool (MUST) identifies specific characteristics of patients at risk, in patients with gastro-entero-pancreatic neuroendocrine tumours (GEP-NET).DesignCross-sectional study.SettingUniversity Hospitals Coventry & Warwickshire NHS Trust; European Neuroendocrine Tumour Society Centre of Excellence.ParticipantsPatients with confirmed GEP-NET (n=161) of varying primary tumour sites, functioning status, grading, staging and treatment modalities.Main outcome measureTo identify disease and treatment-related characteristics of patients with GEP-NET who score using MUST, and should be directed to detailed nutritional assessment.ResultsMUST score was positive (≥1) in 14% of outpatients with GEP-NET. MUST-positive patients had lower faecal elastase concentrations compared to MUST-negative patients (244±37 vs 383±20 µg/g stool; p=0.018), and were more likely to be on treatment with long-acting somatostatin analogues (65 vs 38%, p=0.021). MUST-positive patients were also more likely to have rectal or unknown primary NET, whereas, frequencies of other GEP-NET including pancreatic NET were comparable between MUST-positive and MUST-negative patients.ConclusionsGiven the frequency of patients identified at malnutrition risk using MUST in our relatively large and diverse GEP-NET cohort and the clinical implications of detecting malnutrition early, we recommend routine use of malnutrition screening in all patients with GEP-NET, and particularly in patients who are treated with long-acting somatostatin analogues.
Occupational outcomes following mild traumatic brain injury in Canadian military personnel deployed in support of the mission in Afghanistan: a retrospective cohort study
Authors: Garber Bryan G , Rusu Corneliu , Zamorski Mark A , Boulos David 
Published: May 2016

ObjectiveDeployment-related mild traumatic brain injury (MTBI) occurs in a significant number of military personnel but its long-term impacts are unclear. This study explores the impact of deployment-related MTBI on continued fitness-for-duty, with the ultimate intent of identifying potential targets for intervention to attenuate its effects.ParticipantsConsisted of 16 193 Canadian Armed Forces (CAF) personnel who deployed in support of the mission in Afghanistan and completed an enhanced postdeployment screening (EPDS) questionnaire over the period January 2009–July 2012.Primary outcomeThe primary outcome was development of permanent medical unfitness defined as a ‘career-limiting medical condition’ (CL-MC). The secondary outcome was the diagnostic categories recorded for each individual at the time a CL-MC was established.DesignThis study used a retrospective cohort design. Linked administrative and health data provided the primary outcome and the diagnoses responsible for it. Survival analysis was used to estimate the risk of a CL-MC and Cox regression provided adjusted HRs (aHRs) for the association between a CL-MC and MTBI, accounting for key covariates and confounders. Diagnostic categories associated with CL-MCs were identified.ResultsOver a median follow-up period of 3.42 years, 6.57% of the study population developed a CL-MC. MTBI was independently associated with CL-MCs (aHR=1.65, 95% CI 1.35 to 2.03). Mental disorders and musculoskeletal conditions were the primary diagnoses associated with CL-MCs (identified as the primary diagnosis in 55.4% and 25.9%, respectively), and a neurological condition was only documented in 5.8% of those with MTBI who developed a CL-MCConclusionsDeployment-related MTBI was associated with adverse occupational outcome but mental disorders and musculoskeletal conditions primarily drove subsequent medical unfitness. These findings support a diagnostic and treatment approach focusing on these comorbidities as the most promising strategy to minimise the burden of disability in MTBI-exposed military personnel.
Longitudinal study of patients with chronic Chagas cardiomyopathy in Brazil (SaMi-Trop project): a cohort profile
Authors: Cardoso Clareci Silva , Sabino Ester Cerdeira , Oliveira Claudia Di Lorenzo , de Oliveira Lea Campos , Ferreira Ariela Mota , Cunha-Neto Edécio , Bierrenbach Ana Luiza , Ferreira João Eduardo , Haikal Desirée Sant'Ana , Reingold Arthur L , Ribeiro Antonio Luiz P 
Published: May 2016

PurposeWe have established a prospective cohort of 1959 patients with chronic Chagas cardiomyopathy to evaluate if a clinical prediction rule based on ECG, brain natriuretic peptide (BNP) levels, and other biomarkers can be useful in clinical practice. This paper outlines the study and baseline characteristics of the participants.ParticipantsThe study is being conducted in 21 municipalities of the northern part of Minas Gerais State in Brazil, and includes a follow-up of 2 years. The baseline evaluation included collection of sociodemographic information, social determinants of health, health-related behaviours, comorbidities, medicines in use, history of previous treatment for Chagas disease, functional class, quality of life, blood sample collection, and ECG. Patients were mostly female, aged 50–74 years, with low family income and educational level, with known Chagas disease for >10 years; 46% presented with functional class >II. Previous use of benznidazole was reported by 25.2% and permanent use of pacemaker by 6.2%. Almost half of the patients presented with high blood cholesterol and hypertension, and one-third of them had diabetes mellitus. N-terminal of the prohormone BNP (NT-ProBNP) level was >300 pg/mL in 30% of the sample.Findings to dateClinical and laboratory markers predictive of severe and progressive Chagas disease were identified as high NT-ProBNP levels, as well as symptoms of advanced heart failure. These results confirm the important residual morbidity of Chagas disease in the remote areas, thus supporting political decisions that should prioritise in addition to epidemiological surveillance the medical treatment of chronic Chagas cardiomyopathy in the coming years. The São Paulo-Minas Gerais Tropical Medicine Research Center (SaMi-Trop) represents a major challenge for focused research in neglected diseases, with knowledge that can be applied in primary healthcare.Future plansWe will continue following this patients’ cohort to provide relevant information about the development and progression of Chagas disease in remotes areas, with social and economic inequalities.Trial registration numberNCT02646943; Pre-results.
Gender differences in risk factors and clinical outcomes in young patients with acute myocardial infarction
Authors: Cho Kyoung Im , Shin Eun-Seok , Ann Soe Hee , Garg Scot , Her Ae-Young , Kim Jeong Su , Han Jun Hee , Jeong Myung Ho 
Published: May 2016

BackgroundThere are limited data on the influence of gender on risk factors and clinical outcomes in young patients with acute myocardial infarction (AMI).MethodsThis prospective study stratified outcomes according to gender in patients of age ≤50 years with a diagnosis of AMI, and who were enrolled in the nationwide registry of the Korea Working Group of Myocardial Infarction. The end point was the incidence of major adverse cardiovascular events (MACEs) defined as the composite of cardiac death, recurrent myocardial infarction (MI), and repeat revascularisation at 30 days and 1 year after admission.ResultsThe registry enrolled 30 001 patients with AMI, of whom 5200 met the study inclusion criteria; 4805 patients were male and 395 were female. Current smoking was significantly higher in men, while hypertension and diabetes mellitus were significantly more common in women. Women underwent less coronary revascularisation, and were less likely to be on optimal medical therapy compared with men despite having a higher Killip class at presentation and higher risk angiographic findings. Although women had higher rates of MACEs (3.8% vs 1.8%, p=0.018 at 30 days and 7.8% vs 4.7%, p=0.004 at 1-year follow-up) compared with men, female gender was not an independent predictor of MACEs after adjusting for propensity score.ConclusionsThere were significant gender differences in the risk factors for coronary artery disease and the short-term and long-term clinical outcomes of young patients with AMI. Continued preventive strategies should be focused on gender-different risk factor reduction in these young patients.
Computational Complexity of Quantum Satisfiability
Authors: Herrmann Christian , Ziegler Martin 
Published: May 2016

We connect both discrete and algebraic complexity theory with the satisfiability problem in certain non-Boolean lattices.
Specifically, quantum logic was introduced in 1936 by Garrett Birkhoff and John von Neumann as a framework for capturing the logical peculiarities of quantum observables: in the 1D case it coincides with Boolean propositional logic but, starting with dimension two, violates the distributive law.

We introduce the weak and strong satisfiability problem for quantum logic propositional formulae. It turns out that in dimension two, both are also
NP
--complete.

For higher-dimensional spaces ℝ

d

and ℂ

d

with
d
≥ 3 fixed, on the other hand, we show both problems to be complete for the nondeterministic Blum-Shub-Smale (BSS) model of real computation. This provides a unified view on both Turing and real BSS complexity theory, and extends the (still relatively scarce) list of problems established
NP
ℝ
--complete with one, perhaps, closest in spirit to the classical Cook-Levin Theorem. More precisely, strong satisfiability of ∧ ∨ ∧ --terms is complete, while that of ∧ ∨--terms (i.e., those in conjunctive form) can be decided in polynomial time in dimensions
d
≥ 2.

The decidability of the infinite-dimensional case being still open, we proceed to investigate the case of indefinite finite dimensions. Here, weak satisfiability still belongs to
NP
R
and strong satisfiability is still hard; the latter, in fact, turns out as polynomial-time equivalent to the feasibility of noncommutative integer polynomial equations over matrix rings.
ХАРАКТЕРИСТИКА ОСОБЛИВОСТЕЙ СИСТЕМ И РЕГУЛЯЦІЇ АГРЕГАТНОГО СТАНУ КРОВІ ЖІНОК З АНЕМІЄЮ ІІІ СТУ - ПЕНЯ НА ФОНІ АНОМАЛЬНИХ МАТКОВ ИХ КРОВОТЕЧ.
Authors: Byrchak I. V. , Kuritsyna S. A. 
Published: May 2016

<p> У жінок з анемією ІІІ ступеня на тлі аномальних маткових кровотеч,<br />за високої активності первинного гемостазу розвивається структурна та хронометрична гіпокоагуляція, що зумовлено різким<br />зниженням вмісту в крові фібриногену. Основною причиною гіпофібриногенемії є надмірна активація неферментативного<br />фібринолізу. Загалом, зміни в системі регуляції агрегатного стану крові у жінок з високим ступенем анемізації є проявом<br />субклінічного внутрішньосудинного згортання крові, яке розвивається внаслідок високої функціональної активності тром-<br />боцитів.</p>
ЗМІНИ ІМУНОЛОГІЧНОГО СТАТУСУ ВАГІТНИХ ПРИ ПЛАЦЕНТАРНІЙ ДИСФУНКЦІЇ.
Authors: Кalinovska І. V. 
Published: May 2016

<p> У статті наведено результати змін імунологічного статусу вагітних при плацентарній формі фетоплацентарної недостатності. Показано збільшення рівня<br />прозапальних IL-2 та зменшення рівня протизапальних IL-4, що призводить до порушень функції ендотеліальних клітин судинної стінки, до судинного спазму та ішемії плаценти.</p>
ПРОЛОНГОВАНА ТА ПЕРЕНОШЕНА ВАГІТНІСТЬ. КЛІНІКО-МОРФОЛОГІЧНІ АСПЕКТИ.
Authors: Markin L. B. , Yashchenko L. M. 
Published: May 2016

<p>Нами проведене динамічне спостереження за 15 вагітними з моменту їх госпіталізації до виписки після пологів. Жінки розподілені на 3 групи: перша – 5 жінок із пролонгованою вагітністю 41 тиждень; друга група – 5 жінок з переношеною вагітністю 42 тижні; третя група – 5 жінок з фізіологічним перебігом вагітності. Критерії включення до дослідження: одноплідна вагітність, гестаційний вік &gt;280 днів, відсутність тяжкої екстрагенітальної патології, переношена вагітність в анамнезі. Усі вагітні були обстежені в повному клініко-лабораторному обсязі. У процесі обстеження проводили загальноклінічні (клініко-анамнестичні, лабораторні), спеціальні дослідження: ультразвукове дослідження з доплерометрією, ардіотокографію, морфологічні дослідження плаценти та амніотичної оболонки. Показано, що в 60 % жінок із пролонгованою вагітністю в анамнезі спостерігалися перенесені в дитинстві інфекційні захворювання (краснуха, скарлатина, паротит). Середній вік менархе у жінок із пролонгованою й переношеною вагітністю становив 15±0,5 років. У 40 % вагітних із переношеною вагітністю виявлено анемію легкого ступеня<br />(Нв 98–100 г/л). Під час пологів у 60 % жінок із переношеною та в 40 % зі пролонгованою вагітністю спостерігалось передчасне вилиття навколоплодових вод. Морфологічні дослідження показали, що дистрофічні зміни у плаценті та у судинах плодово-плацентарної системи із зміною структури гемохоріального (плацентарного) бар’єра можуть бути однією з причин переношування вагітності та факторами ризику негативного впливу на життєдіяльність плода.<br /><br /></p>
ВИВЧЕННЯ ПОКАЗНИКІВ ПЕРЕНОСИМОСТІ ГОРМОНАЛЬНОЇ ТЕРАПІЇ У ЖІНОК ІЗ МЕТАБОЛІЧНИМИ ПОРУШЕННЯМИ ПІСЛЯ ГІСТЕРЕКТОМІЇ.
Authors: Міsiurа А. H. 
Published: May 2016

<p>Патогенетична терапія хірургічної менопаузи у категорії жінок з предикторами метаболічних порушень чи клінічними проявами метаболічного синдрому не супроводжується розвитком ускладнень і появою побічних<br />ефектів, що є необхідними умовами, які гарантують прийнятність гормональної терапії. Застосування препарату «Фемостон 2/10» у жінок із метаболічними порушеннями після гістеректомії при відсутності протипоказань, індивідуалізованому підборі дозування та тривалості терапії – безпечний лікувально-профілактичний крок, з доброю переносимістю і хорошим<br />комплаєнсом.</p>
КАРДІОТОКОГРАФІЧНІ ОСОБЛИВОСТІ У ЖІНОК ІЗ ЗАТРИМКОЮ РОСТУ ПЛОДА.
Authors: Ovcharuk V. V. , Boychuk A. V. , Khlibovska O. I. , Dzhyvak V. H. 
Published: May 2016

<p>Нами проаналізовано особливості кардіотокограм у 30 вагітних жінок із затримкою росту плода. Контрольну групу склали 25 вагітних із фізіологічним перебігом. Проведений аналіз кардіотокографічних показників у 30 вагітних віком 26,2±0,2 року в термінах вагітності 32–36 тижнів і у яких за результатами ультразвукового скринінгу діагностовано затримку росту плода. Кардіотокограми у вагітних із затримкою росту плода характеризуються достовірним зменшенням базальної частоти серцевих скорочень плода, пониженою амплітудою, зменшенням кількості акцелерацій, наявністю децелерацій. Ці дані свідчать про плацентарну дисфункцію та<br />хронічну внутрішньоутробну гіпоксію.<br /><br /></p>
КЛІНІЧНІ І ПАТОМОРФОЛОГІЧНІ КРИТЕРІЇ ВИБОРУ МЕТОДУ ЛІКУВАННЯ ПАТОЛОГІЇ ЕНДОМЕТРІЯ.
Authors: Senchuk A. Ya. , Hychka S. H. , Zakordonets R. M. , Ivanenko S. V. 
Published: May 2016

<p>Проаналізовано 320 патогістологічних висновків діагностичних зскрібків пацієнток із лейоміомою матки і геморагічним синдромом. Виявлено, що патоморфологічно лейоміома матки з геморагічним синдромом найчастіше проявляється залозистою і залозистокістозною гіперплазією ендометрія (50,7 %), поліпозом ендометрія (36,9 %). Вважаємо, що під час вибору методу лікування<br />пацієнток із лейоміомою матки і геморагічним синдромом необхідно враховувати дані анамнезу, наявність екстрагенітальної патології, клінічні та патоморфологічні результати обстеження даної групи пацієнток.<br /><br /></p>