bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tetraspanin CD151 Promotes Initial Events in Human Cytomegalovirus Infection
Authors: Hochdorfer Daniel , Florin Luise , Sinzger Christian , Lieber Diana 
Published: May 2016

ABSTRACT
Human cytomegalovirus (HCMV), a betaherpesvirus, can cause life-threatening disease in immunocompromised individuals. Viral envelope glycoproteins that mediate binding to and penetration into target cells have been identified previously. In contrast, cellular proteins supporting HCMV during entry are largely unknown. In order to systematically identify host genes affecting initial steps of HCMV infection, a targeted RNA interference screen of 96 cellular genes was performed in endothelial cells by use of a virus strain expressing the full set of known glycoprotein H and L (gH/gL) complexes. The approach yielded five proviral host factors from different protein families and eight antiviral host factors, mostly growth factor receptors. The tetraspanin CD151 was uncovered as a novel proviral host factor and was analyzed further. Like endothelial cells, fibroblasts were also less susceptible to HCMV infection after CD151 depletion. Virus strains with different sets of gH/gL complexes conferring either broad or narrow cell tropism were equally impaired. Infection of CD151-depleted cells by a fluorescent virus with differentially labeled capsid and envelope proteins revealed a role of CD151 in viral penetration but not in adsorption to the cell. In conclusion, the tetraspanin CD151 has emerged as a novel host factor in HCMV entry and as a putative antiviral target.

IMPORTANCE
At present, the events at the virus-cell interface and the cellular proteins involved during the HCMV entry steps are scarcely understood. In this study, several host factors with putative roles in this process were identified. The tetraspanin CD151 was discovered as a previously unrecognized proviral host factor for HCMV and was found to support viral penetration into the target cells. The findings of this study shed light on the cellular contribution during the initial steps of HCMV infection and open a new direction in HCMV research.
Human Cytomegalovirus Induces an Atypical Activation of Akt To Stimulate the Survival of Short-Lived Monocytes
Authors: Cojohari Olesea , Peppenelli Megan A. , Chan Gary C. 
Published: May 2016

ABSTRACTHuman cytomegalovirus (HCMV) is a pervasive herpesvirus responsible for significant morbidity and mortality among immunodeficient/naive hosts. Following a primary HCMV infection, circulating blood monocytes mediate the systemic spread of the virus. Extending the short 48-h life span of monocytes is critical to the viral dissemination process, as these blood-borne cells are nonpermissive for virus replication until they are fully differentiated into macrophages. Here, we show that HCMV glycoprotein gB binding to cellular epidermal growth factor receptor (EGFR) during HCMV entry initiated a rapid (within 15 min) activation of the apoptosis suppressor Akt, which was maintained through 72 h. The virus-induced activation of Akt was more robust than that with the normal myeloid growth factor macrophage colony-stimulating factor (M-CSF) and was essential for infected monocytes to bypass the 48-h viability checkpoint. Activation of phosphoinositide 3-kinase (PI3K) following EGFR engagement by HCMV mediated the phosphorylation of Akt. Moreover, HCMV entry drove a switch away from the PI3K p110δ isoform, which was required for the viability of uninfected monocytes, to the p110β isoform in order to facilitate the Akt-dependent prosurvival state within infected cells. Simultaneously, in contrast to M-CSF, HCMV promoted a rapid increase in SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) expression, leading to signaling through a noncanonical Akt activation pathway. To ensure maximum Akt activity, HCMV also induced an early phosphorylation-dependent inactivation of the negative regulator phosphatase and tensin homolog. Overall, our data indicate that HCMV hijacks the upstream Akt signaling network to induce a nontraditional activation of Akt and subsequently a prosurvival decision at the 48-h cell fate checkpoint, a vital step for HCMV's dissemination and persistence strategy.IMPORTANCEHCMV is found throughout the world with a prevalence of 55 to 100% within the human population. HCMV infection is generally asymptomatic in immunocompetent or naive individuals but is a significant cause of morbidity and mortality among the immunocompromised. Widespread organ inflammation is associated with symptomatic infections, which is a direct consequence of the viral dissemination strategy. Inflammatory peripheral blood monocytes facilitate the spread of HCMV. However, HCMV must subvert the naturally short life span of monocytes. In this work, we demonstrate that HCMV induces the activation of Akt, an antiapoptotic protein, in a manner distinct from that of normal myeloid growth factors. Moreover, we decipher how HCMV dysregulates the upstream Akt signaling network during viral entry to promote an Akt-dependent prosurvival state following infection. Delineation of the virus-specific mechanisms that regulate cellular prosurvival pathways in order to drive the survival of HCMV-infected monocytes is important to identifying new anti-HCMV therapeutic targets.
Membrane Anchors of the Structural Flavivirus Proteins and Their Role in Virus Assembly
Authors: Blazevic Janja , Rouha Harald , Bradt Victoria , Heinz Franz X. , Stiasny Karin 
Published: May 2016

ABSTRACT

The structural proteins of flaviviruses carry a unique set of transmembrane domains (TMDs) at their C termini that are derived from the mode of viral polyprotein processing. They function as internal signal and stop-transfer sequences during protein translation, but possible additional roles in protein interactions required during assembly and maturation of viral particles are ill defined. To shed light on the role of TMDs in these processes, we engineered a set of tick-borne encephalitis virus mutants in which these structural elements were replaced in different combinations by the homologous sequences of a distantly related flavivirus (Japanese encephalitis virus). The effects of these modifications were analyzed with respect to protein synthesis, viral particle secretion, specific infectivity, and acidic-pH-induced maturation processes. We provide evidence that interactions involving the double-membrane anchor of the envelope protein E (a unique feature compared to other viral fusion proteins) contribute substantially to particle assembly, stability, and maturation. Disturbances of the inter- and intra-TMD interactions of E resulted in the secretion of a larger proportion of capsidless subviral particles at the expense of whole virions, suggesting a possible role in the still incompletely understood mechanism of capsid integration during virus budding. In contrast, the TMD initially anchoring the C protein to the endoplasmic reticulum membrane does not appear to take part in envelope protein interactions. We also show that E TMDs are involved in the envelope protein rearrangements that are triggered by acidic pH in the
trans
-Golgi network and represent a hallmark of virus maturation.

IMPORTANCE
The assembly of flaviviruses occurs in the endoplasmic reticulum and leads to the formation of immature, noninfectious particles composed of an RNA-containing capsid surrounded by a lipid membrane, with the two integrated envelope proteins, prM and E, arranged in an icosahedral lattice. The mechanism by which the capsid is formed and integrated into the budding viral envelope is currently unknown. We provide evidence that the transmembrane domains (TMDs) of E are essential for the formation of capsid-containing particles and that disturbances of these interactions lead to the preferential formation of capsidless subviral particles at the expense of whole virions. E TMD interactions also appear to be essential for the envelope protein rearrangements required for virus maturation and for the generation of infectious virions. Our data thus provide new insights into the biological functions of E TMDs and extend their role during viral polyprotein processing to additional functions in particle assembly and maturation.
Unexpected Interfarm Transmission Dynamics during a Highly Pathogenic Avian Influenza Epidemic
Authors: Fusaro Alice , Tassoni Luca , Milani Adelaide , Hughes Joseph , Salviato Annalisa , Murcia Pablo R. , Massi Paola , Zamperin Gianpiero , Bonfanti Lebana , Marangon Stefano , Cattoli Giovanni , Monne Isabella 
Published: May 2016

ABSTRACT
Next-generation sequencing technology is now being increasingly applied to study the within- and between-host population dynamics of viruses. However, information on avian influenza virus evolution and transmission during a naturally occurring epidemic is still limited. Here, we use deep-sequencing data obtained from clinical samples collected from five industrial holdings and a backyard farm infected during the 2013 highly pathogenic avian influenza (HPAI) H7N7 epidemic in Italy to unravel (i) the epidemic virus population diversity, (ii) the evolution of virus pathogenicity, and (iii) the pathways of viral transmission between different holdings and sheds. We show a high level of genetic diversity of the HPAI H7N7 viruses within a single farm as a consequence of separate bottlenecks and founder effects. In particular, we identified the cocirculation in the index case of two viral strains showing a different insertion at the hemagglutinin cleavage site, as well as nine nucleotide differences at the consensus level and 92 minority variants. To assess interfarm transmission, we combined epidemiological and genetic data and identified the index case as the major source of the virus, suggesting the spread of different viral haplotypes from the index farm to the other industrial holdings, probably at different time points. Our results revealed interfarm transmission dynamics that the epidemiological data alone could not unravel and demonstrated that delay in the disease detection and stamping out was the major cause of the emergence and the spread of the HPAI strain.

IMPORTANCE
The within- and between-host evolutionary dynamics of a highly pathogenic avian influenza (HPAI) strain during a naturally occurring epidemic is currently poorly understood. Here, we perform for the first time an in-depth sequence analysis of all the samples collected during a HPAI epidemic and demonstrate the importance to complement outbreak investigations with genetic data to reconstruct the transmission dynamics of the viruses and to evaluate the within- and between-farm genetic diversity of the viral population. We show that the evolutionary transition from the low pathogenic form to the highly pathogenic form occurred within the first infected flock, where we identified haplotypes with hemagglutinin cleavage site of different lengths. We also identify the index case as the major source of virus, indicating that prompt application of depopulation measures is essential to limit virus spread to other farms.
Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase
Authors: Cheng Fan , He Meilan , Jung Jae U. , Lu Chun , Gao Shou-Jiang 
Published: May 2016

ABSTRACT
The host intracellular antiviral restriction factors inhibit viral infection and replication. The 5′-AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. Activated AMPK inhibits the replication of numerous RNA viruses but enhances the entry of vaccinia virus. However, the role of AMPK in herpesvirus infection is unclear. In this study, we showed that the constitutive AMPK activity restricted Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in primary human umbilical vein endothelial cells while KSHV infection did not markedly affect the endogenous AMPK activity. Knockdown of the AMPKα1 considerably enhanced the expression of viral lytic genes and the production of infectious virions, while overexpression of a constitutively active AMPK had the opposite effects. Accordingly, an AMPK inhibitor, compound C, augmented viral lytic gene expressions and virion productions but an AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), suppressed both. Furthermore, a common diabetes drug, metformin, which carries an AMPK-agonistic activity, drastically inhibited the expression of viral lytic genes and the production of infectious virions, suggesting the use of metformin as a therapeutic agent for KSHV infection and replication. Together, these results identify the host AMPK as a KSHV restriction factor that can serve as a potential therapeutic target.

IMPORTANCE
Host cells encode specific proteins to restrict viral infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. In this study, we have identified 5′-AMP-activated protein kinase (AMPK), a cellular energy sensor, as a restriction factor of KSHV lytic replication during primary infection. Activation of AMPK suppresses, while inhibition of AMPK enhances, KSHV lytic replication by regulating the expression of viral genes. AICAR and metformin, both of which are AMPK agonists currently used in clinics for the treatment of conditions associated with metabolic disorders, inhibit KSHV lytic replication. Thus, our work has identified AMPK as a potential therapeutic target and AICAR and metformin as potential therapeutic agents for KSHV-associated cancers.
Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses
Authors: Verhalen Brandy , Starrett Gabriel J. , Harris Reuben S. , Jiang Mengxi 
Published: May 2016

ABSTRACT
The APOBEC3 family of DNA cytosine deaminases has important roles in innate immunity and cancer. It is unclear how DNA tumor viruses regulate these enzymes and how these interactions, in turn, impact the integrity of both the viral and cellular genomes. Polyomavirus (PyVs) are small DNA pathogens that contain oncogenic potentials. In this study, we examined the effects of PyV infection on APOBEC3 expression and activity. We demonstrate that APOBEC3B is specifically upregulated by BK polyomavirus (BKPyV) infection in primary kidney cells and that the upregulated enzyme is active. We further show that the BKPyV large T antigen, as well as large T antigens from related polyomaviruses, is alone capable of upregulating APOBEC3B expression and activity. Furthermore, we assessed the impact of A3B on productive BKPyV infection and viral genome evolution. Although the specific knockdown of APOBEC3B has little short-term effect on productive BKPyV infection, our informatics analyses indicate that the preferred target sequences of APOBEC3B are depleted in BKPyV genomes and that this motif underrepresentation is enriched on the nontranscribed stand of the viral genome, which is also the lagging strand during viral DNA replication. Our results suggest that PyV infection upregulates APOBEC3B activity to influence virus sequence composition over longer evolutionary periods. These findings also imply that the increased activity of APOBEC3B may contribute to PyV-mediated tumorigenesis.

IMPORTANCE
Polyomaviruses (PyVs) are a group of emerging pathogens that can cause severe diseases, including cancers in immunosuppressed individuals. Here we describe the finding that PyV infection specifically induces the innate immune DNA cytosine deaminase APOBEC3B. The induced APOBEC3B enzyme is fully functional and therefore may exert mutational effects on both viral and host cell DNA. We provide bioinformatic evidence that, consistent with this idea, BK polyomavirus genomes are depleted of APOBEC3B-preferred target motifs and enriched for the corresponding predicted reaction products. These data imply that the interplay between PyV infection and APOBEC proteins may have significant impact on both viral evolution and virus-induced tumorigenesis.
Influence of CT utilisation on patient flow in the emergency department: a retrospective 1-year cohort study
Authors: Li Chao-Jui , Syue Yuan-Jhen , Lin Yan-Ren , Cheng Hsien-Hung , Cheng Fu-Jen , Tsai Tsung-Cheng , Chen Kuan-Fu , Lee Chien-Hung 
Published: May 2016

ObjectiveCT, an important diagnostic tool in the emergency department (ED), might increase the ED length of stay (LOS). Considering the issue of ED overcrowding, it is important to evaluate whether CT use delays or facilitates patient disposition in the ED.DesignA retrospective 1-year cohort study.Setting5 EDs within the same healthcare system dispersed nationwide in Taiwan.ParticipantsAll adult non-trauma patients who visited the 5 EDs from 1 July 2011 to 30 June 2012.InterventionsPatients were grouped by whether or not they underwent a CT scan (CT and non-CT groups, respectively).Primary and secondary outcome measuresThe ED LOS and hospital LOS between patients who had and had not undergone CT scans were compared by stratifying different dispositions and diagnoses.ResultsCT use prolonged patient ED LOS among those who were directly discharged from the ED. Among patients admitted to the observation unit and then discharged, patients diagnosed with nervous system disease had shorter ED LOS if they underwent a CT scan. CT use facilitated patient admission to the general ward. CT use also accelerated patients' admission to the intensive care unit (ICU) for patients with nervous system disease, neoplasm and digestive disease. Finally, patients admitted to the general wards had shorter hospital LOS if they underwent CT scans in the ED.ConclusionsCT use did not seem to have delayed patient disposition in ED. While CT use facilitated patient disposition if they were finally hospitalised, it mildly prolonged ED LOS in cases of patients discharged from the ED.
Improving Resource Efficiency at Scale with Heracles
Authors: Lo David , Cheng Liqun , Govindaraju Rama , Ranganathan Parthasarathy , Kozyrakis Christos 
Published: May 2016

User-facing, latency-sensitive services, such as websearch, underutilize their computing resources during daily periods of low traffic. Reusing those resources for other tasks is rarely done in production services since the contention for shared resources can cause latency spikes that violate the service-level objectives of latency-sensitive tasks. The resulting under-utilization hurts both the affordability and energy efficiency of large-scale datacenters. With the slowdown in technology scaling caused by the sunsetting of Moore’s law, it becomes important to address this opportunity.
We present Heracles, a feedback-based controller that enables the safe colocation of best-effort tasks alongside a latency-critical service. Heracles dynamically manages multiple hardware and software isolation mechanisms, such as CPU, memory, and network isolation, to ensure that the latency-sensitive job meets latency targets while maximizing the resources given to best-effort tasks. We evaluate Heracles using production latency-critical and batch workloads from Google and demonstrate average server utilizations of 90% without latency violations across all the load and colocation scenarios that we evaluated.
miR-17-92/p38α Dysregulation Enhances Wnt Signaling and Selects Lgr6+ Cancer Stem-like Cells during Lung Adenocarcinoma Progression
Authors: Guinot Anna , Oeztuerk-Winder Feride , Ventura Juan-Jose 
Published: May 2016

Abstract
Defining the molecular and cellular roots of lung cancer relapse after initial treatment remains an imperative to improve survival. Here we report that the lung stem cell marker Lgr6 becomes enriched in non–small cell lung cancer (NSCLC) cells during malignant progression. Lgr6+ NSCLC cells displayed self-renewal and differentiation properties along with a higher tumorigenic potential. Mechanistic investigations suggested that a defective repression of the miR-17-92 gene cluster was responsible for evolution of a selection for outgrowth of Lgr6+ NSCLC cells. High levels of expression of miR-19 family members were found to target and downregulate levels of p38α kinase, providing a specific survival signal for Lgr6+ cells as mediated by increased Wnt/ß-catenin activity. Our results identify a specific stem-like cell population in NSCLC with increased malignant potential, the elucidation of which may enable earlier prognosis and possibly the development of more effective targeted treatments. Cancer Res; 76(13); 4012–22. ©2016 AACR.
ОСОБЛИВОСТІ ПЕРВИННОЇ ПРОФІЛАКТИКИ АТОПІЧНИХ ЗАХВОРЮВАНЬ У ДІТЕЙ ПІВДЕННО-СХІДНОГО РЕГІОНУ УКРАЇНИ.
Authors: Vrublevska S. V. 
Published: May 2016

<p> В останніх зарубіжних джерелах зроблено спроби запропонувати методи і способи захисту від можливої сенси-<br />білізації, однак немає єдиного підходу. Розглядаються можливості імунної модуляції і розвитку толерантності до харчових<br />продуктів шляхом елімінації потенційних алергенів. Ми пропонуємо комплекс профілактичних заходів, адаптований до<br />нашого регіону, які шляхом імунної модуляції сприяли розвитку толерантності до харчових продуктів і також до можливих<br />алергенів.<br /><br /></p>
КЛІНІКО -ЕПІДЕМІОЛОГІЧНЕ ДОСЛІДЖЕННЯ ДІТЕЙ , ХВОРИХ НА ГРВІ, З ПРОЯВАМИ ЗАХВОРЮВАННЯ В РОТОВІЙ ПОРОЖНИНІ .
Authors: Hevkaliuk N. О. 
Published: May 2016

<p> Результати клініко-епідеміологічних досліджень підтверджують відомості про те, що частота захворюваності,<br />тяжкість перебігу ГРВІ, виникнення ускладнень із проявами в порожнині рота залежать від соціального середовища, яке<br />визначається станом здоров’я батьків, перенесеними та супутніми захворюваннями дитини, рядом біологічних факторів,<br />здатних змінювати рівень сприйнятливості до респіраторних вірусів.</p>
СТАН АНТИОКСИДАНТНОЇ СИСТЕМИ ЗАХИСТУ ОРГАНІЗМУ В НОВОНАРОДЖЕНИХ З ПОРУШЕННЯМИ ФУНКЦІОНАЛЬНОГО СТАНУ СЕРЦЕВО -СУДИННОЇ СИСТЕМИ ПРИ ПЕРИНАТАЛЬНІЙ ПАТОЛОГІЇ.
Authors: Hodovanets Yu. D. , Peryzhnyak A. I. 
Published: May 2016

<p> У статті проаналізовано<br />результати дослідження показників системи вільнорадикального окиснення та антиоксидантної системи захисту організму в<br />новонароджених з порушеннями функціонального стану серцево-судинної системи за умов патологічного пологового стресу.<br />Доцільність визначення показників вищезазначених систем дозволить своєчасно діагностувати антиоксидантну недостатність<br />на субклітинному рівні, наслідками якої є порушення функції систем органів за умов гіпоксії при перинатальній патології.<br /><br /></p>
СУЧАСНИЙ ПІДХІД ЩОДО ПРОВЕДЕННЯ КОНТРОЛЬОВАНОЇ СТИМУЛЯЦІЇ ЯЄЧНИКІВ У ЦИКЛАХ ДОПОМІЖНИХ РЕПРОДУКТИВНИХ ТЕХНОЛОГІЙ У ЖІНОК ІЗ ВИСОКИМ РИЗИКОМ СИНДРОМУ ГІПЕРСТИМУЛЯЦІЇ ЯЄЧНИКІВ.
Authors: Ayziatulova E. M. 
Published: May 2016

<p>Використання розроблених протоколів контрольованої стимуляції яєчників з антагоністом гонадотропін-рилізинг гормону з урахуванням рівня сироваткового прогестерону у програмі допоміжних репродуктивних технологій щодо жінок з високим ризиком розвитку синдрому гіперстимуляції яєчників дозволило зменшити кількість випадків середньо-тяжких форм синдрому гіперстимуляції яєчників (2,5 % проти 17,5 % у разі традиційної схеми з антагоністом гонадотропін-рилізинг-гормону; RR 0,14; 95 % ДІ 0,04–0,46), підвищити частоту настання клінічної вагітності (35,0 % проти 21,7 %; RR 1,62; 95 % ДІ 1,06–2,46)<br />і пологів (33,3 % проти 16,7 %; RR 2,00; 95 % ДІ 1,25–3,21).</p>
ПОРІВНЯЛЬНА ОЦІНКА МЕТОДІВ ВІЗУАЛІЗАЦІЇ АНОМАЛІЙ РОЗВИТКУ МАТКИ.
Authors: Veresnyuk N. S. 
Published: May 2016

<p>У статті представлені результати ретроспективної оцінки різних методів візуалізації аномалій розвитку матки у 132 пацієнток. Наведені дані свідчать про те, що ультрасонографія та гістеросальпінгографія можуть з успіхом використовуватися як скринінгові методи виявлення аномалій жіночих статевих органів у пацієнток із порушеннями репродуктивного здоров’я, однак вони не завжди дають можливість диференціювати їх різновиди.<br /><br /></p>