bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pneumococcal Capsules and Their Types: Past, Present, and Future
Authors: Geno K. Aaron , Gilbert Gwendolyn L. , Song Joon Young , Skovsted Ian C. , Klugman Keith P. , Jones Christopher , Konradsen Helle B. , Nahm Moon H. 
Published: June 2015

SUMMARYStreptococcus pneumoniae(the pneumococcus) is an important human pathogen. Its virulence is largely due to its polysaccharide capsule, which shields it from the host immune system, and because of this, the capsule has been extensively studied. Studies of the capsule led to the identification of DNA as the genetic material, identification of many different capsular serotypes, and identification of the serotype-specific nature of protection by adaptive immunity. Recent studies have led to the determination of capsular polysaccharide structures for many serotypes using advanced analytical technologies, complete elucidation of genetic basis for the capsular types, and the development of highly effective pneumococcal conjugate vaccines. Conjugate vaccine use has altered the serotype distribution by either serotype replacement or switching, and this has increased the need to serotype pneumococci. Due to great advances in molecular technologies and our understanding of the pneumococcal genome, molecular approaches have become powerful tools to predict pneumococcal serotypes. In addition, more-precise and -efficient serotyping methods that directly detect polysaccharide structures are emerging. These improvements in our capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcal capsules.
Evaluation of the Long-Term Anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 Immune Responses Generated by the Quadrivalent HPV Vaccine
Authors: Nygård Mari , Saah Alfred , Munk Christian , Tryggvadottir Laufey , Enerly Espen , Hortlund Maria , Sigurdardottir Lara G. , Vuocolo Scott , Kjaer Susanne K. , Dillner Joakim 
Published: June 2015

ABSTRACT

This quadrivalent human papillomavirus (qHPV) (HPV6, -11, -16, and -18) vaccine long-term follow-up (LTFU) study is an ongoing extension of a pivotal clinical study (FUTURE II) taking place in the Nordic region. The LTFU study was designed to evaluate the effectiveness, immunogenicity, and safety of the qHPV vaccine (Gardasil) for at least 10 years following completion of the base study. The current report presents immunogenicity data from testing samples of the year 5 LTFU visit (approximately 9 years after vaccination). FUTURE II vaccination arm subjects, who consented to being followed in the LTFU, donated serum at regular intervals and in 2012. Anti-HPV6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA), and in addition, serum samples from 2012 were analyzed by the total IgG Luminex immunoassay (LIA) (
n
= 1,598). cLIA geometric mean titers (GMTs) remained between 70% and 93% of their month 48 value depending on HPV type. For all HPV types, the lower bound of the 95% confidence interval (CI) for the year 9 GMTs remained above the serostatus cutoff value. The proportion of subjects who remained seropositive based on the IgG LIA was higher than the proportion based on cLIA, especially for anti-HPV18. As expected, the anti-HPV serum IgG and cLIA responses were strongly correlated for all HPV types. Anti-HPV GMTs and the proportion of vaccinated individuals who are seropositive remain high for up to 9 years of follow-up after vaccination.
Rapidec Carba NP Test for Rapid Detection of Carbapenemase Producers
Authors: Poirel Laurent , Nordmann Patrice 
Published: June 2015

ABSTRACT

Performances of the Rapidec Carba NP test (bioMérieux) were evaluated for detection of all types of carbapenemases in
Enterobacteriaceae
,
Acinetobacter baumannii
, and
Pseudomonas aeruginosa
. In less than 2 h after sample preparation, it showed a sensitivity and specificity of 96%. This ready-to-use test is well adapted to the daily need for detection of carbapenemase producers in any laboratory worldwide.
Biology of Zika Virus Infection in Human Skin Cells
Authors: Hamel Rodolphe , Dejarnac Ophélie , Wichit Sineewanlaya , Ekchariyawat Peeraya , Neyret Aymeric , Luplertlop Natthanej , Perera-Lecoin Manuel , Surasombatpattana Pornapat , Talignani Loïc , Thomas Frédéric , Cao-Lormeau Van-Mai , Choumet Valérie , Briant Laurence , Desprès Philippe , Amara Ali , Yssel Hans , Missé Dorothée 
Published: June 2015

ABSTRACT

Zika virus (ZIKV) is an emerging arbovirus of the
Flaviviridae
family, which includes dengue, West Nile, yellow fever, and Japanese encephalitis viruses, that causes a mosquito-borne disease transmitted by the
Aedes
genus, with recent outbreaks in the South Pacific. Here we examine the importance of human skin in the entry of ZIKV and its contribution to the induction of antiviral immune responses. We show that human dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells are permissive to the most recent ZIKV isolate, responsible for the epidemic in French Polynesia. Several entry and/or adhesion factors, including DC-SIGN, AXL, Tyro3, and, to a lesser extent, TIM-1, permitted ZIKV entry, with a major role for the TAM receptor AXL. The ZIKV permissiveness of human skin fibroblasts was confirmed by the use of a neutralizing antibody and specific RNA silencing. ZIKV induced the transcription of Toll-like receptor 3 (TLR3), RIG-I, and MDA5, as well as several interferon-stimulated genes, including OAS2, ISG15, and MX1, characterized by strongly enhanced beta interferon gene expression. ZIKV was found to be sensitive to the antiviral effects of both type I and type II interferons. Finally, infection of skin fibroblasts resulted in the formation of autophagosomes, whose presence was associated with enhanced viral replication, as shown by the use of Torin 1, a chemical inducer of autophagy, and the specific autophagy inhibitor 3-methyladenine. The results presented herein permit us to gain further insight into the biology of ZIKV and to devise strategies aiming to interfere with the pathology caused by this emerging flavivirus.

IMPORTANCE
Zika virus (ZIKV) is an arbovirus belonging to the
Flaviviridae
family. Vector-mediated transmission of ZIKV is initiated when a blood-feeding female
Aedes
mosquito injects the virus into the skin of its mammalian host, followed by infection of permissive cells via specific receptors. Indeed, skin immune cells, including dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells, were all found to be permissive to ZIKV infection. The results also show a major role for the phosphatidylserine receptor AXL as a ZIKV entry receptor and for cellular autophagy in enhancing ZIKV replication in permissive cells. ZIKV replication leads to activation of an antiviral innate immune response and the production of type I interferons in infected cells. Taken together, these results provide the first general insights into the interaction between ZIKV and its mammalian host.
Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility
Authors: Birse Kenzie , Arnold Kelly B. , Novak Richard M. , McCorrister Stuart , Shaw Souradet , Westmacott Garrett R. , Ball Terry B. , Lauffenburger Douglas A. , Burgener Adam 
Published: June 2015

ABSTRACT

The variable infectivity and transmissibility of HIV/SHIV has been recently associated with the menstrual cycle, with particular susceptibility observed during the luteal phase in nonhuman primate models and
ex vivo
human explant cultures, but the mechanism is poorly understood. Here, we performed an unbiased, mass spectrometry-based proteomic analysis to better understand the mucosal immunological processes underpinning this observed susceptibility to HIV infection. Cervicovaginal lavage samples (
n
= 19) were collected, characterized as follicular or luteal phase using days since last menstrual period, and analyzed by tandem mass spectrometry. Biological insights from these data were gained using a spectrum of computational methods, including hierarchical clustering, pathway analysis, gene set enrichment analysis, and partial least-squares discriminant analysis with LASSO feature selection. Of the 384 proteins identified, 43 were differentially abundant between phases (
P
< 0.05, ≥2-fold change). Cell-cell adhesion proteins and antiproteases were reduced, and leukocyte recruitment (interleukin-8 pathway,
P
= 1.41E–5) and extravasation proteins (
P
= 5.62E–4) were elevated during the luteal phase. LASSO/PLSDA identified a minimal profile of 18 proteins that best distinguished the luteal phase. This profile included cytoskeletal elements and proteases known to be involved in cellular movement. Gene set enrichment analysis associated CD4
+
T cell and neutrophil gene set signatures with the luteal phase (
P
< 0.05). Taken together, our findings indicate a strong association between proteins involved in tissue remodeling and leukocyte infiltration with the luteal phase, which may represent potential hormone-associated mechanisms of increased susceptibility to HIV.

IMPORTANCE
Recent studies have discovered an enhanced susceptibility to HIV infection during the progesterone-dominant luteal phase of the menstrual cycle. However, the mechanism responsible for this enhanced susceptibility has not yet been determined. Understanding the source of this vulnerability will be important for designing efficacious HIV prevention technologies for women. Furthermore, these findings may also be extrapolated to better understand the impact of exogenous hormone application, such as the use of hormonal contraceptives, on HIV acquisition risk. Hormonal contraceptives are the most widely used contraceptive method in sub-Saharan Africa, the most HIV-burdened area of the world. For this reason, research conducted to better understand how hormones impact host immunity and susceptibility factors important for HIV infection is a global health priority.
ERdj5 Reductase Cooperates with Protein Disulfide Isomerase To Promote Simian Virus 40 Endoplasmic Reticulum Membrane Translocation
Authors: Inoue Takamasa , Dosey Annie , Herbstman Jeffrey F. , Ravindran Madhu Sudhan , Skiniotis Georgios , Tsai Billy 
Published: June 2015

ABSTRACT
The nonenveloped polyomavirus (PyV) simian virus 40 (SV40) traffics from the cell surface to the endoplasmic reticulum (ER), where it penetrates the ER membrane to reach the cytosol before mobilizing into the nucleus to cause infection. Prior to ER membrane penetration, ER lumenal factors impart structural rearrangements to the virus, generating a translocation-competent virion capable of crossing the ER membrane. Here we identify ERdj5 as an ER enzyme that reduces SV40's disulfide bonds, a reaction important for its ER membrane transport and infection. ERdj5 also mediates human BK PyV infection. This enzyme cooperates with protein disulfide isomerase (PDI), a redox chaperone previously implicated in the unfolding of SV40, to fully stimulate membrane penetration. Negative-stain electron microscopy of ER-localized SV40 suggests that ERdj5 and PDI impart structural rearrangements to the virus. These conformational changes enable SV40 to engage BAP31, an ER membrane protein essential for supporting membrane penetration of the virus. Uncoupling of SV40 from BAP31 traps the virus in ER subdomains called foci, which likely serve as depots from where SV40 gains access to the cytosol. Our study thus pinpoints two ER lumenal factors that coordinately prime SV40 for ER membrane translocation and establishes a functional connection between lumenal and membrane events driving this process.

IMPORTANCE
PyVs are established etiologic agents of many debilitating human diseases, especially in immunocompromised individuals. To infect cells at the cellular level, this virus family must penetrate the host ER membrane to reach the cytosol, a critical entry step. In this report, we identify two ER lumenal factors that prepare the virus for ER membrane translocation and connect these lumenal events with events on the ER membrane. Pinpointing cellular components necessary for supporting PyV infection should lead to rational therapeutic strategies for preventing and treating PyV-related diseases.
Immunoglobulin with High-Titer
In Vitro
Cross-Neutralizing Hepatitis C Virus Antibodies Passively Protects Chimpanzees from Homologous, but Not Heterologous, Challenge
Authors: Bukh Jens , Engle Ronald E. , Faulk Kristina , Wang Richard Y. , Farci Patrizia , Alter Harvey J. , Purcell Robert H. 
Published: June 2015

ABSTRACT

The importance of neutralizing antibodies (NAbs) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06 immunoglobulin from a genotype 1a HCV-infected patient and challenged with genotype strains efficiently neutralized by H06
in vitro
. Genotype 1a NAbs afforded no protection against genotype 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NAb titers waned. However, 6a infection was prevented. The differential
in vivo
neutralization patterns have implications for HCV vaccine development.
Human Cytomegalovirus gH/gL/gO Promotes the Fusion Step of Entry into All Cell Types, whereas gH/gL/UL128-131 Broadens Virus Tropism through a Distinct Mechanism
Authors: Zhou Momei , Lanchy Jean-Marc , Ryckman Brent J. 
Published: June 2015

ABSTRACT
Interaction between gH/gL and the fusion protein gB is likely a conserved feature of the entry mechanism for all herpesviruses. Human cytomegalovirus (HCMV) gH/gL can be bound by gO or by the set of proteins UL128, UL130, and UL131, forming gH/gL/gO and gH/gL/UL128-131. The mechanisms by which these complexes facilitate entry are poorly understood. Mutants lacking UL128-131 replicate well on fibroblasts but fail to enter epithelial/endothelial cells, and this has led to the general assumption that gH/gL/UL128-131 promotes gB-mediated fusion on epithelial/endothelial cells whereas gH/gL/gO provides this function on fibroblasts. This was challenged by observations that gO-null mutants were defective on all of these cell types, suggesting that entry into epithelial/endothelial cells requires both of the gH/gL complexes, but the severe replication defect of the gO mutants precluded detailed analysis. We previously reported that the ratio of gH/gL/gO and gH/gL/UL128-131 in the virion envelope varied dramatically among HCMV strains. Here, we show that strains not only differ in the ratio, but also vary in the total amount of gH/gL in the virion. Cell-type-specific particle-to-PFU ratios of HCMV strains that contained different amounts of gH/gL/gO and gH/gL/UL128-131 were determined. Infection of both fibroblasts and epithelial cells was generally correlated with the abundance of gH/gL/gO, but not with that of gH/gL/UL128-131. The low infectivity of virions rich in gH/gL/UL128-131 but low in gH/gL/gO could be overcome by treatment with the chemical fusogen polyethylene glycol (PEG), strongly arguing that gH/gL/gO provides the conserved herpesvirus gH/gL entry function of promoting gB-mediated fusion for entry into all cell types, whereas gH/gL/UL128-131 acts through a distinct mechanism to allow infection of select cell types.

IMPORTANCE
The functions of HCMV gH/gL complexes in entry are unclear. Unlike the well-studied Epstein-Barr virus (EBV), where gH/gL and gH/gL/gp42 complexes both seem capable of promoting gB fusion during entry into different cell types, our studies here suggest that for HCMV, gH/gL/gO promotes gB fusion on all cell types, whereas gH/gL/UL128-131 broadens virus tropism through a distinct, as yet unknown mechanism. To our knowledge, this is the first suggestion of a herpesvirus gH/gL that does not act by promoting gB fusion, which might make HCMV a useful model to study the fundamental mechanisms by which herpesvirus gH/gL regulates gB fusion. Moreover, gH/gL/UL128-131 is a candidate vaccine target. Our findings help to explain the cell-type-dependent virus neutralization exhibited by anti-gH/gL/UL128-131 antibodies and underscore the importance of gH/gL/gO as another important part of vaccine or therapeutic strategies.
The risk of copper deficiency in patients prescribed zinc supplements
Authors: Duncan Andrew , Yacoubian Calum , Watson Neil , Morrison Ian 
Published: June 2015

AimsIn high doses zinc may cause copper deficiency, a diagnosis that is often missed resulting in anaemia, neutropenia and irreversible neurological symptoms. The aim of this study was to assess if zinc deficiency is erroneously diagnosed by misinterpretation of plasma zinc concentrations and whether copper deficiency is induced in patients prescribed zinc.MethodsCasenotes of 70 patients prescribed zinc were scrutinised. Plasma concentrations of zinc, copper, C reactive protein and albumin were recorded from the laboratory database.Results62% of patients were prescribed zinc at doses sufficient to cause copper deficiency. In 48% of the patients, plasma zinc concentrations were low as a probable result of hypoalbuminaemia or the systemic inflammatory response rather than deficiency. Awareness of copper deficiency was lacking; it was only documented as a possible side effect in one patient and plasma copper was measured in only two patients prescribed zinc. 9% of patients developed unexplained anaemia and 7% developed neurological symptoms typical of copper deficiency.ConclusionsZinc deficiency is frequently misdiagnosed on the basis of low plasma zinc concentrations. The potential risk of copper deficiency developing in patients prescribed high doses of zinc is apparently infrequently considered. It is probable that a significant minority of patients prescribed with high doses of zinc develop iatrogenic copper deficiency.
National surveillance for type 1, type 2 diabetes and prediabetes among children and adolescents: a population-based study (SAUDI-DM)
Authors: Al-Rubeaan Khalid 
Published: June 2015

BackgroundThere is a paucity of data on the national prevalence of diabetes and prediabetes among youth. The Saudi Abnormal Glucose Metabolism and Diabetes Impact Study (SAUDI-DM) was used to assess the prevalence of type 1 and type 2 diabetes as well as impaired fasting glucose (IFG) among children and adolescents.MethodsSociodemographic, anthropometric and clinical data were collected through a nationwide household randomly selected 23 523 children and adolescents aged ≤18 years. Known participants with diabetes were classified according to their diabetes type, while participants without diabetes were subjected to fasting plasma glucose assessment and patients with diabetes were identified using the American Diabetes Association (ADA) criteria. All the studied participants were tested for lipid parameters. Multivariate logistic regression analysis was used to assess different risk factors.ResultsThe overall prevalence of diabetes was 10.84%, of which 0.45% were known type 1 and type 2 patients with diabetes and 10.39% were either newly identified cases of diabetes (4.27%) or IFG (6.12%) with more than 90% of the participants with diabetes being unaware of their disease. The prevalence of known type 1 and type 2 diabetes as well as the newly identified cases was higher than what has been reported internationally. Age, male gender, obesity, urban residency, high family income and presence of dyslipidaemia were found to be significant risk factors for diabetes and IFG.ConclusionsDiabetes and IFG are highly prevalent in this society with the majority of the patients being unaware of their disease, which warrants urgent adoption of early detection, treatment and prevention programmes.
The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas
Authors: Nussinov Ruth , Muratcioglu Serena , Tsai Chung-Jung , Jang Hyunbum , Gursoy Attila , Keskin Ozlem 
Published: June 2015

Abstract
KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca2+/calmodulin promote PI3Kα/Akt signaling, and suggest how. The elevated calcium levels clinically observed in adenocarcinomas may explain calmodulin's involvement in recruiting and stimulating PI3Kα through interaction with its n/cSH2 domains as well as K-Ras4B; importantly, it also explains why K-Ras4B specifically is a key player in ductal carcinomas, such as pancreatic (PDAC), colorectal (CRC), and lung cancers. We hypothesize that calmodulin recruits and helps activate PI3Kα at the membrane, and that this is the likely reason for Ca2+/calmodulin dependence in adenocarcinomas. Calmodulin can contribute to initiation/progression of ductal cancers via both PI3Kα/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras4B/MAPK pathway and calmodulin/PI3Kα binding in a K-Ras4B/calmodulin/PI3Kα trimer could be a promising adenocarcinoma-specific therapeutic strategy. Mol Cancer Res; 13(9); 1265–73. ©2015 AACR.
A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma
Authors: Mirabello Lisa , Koster Roelof , Moriarity Branden S. , Spector Logan G. , Meltzer Paul S. , Gary Joy , Machiela Mitchell J. , Pankratz Nathan , Panagiotou Orestis A. , Largaespada David , Wang Zhaoming , Gastier-Foster Julie M. , Gorlick Richard , Khanna Chand , de Toledo Silvia Regina Caminada , Petrilli Antonio S. , Patiño-Garcia Ana , Sierrasesúmaga Luis , Lecanda Fernando , Andrulis Irene L. , Wunder Jay S. , Gokgoz Nalan , Serra Massimo , Hattinger Claudia , Picci Piero , Scotlandi Katia , Flanagan Adrienne M. , Tirabosco Roberto , Amary Maria Fernanda , Halai Dina , Ballinger Mandy L. , Thomas David M. , Davis Sean , Barkauskas Donald A. , Marina Neyssa , Helman Lee , Otto George M. , Becklin Kelsie L. , Wolf Natalie K. , Weg Madison T. , Tucker Margaret , Wacholder Sholom , Fraumeni Joseph F. , Caporaso Neil E. , Boland Joseph F. , Hicks Belynda D. , Vogt Aurelie , Burdett Laurie , Yeager Meredith , Hoover Robert N. , Chanock Stephen J. , Savage Sharon A. 
Published: June 2015

Abstract
Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10−9; OR, 2.43; 95% confidence interval, 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene.
Significance: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma. Cancer Discov; 5(9); 920–31. ©2015 AACR.
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