bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human T-Lymphotropic Virus Type 1-Induced Overexpression of Activated Leukocyte Cell Adhesion Molecule (ALCAM) Facilitates Trafficking of Infected Lymphocytes through the Blood-Brain Barrier
Authors: Curis Céline , Percher Florent , Jeannin Patricia , Montange Thomas , Chevalier Sébastien A. , Seilhean Danielle , Cartier Luis , Couraud Pierre-Olivier , Gout Olivier , Gessain Antoine , Ceccaldi Pierre-Emmanuel , Afonso Philippe V. 
Published: June 2016

ABSTRACT

Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease develops upon infiltration of HTLV-1-infected lymphocytes into the central nervous system, mostly the thoracic spinal cord. The central nervous system is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. In this study, we investigated the role of activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, in the crossing of the BBB by HTLV-1-infected lymphocytes. We demonstrated that ALCAM is overexpressed on the surface of HTLV-1-infected lymphocytes, both in chronically infected cell lines and in primary infected CD4
+
T lymphocytes. ALCAM overexpression results from the activation of the canonical NF-κB pathway by the viral transactivator Tax. In contrast, staining of spinal cord sections of HAM/TSP patients showed that ALCAM expression is not altered on the BBB endothelium in the context of HTLV-1 infection. ALCAM blockade or downregulation of ALCAM levels significantly reduced the migration of HTLV-1-infected lymphocytes across a monolayer of human BBB endothelial cells. This study suggests a potential role for ALCAM in HAM/TSP pathogenesis.

IMPORTANCE
Human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of a slowly progressive neurodegenerative disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This disease is the consequence of the infiltration of HTLV-1-infected lymphocytes into the central nervous system (CNS), mostly the thoracic spinal cord. The CNS is normally protected by a physiological structure called the blood-brain barrier (BBB), which consists primarily of a continuous endothelium with tight junctions. The mechanism of migration of lymphocytes into the CNS is unclear. Here, we show that the viral transactivator Tax increases activated leukocyte cell adhesion molecule (ALCAM/CD166) expression. This molecule facilitates the migration of lymphocytes across the BBB endothelium. Targeting this molecule could be of interest in preventing or reducing the development of HAM/TSP.
Two Polypyrimidine Tracts in Intron 4 of the Major Immediate Early Gene Are Critical for Gene Expression Switching from IE1 to IE2 and for Replication of Human Cytomegalovirus
Authors: Hou Wangheng , Torres Lilith , Cruz-Cosme Ruth , Arroyo Fernando , Irizarry Luis , Luciano Dalia , Márquez Arturo , Rivera Leslie L. , Sala Antonio L. , Luo Min-hua , Tang Qiyi 
Published: June 2016

ABSTRACT
The human cytomegalovirus (HCMV) major immediate early (MIE) gene is essential for viral replication. The most abundant products encoded by the MIE gene include IE1 and IE2. Genes of IE1 and IE2 share the MIE promoter (MIEP), the first 3 exons, and the first 2 introns. IE1 is expressed earlier than IE2 after CMV infection or MIE gene transfection. In this study, we identified 2 polypyrimidine (Py) tracts in intron 4 (between exons 4 and 5) that are responsible for transcriptional switching from IE1 to IE2. The first Py is important and the second one is essential for the splicing and expression of IE2. In searching for the mechanisms of MIE gene switching from IE1 to IE2, we found that the second Py was required for the IE2's fourth intron to bind to a splicing factor such as U2AF65, as determined by an RNA electrophoretic mobility shift assay and a chromatin immunoprecipitation (ChIP) assay, while the first Py enhanced the binding of U2AF65 with the intron. An HCMV BACmid with the second Py mutated failed to produce any virus, while the HCMV with the first Py mutated replicated with a defective phenotype. Furthermore, we designed a small RNA (scRNAPy) that is complementary to the intron RNA covering the two Pys. The scRNAPy interfered with the interaction of U2AF65 with the intron and repressed the IE2 expression. Therefore, our studies implied that IE2 gene splicing might be an anti-CMV target.

IMPORTANCE
CMV is a ubiquitous herpesvirus and a significant cause of disease and death in the immunocompromised and elderly. Insights into its gene regulation will provide clues in designing anti-CMV strategies. The MIE gene is one of the earliest genes of CMV and is essential for CMV replication. It is known that the MIE gene needs to be spliced to produce more than two proteins; however, how MIE gene splicing is regulated remains elusive. In the present studies, we identified two Pys in intron 4 and found that the first Py is important and the second is required for the splicing and expression of IE2. We further investigated the mechanisms of gene switching from IE1 to IE2 and found that the two Pys are responsible for U2AF65's binding with intron 4. Therefore, the Pys in intron 4 are the
cis
elements that determine the fate of IE2 splicing. Furthermore, we found that a small RNA that is complementary to intron 4 repressed IE2 expression. Hence, we provide the first piece of evidence for a unique mechanism of MIE gene regulation at the splicing level.
Herpes Simplex Virus Capsid Localization to ESCRT-VPS4 Complexes in the Presence and Absence of the Large Tegument Protein UL36p
Authors: Kharkwal Himanshu , Smith Caitlin G. , Wilson Duncan W. 
Published: June 2016

ABSTRACT
UL36p (VP1/2) is the largest protein encoded by herpes simplex virus 1 (HSV-1) and resides in the innermost layer of tegument, the complex protein layer between the capsid and envelope. UL36p performs multiple functions in the HSV life cycle, including a critical but unknown role in capsid cytoplasmic envelopment. We tested whether UL36p is essential for envelopment because it is required to engage capsids with the cellular ESCRT/Vps4 apparatus. A green fluorescent protein (GFP)-fused form of the dominant negative ATPase Vps4-EQ was used to irreversibly tag ESCRT envelopment sites during infection by UL36p-expressing and UL36-null HSV strains. Using fluorescence microscopy and scanning electron microscopy, we quantitated capsid/Vps4-EQ colocalization and examined the ultrastructure of the corresponding viral assembly intermediates. We found that loss of UL36p resulted in a two-thirds reduction in the efficiency of capsid/Vps4-EQ association but that the remaining UL36p-null capsids were still able to engage the ESCRT envelopment apparatus. It appears that although UL36p helps to couple HSV capsids to the ESCRT pathway, this is likely not the sole reason for its absolute requirement for envelopment.

IMPORTANCE
Envelopment of the HSV capsid is essential for the assembly of an infectious virion and requires the complex interplay of a large number of viral and cellular proteins. Critical to envelope assembly is the virally encoded protein UL36p, whose function is unknown. Here we test the hypothesis that UL36p is essential for the recruitment of cellular ESCRT complexes, which are also known to be required for envelopment.
The Epigenetic Pathways to Ribosomal DNA Silencing
Authors: Srivastava Rakesh , Srivastava Rashmi , Ahn Seong Hoon 
Published: June 2016

SUMMARY

Heterochromatin is the transcriptionally repressed portion of eukaryotic chromatin that maintains a condensed appearance throughout the cell cycle. At sites of ribosomal DNA (rDNA) heterochromatin, epigenetic states contribute to gene silencing and genome stability, which are required for proper chromosome segregation and a normal life span. Here, we focus on recent advances in the epigenetic regulation of rDNA silencing in
Saccharomyces cerevisiae
and in mammals, including regulation by several histone modifications and several protein components associated with the inner nuclear membrane within the nucleolus. Finally, we discuss the perturbations of rDNA epigenetic pathways in regulating cellular aging and in causing various types of diseases.
Genetically Engineered Phages: a Review of Advances over the Last Decade
Authors: Pires Diana P. , Cleto Sara , Sillankorva Sanna , Azeredo Joana , Lu Timothy K. 
Published: June 2016

SUMMARY
Soon after their discovery in the early 20th century, bacteriophages were recognized to have great potential as antimicrobial agents, a potential that has yet to be fully realized. The nascent field of phage therapy was adversely affected by inadequately controlled trials and the discovery of antibiotics. Although the study of phages as anti-infective agents slowed, phages played an important role in the development of molecular biology. In recent years, the increase in multidrug-resistant bacteria has renewed interest in the use of phages as antimicrobial agents. With the wide array of possibilities offered by genetic engineering, these bacterial viruses are being modified to precisely control and detect bacteria and to serve as new sources of antibacterials. In applications that go beyond their antimicrobial activity, phages are also being developed as vehicles for drug delivery and vaccines, as well as for the assembly of new materials. This review highlights advances in techniques used to engineer phages for all of these purposes and discusses existing challenges and opportunities for future work.
Mediterranean outflow pump: An alternative mechanism for the Lago-mare and the end of the Messinian Salinity Crisis
Authors: Marzocchi Alice , Flecker Rachel , van Baak Christiaan G.C. , Lunt Daniel J. , Krijgsman Wout 
Published: June 2016

Abstract
The final stage of the Messinian salinity crisis (MSC) was characterized by brackish-water “Lago-mare” conditions in the intermediate and marginal basins of the Mediterranean Sea. The presence of Paratethyan (former Black Sea) fauna in these deposits has fueled long-lasting controversies over the connectivity between the Mediterranean and Paratethys and contemporary sea-level drops in both basins. Here, we use the results of sub-precessional climate simulations to calculate the freshwater budget of the Mediterranean and Paratethys in the Messinian. We show that, during the MSC, the freshwater budget of Paratethys was positive, while the Mediterranean was negative. Using these numerical constraints, we propose a Mediterranean outflow pump as an alternative scenario for the two most dramatic hydrological changes in the MSC: (1) the Halite–Lago-mare transition and (2) the Pliocene reestablishment of marine conditions. Following the maximum MSC lowstand during halite formation, progressive Mediterranean sea-level rise resulting from African river runoff and overspill from both the Atlantic and Paratethys eventually reached the level of the Paratethys sill. A density contrast at this gateway caused dense Mediterranean waters to flow into the Paratethys, driving a compensatory return flow. This “pump” mechanism significantly enhanced Paratethyan inflow to the Mediterranean, creating suitable conditions for the Lago-mare fauna to migrate and thrive. When the Mediterranean sea level finally reached the height of the Gibraltar sill, Mediterranean outflow restarted there and enhanced exchange with the Atlantic Ocean. During this reorganization of the circulation, brackish and hypersaline waters were pumped out of the Mediterranean, and open-marine conditions were reestablished without major flooding of the basin at the Miocene-Pliocene boundary.
Hydrothermal alteration of seafloor peridotites does not influence oxygen fugacity recorded by spinel oxybarometry
Authors: Birner Suzanne K. , Warren Jessica M. , Cottrell Elizabeth , Davis Fred A. 
Published: June 2016

Abstract
Olivine, orthopyroxene, and spinel compositions within seafloor peridotites yield important information about the nature of Earth’s mantle. Major element compositions of these minerals can be used to calculate oxygen fugacity, a thermodynamic property critical to understanding phase equilibria in the upper mantle. This study examines how hydrothermal alteration at the seafloor influences peridotite chemistry. The Tonga Trench (South Pacific Ocean) exposes lithospheric forearc peridotites that range from highly altered to completely unaltered and provides an ideal sample suite for investigating the effect of alteration on spinel peridotite major element chemistry and calculated oxygen fugacity. Using the Tonga peridotites, we develop a qualitative alteration scale rooted in traditional point-counting methodology. We show that high degrees of serpentinization do not affect mineral parameters such as forsterite number in olivine, iron site occupancy in orthopyroxene, and Fe3+/ΣFe ratio in spinel. Additionally, while serpentinization is a redox reaction that leaves behind an oxidized residue, the oxygen fugacity recorded by mantle minerals is unaffected by nearby low-temperature serpentinization. As a result, oxygen fugacity measured by spinel oxybarometry in seafloor peridotites is representative of mantle processes, rather than an artifact of late-stage seafloor alteration.
Identification of responders to inhaled corticosteroids in a chronic obstructive pulmonary disease population using cluster analysis
Authors: Hinds David R , DiSantostefano Rachael L , Le Hoa V , Pascoe Steven 
Published: June 2016

ObjectivesTo identify clusters of patients who may benefit from treatment with an inhaled corticosteroid (ICS)/long-acting β2agonist (LABA) versus LABA alone, in terms of exacerbation reduction, and to validate previously identified clusters of patients with chronic obstructive pulmonary disease (COPD) (based on diuretic use and reversibility).DesignPost hoc supervised cluster analysis using a modified recursive partitioning algorithm of two 1-year randomised, controlled trials of fluticasone furoate (FF)/vilanterol (VI) versus VI alone, with the primary end points of the annual rate of moderate-to-severe exacerbations.SettingGlobal.Participants3255 patients with COPD (intent-to-treat populations) with a history of exacerbations in the past year.InterventionsFF/VI 50/25 µg, 100/25 µg or 200/25 µg, or VI 25 µg; all one time per day.Outcome measuresMean annual COPD exacerbation rate to identify clusters of patients who benefit from adding an ICS (FF) to VI bronchodilator therapy.ResultsThree clusters were identified, including two groups that benefit from FF/VI versus VI: patients with blood eosinophils >2.4% (RR=0.68, 95% CI 0.58 to 0.79), or blood eosinophils ≤2.4% and smoking history ≤46 pack-years, experienced a reduced rate of exacerbations with FF/VI versus VI (RR=0.78, 95% CI 0.63 to 0.96), whereas those with blood eosinophils ≤2.4% and smoking history >46 pack-years were identified as non-responders (RR=1.22, 95% CI 0.94 to 1.58). Clusters of patients previously identified in the fluticasone propionate/salmeterol (SAL) versus SAL trials of similar design were not validated; all clusters of patients tended to benefit from FF/VI versus VI alone irrespective of diuretic use and reversibility.ConclusionsIn patients with COPD with a history of exacerbations, those with greater blood eosinophils or a lower smoking history may benefit more from ICS/LABA versus LABA alone as measured by a reduced rate of exacerbations. In terms of eosinophils, this finding is consistent with findings from other studies; however, the validity of the 2.4% cut-off and the impact of smoking history require further investigation.Trial registration numbersNCT01009463;NCT01017952; Post-results.
Conflict of interest between professional medical societies and industry: a cross-sectional study of Italian medical societies’ websites
Authors: Fabbri Alice , Gregoraci Giorgia , Tedesco Dario , Ferretti Filippo , Gilardi Francesco , Iemmi Diego , Lisi Cosima , Lorusso Angelo , Natali Francesca , Shahi Edit , Rinaldi Alessandro 
Published: June 2016

ObjectiveTo describe how Italian medical societies interact with pharmaceutical and medical device industries through an analysis of the information available on their websites.DesignCross sectional study.SettingItaly.Participants154 medical societies registered with the Italian Federation of Medical-Scientific Societies.Main outcome measuresIndicators of industry sponsorship (presence of industry sponsorship in the programme of the last medical societies’ annual conference; presence of manufacturers’ logos on the homepage; presence of industry sponsorship of satellite symposia during the last annual conference).Results131 Italian medical societies were considered. Of these, 4.6% had an ethical code covering relationships with industry on their websites, while 45.6% had a statute that mentioned the issue of conflict of interest and 6.1% published the annual financial report. With regard to industry sponsorship, 64.9% received private sponsorship for their last conference, 29.0% had manufacturers’ logos on their webpage, while 35.9% had industry-sponsored satellite symposia at their last conference. The presence of an ethical code on the societies’ websites was associated with both an increased risk of industry sponsorship of the last conference (relative risk (RR) 1.22, 95% CIs 1.01 to 1.48 after adjustment) and of conferences and/or satellite symposia (RR 1.22, 95% CIs 1.02 to 1.48 after adjustment) but not with the presence of manufacturers’ logos on the websites (RR 1.79, 95% CIs 0.66 to 4.82 after adjustment). No association was observed with the other indicators of governance and transparency.ConclusionsThis survey shows that industry sponsorship of Italian medical societies’ conferences is common, while the presence of a structured regulatory system is not. Disclosure of the amount of industry funding to medical societies is scarce. The level of transparency therefore needs to be improved and the whole relationship between medical societies and industry should be further disciplined in order to avoid any potential for conflict of interest.
Validation of chronic obstructive pulmonary disease (COPD) diagnoses in healthcare databases: a systematic review protocol
Authors: Rimland Joseph M , Abraha Iosief , Luchetta Maria Laura , Cozzolino Francesco , Orso Massimiliano , Cherubini Antonio , Dell'Aquila Giuseppina , Chiatti Carlos , Ambrosio Giuseppe , Montedori Alessandro 
Published: June 2016

IntroductionHealthcare databases are useful sources to investigate the epidemiology of chronic obstructive pulmonary disease (COPD), to assess longitudinal outcomes in patients with COPD, and to develop disease management strategies. However, in order to constitute a reliable source for research, healthcare databases need to be validated. The aim of this protocol is to perform the first systematic review of studies reporting the validation of codes related to COPD diagnoses in healthcare databases.Methods and analysisMEDLINE, EMBASE, Web of Science and the Cochrane Library databases will be searched using appropriate search strategies. Studies that evaluated the validity of COPD codes (such as the International Classification of Diseases 9th Revision and 10th Revision system; the Real codes system or the International Classification of Primary Care) in healthcare databases will be included. Inclusion criteria will be: (1) the presence of a reference standard case definition for COPD; (2) the presence of at least one test measure (eg, sensitivity, positive predictive values, etc); and (3) the use of a healthcare database (including administrative claims databases, electronic healthcare databases or COPD registries) as a data source. Pairs of reviewers will independently abstract data using standardised forms and will assess quality using a checklist based on the Standards for Reporting of Diagnostic accuracy (STARD) criteria. This systematic review protocol has been produced in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) 2015 statement.Ethics and disseminationEthics approval is not required. Results of this study will be submitted to a peer-reviewed journal for publication. The results from this systematic review will be used for outcome research on COPD and will serve as a guide to identify appropriate case definitions of COPD, and reference standards, for researchers involved in validating healthcare databases.Trial registration numberCRD42015029204.
The impact of changing economic conditions on overweight risk among children in California from 2008 to 2012
Authors: Oddo Vanessa M , Nicholas Lauren Hersch , Bleich Sara N , Jones-Smith Jessica C 
Published: June 2016

BackgroundThe recent economic recession represents an opportunity to test whether decreases in economic resources may have deleterious consequences on childhood overweight/obesity risk.MethodsWe investigated the association between indicators of changing macroeconomic conditions from 2008 to 2012 and overweight/obesity risk among school-aged children in California (n=1 741 712) using longitudinal anthropometric measurements. Multivariate regression, with individual and county fixed effects, was used to examine the effects of annual county-level unemployment and foreclosure rates on risk of child overweight/obesity, overall and among subgroups (race/ethnicity, sex, county-level median household income and county-level urban/rural status).ResultsFrom 2008 to 2012, ∼38% of children were overweight/obese and unemployment and foreclosure rates averaged 11% and 6.9%, respectively. A 1-percentage point (pp) increase in unemployment was associated with a 1.4 pp (95% CI 1.3 to 1.5) increase in overweight/obesity risk. Therefore, a child of average weight could expect a 14% increase in their body mass index z-score in association with a 1 pp increase in unemployment during the study period. We found some differences in the magnitude of the effects for unemployment among demographic subgroups, with the largest effects observed for unemployment among American Indians and Pacific Islanders.ConclusionsComparing children to themselves over time, we provide evidence that increases in county-level unemployment are associated with increased overweight/obesity risk. Given that overweight among children with lower economic resources remains a challenge for public health, these findings highlight the importance of policy-level approaches, which aim to mitigate the impact of decreased resources as economic conditions change.