bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure, Immunogenicity, and Protective Mechanism of an Engineered Enterovirus 71-Like Particle Vaccine Mimicking 80S Empty Capsid
Authors: Wang Xiaoli , Ku Zhiqiang , Zhang Xiang , Ye Xiaohua , Chen Jinhuan , Liu Qingwei , Zhang Wei , Zhang Chao , Fu Zhenglin , Jin Xia , Cong Yao , Huang Zhong 
Published: October 2017

ABSTRACT

Enterovirus 71 (EV71) is the major causative agent of severe hand, foot, and mouth disease, which affects millions of young children in the Asia-Pacific region annually. In this study, we engineered a novel EV71 virus-like particle (VLP) that lacks VP4 (therefore designated VLP
ΔVP4
) and investigated its structure, antigenicity, and vaccine potential. The cryo-electron microscopy (cryo-EM) structure of VLP
ΔVP4
was reconstructed to 3.71-Å resolution. Results from structural and biochemical analyses revealed that VLP
ΔVP4
resembles the end product of the viral uncoating process, the 80S empty capsid. VLP
ΔVP4
is able to elicit high-titer neutralizing antibodies and to fully protect mice against lethal viral challenge. Mechanistic studies showed that, at the cellular level, the anti-VLP
ΔVP4
sera exert neutralization effects at both pre- and postattachment stages by inhibiting both virus attachment and internalization, and at the molecular level, the antisera can block multiple interactions between EV71 and its key receptors. Our study gives a better understanding of EV71 capsid assembly and provides important information for the design and development of new-generation vaccines for EV71, and perhaps for other enteroviruses, as well.

IMPORTANCE
Enterovirus 71 (EV71) infection may lead to severe hand, foot, and mouth disease, with significant morbidity and mortality. Knowledge regarding EV71 particle assembly remains limited. Here, we report the generation and characterization of a novel EV71 virus-like particle that lacks the VP4 capsid subunit protein. This particle, termed VLP
ΔVP4
, structurally mimics the 80S empty capsid, which is the end stage of EV71 uncoating. We further show that VLP
ΔVP4
exhibits desirable immunogenicity and protective efficacy in proof-of-concept studies. In addition, the inhibitory mechanisms of the VLP
ΔVP4
-induced antibodies are unraveled at both the cellular and molecular levels. Our work provides the first evidence of picornaviral particle assembly in the complete absence of VP4 and identifies VLP
ΔVP4
as an improved EV71 vaccine candidate with desirable traits. These findings not only enhance our understanding of particle assembly and uncoating of picornaviruses, but also provide important information for structure-guided vaccine design for EV71 and other enteroviruses.
The Postfusion Structure of the Heartland Virus Gc Glycoprotein Supports Taxonomic Separation of the Bunyaviral Families Phenuiviridae and Hantaviridae
Authors: Zhu Yaohua , Wu Yan , Chai Yan , Qi Jianxun , Peng Ruchao , Feng Wen-Hai , Gao George Fu 
Published: October 2017

ABSTRACT

Heartland virus
(HRTV) is an emerging human pathogen that belongs to the newly defined family
Phenuiviridae
, order
Bunyavirales
. Gn and Gc are two viral surface glycoproteins encoded by the M segment and are required for early events during infection. HRTV delivers its genome into the cytoplasm by fusion of the viral envelope and endosomal membranes under low-pH conditions. Here, we describe the crystal structure of HRTV Gc in its postfusion conformation. The structure shows that Gc displays a typical class II fusion protein conformation, and the overall structure is identical to severe fever with thrombocytopenia syndrome virus (SFTSV) Gc, which also belongs to the
Phenuiviridae
family. However, our structural analysis indicates that the hantavirus Gc presents distinct features in the aspects of subdomain orientation,
N
-linked glycosylation, the interaction pattern between protomers, and the fusion loop conformation. This suggests their family-specific subunit arrangement during the fusogenic process and supports the recent taxonomic revision of bunyaviruses. Our results provide insights into the comprehensive comparison of class II membrane fusion proteins in two bunyavirus families, yielding valuable information for treatments against these human pathogens.

IMPORTANCE
HRTV is an insect-borne virus found in America that can infect humans. It belongs to the newly defined family
Phenuiviridae
, order
Bunyavirales
. HRTV contains three single-stranded RNA segments (L, M, and S). The M segment of the virus encodes a polyprotein precursor that is cleaved into two glycoproteins, Gn and Gc. Gc is a fusion protein facilitating virus entry into host cells. Here, we report the crystal structure of the HRTV Gc protein. The structure displays a typical class II fusion protein conformation. Comparison of HRTV Gc with a recently solved structure of another bunyavirus Gc revealed that these Gc structures display a newly defined family specificity, supporting the recent International Committee on Taxonomy of Viruses reclassification of the bunyaviruses. Our results expand the knowledge of bunyavirus fusion proteins and help us to understand bunyavirus characterizations. This study provides useful information to improve protection against and therapies for bunyavirus infections.
Residues 28 to 39 of the Extracellular Loop 1 of Chicken Na
+
/H
+
Exchanger Type I Mediate Cell Binding and Entry of Subgroup J Avian Leukosis Virus
Authors: Guan Xiaolu , Zhang Yao , Yu Mengmeng , Ren Chaoqi , Gao Yanni , Yun Bingling , Liu Yongzhen , Wang Yongqiang , Qi Xiaole , Liu Changjun , Cui Hongyu , Zhang Yanping , Gao Li , Li Kai , Pan Qing , Zhang Baoshan , Wang Xiaomei , Gao Yulong 
Published: October 2017

ABSTRACT

Chicken Na
+
/H
+
exchanger type I (chNHE1), a multispan transmembrane protein, is a cellular receptor of the subgroup J avian leukosis virus (ALV-J). To identify the functional determinants of chNHE1 responsible for the ALV-J receptor activity, a series of chimeric receptors was created by exchanging the extracellular loops (ECL) of human NHE1 (huNHE1) and chNHE1 and by ECL replacement with a hemagglutinin (HA) tag. These chimeric receptors then were used in binding and entry assays to map the minimal ALV-J gp85-binding domain of chNHE1. We show that ECL1 of chNHE1 (chECL1) is the critical functional ECL that interacts directly with ALV-J gp85; ECL3 is also involved in ALV-J gp85 binding. Amino acid residues 28 to 39 of the N-terminal membrane-proximal region of chECL1 constitute the minimal domain required for chNHE1 binding of ALV-J gp85. These residues are sufficient to mediate viral entry into ALV-J nonpermissive cells. Point mutation analysis revealed that A30, V33, W38, and E39 of chECL1 are the key residues mediating the binding between chNHE1 and ALV-J gp85. Further, the replacement of residues 28 to 39 of huNHE1 with the corresponding chNHE1 residues converted the nonfunctional ALV-J receptor huNHE1 to a functional one. Importantly, soluble chECL1 and huECL1 harboring chNHE1 residues 28 to 39 both could effectively block ALV-J infection. Collectively, our findings indicate that residues 28 to 39 of chNHE1 constitute a domain that is critical for receptor function and mediate ALV-J entry.

IMPORTANCE
chNHE1 is a cellular receptor of ALV-J, a retrovirus that causes infections in chickens and serious economic losses in the poultry industry. Until now, the domains determining the chNHE1 receptor function remained unknown. We demonstrate that chECL1 is critical for receptor function, with residues 28 to 39 constituting the minimal functional domain responsible for chNHE1 binding of ALV-J gp85 and efficiently mediating ALV-J cell entry. These residues are located in the membrane-proximal region of the N terminus of chECL1, suggesting that the binding site of ALV-J gp85 on chNHE1 is probably located on the apex of the molecule; the receptor-binding mode might be different from that of retroviruses. We also found that soluble chECL1, as well as huECL1 harboring chNHE1 residues 28 to 39, effectively blocked ALV-J infection. These findings contribute to a better understanding of the ALV-J infection mechanism and also provide new insights into the control strategies for ALV-J infection.
Tuning of the Lethal Response to Multiple Stressors with a Single-Site Mutation during Clinical Infection by
Staphylococcus aureus
Authors: Kumar Krishan , Chen John , Drlica Karl , Shopsin Bo 
Published: October 2017

ABSTRACT

The
agr
system of
Staphylococcus aureus
promotes invasion of host tissues, and as expected, agents that block
agr
quorum sensing have anti-infective properties. Paradoxically,
agr
-defective mutants are frequently recovered from patients, especially those persistently infected with
S. aureus
. We found that an
agr
deficiency increased survival of cultured bacteria during severe stress, such as treatment with gentamicin, ciprofloxacin, heat, or low pH. With daptomycin, deletion of
agr
decreased survival. Therefore,
agr
activity can be either detrimental or protective, depending on the type of lethal stress. Deletion of
agr
had no effect on the ability of the antimicrobials to block bacterial growth, indicating that
agr
effects are limited to lethal action. Thus, the effect of an
agr
deletion is on bacterial tolerance, not resistance. For gentamicin and daptomycin, activity can be altered by
agr
-regulated secreted factors. For ciprofloxacin, a detrimental function was downregulation of glutathione peroxidase (
bsaA
), an enzyme responsible for defense against oxidative stress. Deficiencies in
agr
and
bsaA
were epistatic for survival, consistent with
agr
having a destructive role mediated by reactive oxygen species. Enhanced susceptibility to lethal stress by wild-type
agr
, particularly antimicrobial stress, helps explain why inactivating mutations in
S. aureus agr
commonly occur in hospitalized patients during infection. Moreover, the
agr
quorum-sensing system of
S. aureus
provides a clinically relevant example in which a single-step change in the response to severe stress alters the evolutionary path of a pathogen during infection.

IMPORTANCE
When phenotypes produced in response to an environmental stress are inadequate to buffer against that stress, changes that do buffer may become genetically encoded by natural selection. A clinically relevant example is seen with
S. aureus
mutants that are deficient in the key virulence regulator
agr
. Paradoxically, defects in
agr
are selected during serious hospital infection and have been associated with worse outcome. The current work helps resolve this paradox:
agr
mutants are often less readily killed by lethal stressors without affecting MIC, a phenomenon known as tolerance. Our results indicate that tolerance, which would not be detected as resistance, can be selected in clinical settings. The data also support the ideas that (i)
S. aureus
broadly hedges against environmental change and stress through genome plasticity, (ii) reactive oxygen can be involved in the self-destructive response in bacteria, and (iii) therapeutic targeting of
agr
and virulence can be counterproductive.
Prevalence of key breastfeeding indicators in 29 sub-Saharan African countries: a meta-analysis of demographic and health surveys (2010–2015)
Authors: Issaka Abukari Ibrahim , Agho Kingsley Emwinyore , Renzaho Andre MN 
Published: October 2017

ObjectivesTo carry out a meta-analysis to assess the prevalence of four key breastfeeding indicators in four subregions of 29 sub-Saharan African countries.Design, settings and participantsThe 29 countries were categorised into four subregions, and using cross-sectional data from the most recent Demographic and Health Surveys (2010–2015) of these countries prevalence of each of four key breastfeeding indicators was estimated for each of the subregions by carrying out a meta-analysis. Due to the presence of significant heterogeneity among the various surveys (I2>50%), a random-effect analytic model was used, and sensitivity analysis was performed to examine the effects of outliers.Main outcome variablesEarly initiation of breast feeding, exclusive breast feeding, predominant breast feeding and bottle feeding.ResultsThe overall prevalence ofearly initiation of breast feedingvaried between a lowest of 37.84% (95% CI 24.62 to 51.05) in Central Africa to a highest of 69.31% (95% CI 67.65 to 70.97) in Southern Africa; the overall prevalence ofexclusive breast feedingranged between a lowest of 23.70% (95% CI 5.37 to 42.03) in Central Africa to a highest of 56.57% (95% CI 53.50 to 59.95) in Southern Africa; the overall prevalence ofpredominant breast feedingranged between a lowest of 17.63% (95% CI 12.70 to 22.55) in East Africa and a highest of 46.37% (95% CI 37.22 to 55.52) in West Africa; while the prevalence ofbottle feedingvaried between a lowest of 8.17% (95% CI 5.51 to 10.84) in West Africa and a highest of 30.05% (95% CI 28.42 to 31.69) in Southern Africa.ConclusionsWest Africa and Central Africa recorded lower overall prevalence ofearly initiation of breast feedingandexclusive breast feedingthan the WHO’s recommended target of 50% by the year 2025. Intervention for improved breastfeeding practices in sub-Saharan Africa should target West and Central Africa, while intervention to minimise bottle feeding should target Southern Africa.
Prevalence and general health status of people with intellectual disabilities in Scotland: a total population study
Authors: Hughes-McCormack Laura Anne , Rydzewska Ewelina , Henderson Angela , MacIntyre Cecilia , Rintoul Julie , Cooper Sally-Ann 
Published: October 2017

BackgroundPrevalence of intellectual disabilities varies considerably between studies. People with intellectual disabilities experience health inequalities, but most studies comprise small or incomplete populations. We investigated in a whole country population the (1) prevalence of intellectual disabilities and (2) general health status compared with the general population.MethodData were from Scotland’s Census, 2011. We calculated the prevalence of intellectual disabilities, reported general health status of people with and without intellectual disabilities and the extent of health-related limitations to daily activities. We conducted logistic regressions to determine the ORs of intellectual disabilities predicting poor health and associations with age and gender.ResultsOf Scotland’s 5 295 403 population, 26 349 (0.5%) had intellectual disabilities; 15 149 (57.5%) were males and 11 200 (42.5%) were females; 5234 (0.6%) were children/youth (0–15) and 21 115 (0.5%) were adults (16–75+ years). Identification of intellectual disabilities rises until age 5 years, with a further small rise by age 9 years. Children and adults with intellectual disabilities reported more poor health (47.9% and 40.3%) than the general population (2.1% and 13.8%) and were more limited in activities by their health. Intellectual disabilities had an OR of 43.2 (95% CI 40.8 to 45.7) in predicting poor health; the influence of increasing age on poor health was markedly interacted by presence of intellectual disabilities, likely to be due to a ‘healthy survivor’ effect within the intellectual disabilities population.ConclusionPeople with intellectual disabilities have poorer general health than other people, especially children and young people. Accurate information on population prevalence and health status is essential to plan appropriate resources.
Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome
Authors: Renaux-Petel Mariette , Charbonnier Françoise , Théry Jean-Christophe , Fermey Pierre , Lienard Gwendoline , Bou Jacqueline , Coutant Sophie , Vezain Myriam , Kasper Edwige , Fourneaux Steeve , Manase Sandrine , Blanluet Maud , Leheup Bruno , Mansuy Ludovic , Champigneulle Jacqueline , Chappé Céline , Longy Michel , Sévenet Nicolas , Paillerets Brigitte Bressac-de , Guerrini-Rousseau Léa , Brugières Laurence , Caron Olivier , Sabourin Jean-Christophe , Tournier Isabelle , Baert-Desurmont Stéphanie , Frébourg Thierry , Bougeard Gaëlle 
Published: October 2017

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.
Prospective, multicentre study of external ventricular drainage-related infections in the UK and Ireland
Authors: Jamjoom Aimun A B , Joannides Alexis J , Poon Michael Tin-Chung , Chari Aswin , Zaben Malik , Abdulla Mutwakil A H , Roach Joy , Glancz Laurence J , Solth Anna , Duddy John , Brennan Paul M , Bayston Roger , Bulters Diederik O , Mallucci Conor L , Jenkinson Michael D , Gray William P , Kandasamy Jothy , Hutchinson Peter J , Kolias Angelos G , Ahmed Aminul I 
Published: October 2017

ObjectivesExternal ventricular drain (EVD) insertion is a common neurosurgical procedure. EVD-related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the UK and Ireland and determine key factors influencing the infection risk.MethodsA prospective multicentre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox regression model was used for multivariate analysis to calculate HR.ResultsA total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in situ for 4700 days (median 8 days; IQR 4–13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days (HR=2.47 (1.12–5.45); p=0.03), regular sampling (daily sampling (HR=4.73 (1.28–17.42), p=0.02) and alternate day sampling (HR=5.28 (2.25–12.38); p<0.01). There was no association between catheter type or tunnelling distance and ERI.ConclusionsIn the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types.
Amyloid-PET burden and regional distribution in cerebral amyloid angiopathy: a systematic review and meta-analysis of biomarker performance
Authors: Charidimou Andreas , Farid Karim , Tsai Hsin-Hsi , Tsai Li-Kai , Yen Rouh-Fang , Baron Jean-Claude 
Published: October 2017

IntroductionWe performed a meta-analysis to synthesise current evidence on amyloid-positron emission tomography (PET) burden and presumed preferential occipital distribution in sporadic cerebral amyloid angiopathy (CAA).MethodsIn a PubMed systematic search, we identified case–control studies with extractable data on global and occipital-to-global amyloid-PET uptake in symptomatic patients with CAA (per Boston criteria) versus control groups (healthy participants or patients with non-CAA deep intracerebral haemorrhage) and patients with Alzheimer’s disease. To circumvent PET studies’ methodological variation, we generated and used ‘fold change’, that is, ratio of mean amyloid uptake (global and occipital-to-global) of CAA relative to comparison groups. Amyloid-PET uptake biomarker performance was then quantified by random-effects meta-analysis on the ratios of the means. A ratio >1 indicates that amyloid-PET uptake (global or occipital/global) is higher in CAA than comparison groups, and a ratio <1 indicates the reverse.ResultsSeven studies, including 106 patients with CAA (>90% with probable CAA) and 138 controls (96 healthy elderly, 42 deep intracerebral haemorrhage controls) and 72 patients with Alzheimer’s disease, were included. Global amyloid-PET ratio between patients with CAA and controls was above 1, with an average effect size of 1.18 (95% CI 1.08 to 1.28; p<0.0001). Occipital-to-global amyloid-PET uptake ratio did not differ between patients with CAA versus patients with deep intracerebral haemorrhage or healthy controls. By contrast, occipital-to-global amyloid-PET uptake ratio was above 1 in patients with CAA versus those with Alzheimer’s disease, with an average ratio of 1.10 (95% CI 1.03 to 1.19; p=0.009) and high statistical heterogeneity.ConclusionsOur analysis provides exploratory actionable data on the overall effect sizes and strength of amyloid-PET burden and distribution in patients with CAA, useful for future larger studies.
Associates and predictors of pleurisy or pericarditis in SLE
Authors: Ryu Seungwon , Fu Wei , Petri Michelle A 
Published: October 2017

Background/PurposeSerositis is one of both ACR and SLICC classification criteria for systemic lupus erythematosus (SLE) and a common type of extra renal flare. However, little is known about clinical or immunological associations of pleurisy or pericarditis. The aim of this study is to analyze associates and predictors of pleurisy versus pericarditis in Caucasians and African Americans with SLE.Methods2,390 SLE patients in the Hopkins Lupus Cohort were analyzed for demographic, clinical and serologic associates of pleurisy or pericarditis, defined using the SELENA revision of the SLE Disease Activity Index (SLEDAI). The cross-sectional and prospective study using either univariate or multivariate analysis were performed to evaluate the associates of serositis in SLE. We reported associates with a p-value of less than 0.05 for pleurisy or pericarditis.Results43% had pleurisy and 22% had pericarditis. African-American ethnicity was a predictive factor for new pericarditis. Hemolytic anemia, proteinuria, lymphadenopathy and anti-Sm were predictive only of pericarditis, whereas pulmonary fibrosis and GI infarction were predictive only of pleurisy. Fever, Raynaud’s syndrome, and anti-DNA were predictors for both pericarditis and pleurisy.ConclusionOur study provides further insights into the associates of pleurisy and pericarditis in SLE. Predictors of pleurisy and pericarditis are shown for the first time. The long term consequences from the cross-sectional analysis gives a lesson that serositis in SLE should not be considered benign.