bluuebunny/crossref_metadata_2025 huggingface dataset:
Agronomic and chemical performance of field‐grown tobacco engineered for triterpene and methylated triterpene metabolism
Authors: Jiang Zuodong , Kempinski Chase , Kumar Santosh , Kinison Scott , Linscott Kristin , Nybo Eric , Janze Sarah , Wood Connie , Chappell Joe
Published: October 2017

Squalene is a linear intermediate to nearly all classes of triterpenes and sterols and is itself highly valued for its use in wide range of industrial applications. Another unique linear triterpene is botryococcene and its methylated derivatives generated by the alga Botryococcus braunii race B, which are progenitors to fossil fuel deposits. Production of these linear triterpenes was previously engineered into transgenic tobacco by introducing the key steps of triterpene metabolism into the particular subcellular compartments. In this study, the agronomic characteristics (height, biomass accumulation, leaf area), the photosynthetic capacity (photosynthesis rate, conductance, internal CO2 levels) and triterpene content of select lines grown under field conditions were evaluated for three consecutive growing seasons. We observed that transgenic lines targeting enzymes to the chloroplasts accumulated 50–150 times more squalene than the lines targeting the enzymes to the cytoplasm, without compromising growth or photosynthesis. We also found that the transgenic lines directing botryococcene metabolism to the chloroplast accumulated 10‐ to 33‐fold greater levels than the lines where the same enzymes were targeted to in the cytoplasm. However, growth of these high botryococcene accumulators was highly compromised, yet their photosynthesis rates remained unaffected. In addition, in the transgenic lines targeting a triterpene methyltransferase (TMT) to the chloroplasts of high squalene accumulators, 55%–65% of total squalene was methylated, whereas in the lines expressing a TMT in the cytoplasm, only 6%–13% of squalene was methylated. The growth of these methylated triterpene‐accumulating lines was more compromised than that of nonmethylated squalene lines.
Clinical profile of congenital rubella syndrome in Yogyakarta, Indonesia
Authors: Herini Elisabeth S. , Gunadi  , Triono Agung , Wirastuti Fita , Iskandar Kristy , Mardin Niprida , Soenarto Yati
Published: October 2017

Background

Congenital rubella syndrome (CRS) has many severe neurological manifestations and other systemic consequences. Although various studies have been done in Indonesia, there are no conclusive results on CRS incidence. The aim of this study was therefore to investigate the incidence, clinical manifestations and outcomes of CRS in Yogyakarta, Indonesia.

Methods

A descriptive study involving a review of congenital anomalies associated with CRS was carried out at Dr Sardjito Hospital, Yogyakarta, Indonesia, from July 2008 to June 2013. CRS was categorized according to the World Health Organization (WHO) classification. This study involved children aged <1 year old, and was conducted at the outpatient clinic, pediatric and neonatology wards.

Results

A total of 201 children met the criteria for suspected CRS during the 5 year study. Of those patients, 6% were classified as having laboratory‐confirmed CRS, 21.4% as having clinically compatible CRS, and 72.6% as having discarded CRS (i.e. a suspected case that does not meet the criteria for CRS). The estimated incidence of laboratory‐confirmed CRS and laboratory‐confirmed and clinically compatible CRS in Yogyakarta, Indonesia during the study period was 0.05:1,000 and 0.25:1,000 live births, respectively. Of the laboratory‐confirmed CRS patients, 83.3% of children had congenital heart disease (CHD), 75% had hearing impairment, 66.7% had congenital cataract and 50% had microcephaly. Furthermore, none of the mothers was vaccinated against rubella.

Conclusions

The incidence of CRS in infants in Yogyakarta Indonesia is considered high, with most clinical manifestations being CHD, hearing impairment and congenital cataract. This emphasizes the necessity for epidemiological study of CRS in other hospitals and the importance of establishing a national rubella vaccination program in Indonesia.
The Modern Profile of Tuberculosis: Developing the TB Social Survey to understand contemporary social patterns in tuberculosis
Authors: Noppert Grace A. , Clarke Philippa
Published: October 2017

Social disparities in tuberculosis have been documented for decades, yet to date there has not been a comprehensive study to examine the contemporary causes of these disparities. Local public health departments, and particularly public health nursing staff are charged with delivering directly observed therapy to individuals with tuberculosis disease. As a result of the frequency and duration of treatment, practitioners delivering therapy are often well‐acquainted with the lives and challenges of their constituents. Thus, through these practitioners there exists a deep repository of knowledge on the drivers of social disparities in tuberculosis disease. Partnering with local public health departments, we developed a survey instrument aimed at understanding the social profile of individuals with tuberculosis disease in metropolitan Detroit, Michigan. We discuss the development and implementation of the survey instrument as well as challenges in developing partnerships between academic researchers and local public health practitioners. This study can serve as a framework for both academic researchers and public health practitioners interested in addressing social disparities in infectious disease.
Unexpectedly high genetic diversity and divergence among populations of the apomictic Neotropical tree Miconia albicans
Authors: Dias A. C. C. , Serra A. C. , Sampaio D. S. , Borba E. L. , Bonetti A. M. , Oliveira P. E.
Published: October 2017

Since tropical trees often have long generation times and relatively small reproductive populations, breeding systems and genetic variation are important for population viability and have consequences for conservation. Miconia albicans is an obligate, diplosporous, apomictic species widespread in the Brazilian Cerrado, the savanna areas in central Brazil and elsewhere in the Neotropics. The genetic variability would be, theoretically, low within these male‐sterile and possibly clonal populations, although some variation would be expected due to recombination during restitutional meiosis.

We used ISSR markers to assess genetic diversity of M. albicans and to compare with other tropical trees, including invasive species of Melastomataceae. A total of 120 individuals from six populations were analysed using ten ISSR primers, which produced 153 fully reproducible fragments.

The populations of M. albicans presented mean Shannon's information index (I) of 0.244 and expected heterozygosity (He) of 0.168. Only two pairs of apparently clonal trees were identified, and genetic diversity was relatively high. A hierarchical amova for all ISSR datasets showed that 74% of the variance was found among populations, while only 26% of the variance was found within populations of this species. Multivariate and Bayesian analyses indicated marked separation between the studied populations.

The genetic diversity generated by restitutional meiosis, polyploidy and possibly other genome changes may explain the morpho‐physiological plasticity and the ability of these plants to differentiate and occupy such a wide territory and different environmental conditions. Producing enormous amounts of bird‐dispersed fruits, M. albicans possess weedy potential that may rival other Melastomataceae alien invaders.
An Assessment of the Causes of the Errors in the 2015 UK Gseneral Election Opinion Polls
Authors: Sturgis Patrick , Kuha Jouni , Baker Nick , Callegaro Mario , Fisher Stephen , Green Jane , Jennings Will , Lauderdale Benjamin E. , Smith Patten
Published: October 2017

The opinion polls that were undertaken before the 2015 UK general election underestimated the Conservative lead over Labour by an average of 7 percentage points. This collective failure led politicians and commentators to question the validity and utility of political polling and raised concerns regarding a broader public loss of confidence in survey research. We assess the likely causes of the 2015 polling errors. We begin by setting out a formal account of the statistical methodology and assumptions that are required for valid estimation of party vote shares by using quota sampling. We then describe the current approach of polling organizations for estimating sampling variability and suggest a new method based on bootstrap resampling. Next, we use poll microdata to assess the plausibility of different explanations of the polling errors. Our conclusion is that the primary cause of the polling errors in 2015 was unrepresentative sampling.
Financial Development, Growth Volatility and Information Asymmetry in Sub‐Saharan Africa: Does Law Matter?
Authors: Ibrahim Muazu , Alagidede Paul
Published: October 2017

We re‐examine the law–finance theory relying on 33 countries in sub‐Saharan Africa over the period 2004–2011. Our evidence suggests that legal origin significantly explains cross‐country differences in financial development and economic volatility. More importantly, relative to civil law, English common law countries and those in Southern Africa have higher financial sector development both in terms of financial activity and banking efficiency on the back of lower volatility. While private credit bureau positively (negatively) affects financial development (economic volatility) with economically large impact for English legal legacy countries, the latter effect is contingent on the form of legal origin suggesting that, the establishment of information sharing offices per se may be insufficient in taming growth vagaries.
Home environmental influences on children's language and reading skills in a genetically sensitive design: Are socioeconomic status and home literacy environment environmental mediators and moderators?
Authors: Chow Bonnie Wing‐Yin , Ho Connie Suk‐Han , Wong Simpson W. L. , Waye Mary M. Y. , Zheng Mo
Published: October 2017

This twin study examined how family socioeconomic status (SES) and home literacy environment (HLE) contributes to Chinese language and reading skills. It included 312 Chinese twin pairs aged 3 to 11. Children were individually administered tasks of Chinese word reading, receptive vocabulary and reading‐related cognitive skills, and nonverbal reasoning ability. Information on home environment was collected through parent‐reported questionnaires. Results showed that SES and HLE mediated shared environmental influences but did not moderate genetic influences on general language and reading abilities. Also, SES and HLE mediated shared environmental contributions to receptive vocabulary and syllable and rhyme awareness, but not orthographic skills. The findings of this study add to past twin studies that focused on alphabetic languages, suggesting that these links could be universal across languages. They also extend existing findings on SES and HLE's contributions to reading‐related cognitive skills.
A Geo‐spatial study for analysing temporal responses of NDVI to rainfall
Authors: Kundu Arnab , Denis DM , Patel NR , Dutta Dipanwita
Published: October 2017

Climate change has become a serious concern worldwide owing to its multifaceted impact upon the physical as well as socio‐economic environment (IPCC, 2013). Vulnerability to climate change is much higher in the developing countries like India, where the economy is mainly agro‐based and productivity from the agricultural sector is dependent upon summer monsoon rainfall. Hence, assessing the quantitative relationship between vegetation patterns and climatic influence has become an increasingly important study conducted on regional and global scales. As vegetation cover plays a key role in conserving the natural environment, studying the spatio‐temporal trend of vegetation is crucial in identifying changes in the natural environment. We analysed the spatial responses of SPOT‐VGT NDVI to TRMM based rainfall during a sixteen year period (1998–2013) in the Bundelkhand region of Central India. The Normalized Difference Vegetation Index (NDVI) has proven to be a strong indicator of global vegetation productivity. Among climatic factors, rainfall robustly influences both spatial and temporal outline of NDVI. In this study, we used linear regression for analysing the statistical relationship among NDVI and rainfall and their trends. The study reveals a varying pattern of vegetation dynamics in response to rainfall over the area.
Childhood Abuse, the Interpersonal–Psychological Theory of Suicide, and the Mediating Role of Depression
Authors: Smith Noelle B. , Monteith Lindsey L. , Rozek David C. , Meuret Alicia E.
Published: October 2017

Although childhood abuse is a well‐known risk factor for suicide, no studies have investigated the role of interpersonal–psychological (Joiner, 2005), constructs in this association. This study examined whether childhood physical, sexual, and emotional abuse were associated with IPTS constructs, and whether depressive symptoms mediated these associations. Ninety‐one participants completed self‐report measures. Emotional abuse predicted perceived burdensomeness and thwarted belongingness, and depressive symptoms mediated these associations. Physical abuse predicted the acquired capability for suicide, although depression did not mediate this association. These findings suggest that specific types of abuse differentially predict IPTS components and underscore depression as a potential mechanism.
Soil physical changes and maize growth in a structurally fragile tropical soil due to mulching and duration between irrigation intervals
Authors: Moura E. G. , Macedo V. R. A. , Sena V. G. L. , Campos L. S. , Aguiar A. C. F.
Published: October 2017

Under tropical meteorological conditions, the volume of soil explored by plant roots is crucial for crop growth as it allows increased water and nutrient use efficiency. We hypothesized that, under different irrigation intervals, leguminous mulch can extend the duration between irrigation events but maintain crop performance, because decreased evaporative fluxes also reduce constraints to root exploration imposed by mechanical stress. We evaluated the combined effects of leguminous mulch and irrigation intervals on soil physical properties to determine whether the growth and productivity of maize were modified in a structurally fragile tropical soil. The experiment involved the following treatments: 4‐day irrigation intervals with soil mulched (4C) or bare (4S), 6‐day irrigation intervals with soil mulched (6C) or bare (6S), 8‐day irrigation intervals with soil mulched (8C) or bare (8S) and 10‐day irrigation intervals with soil mulched (10C) or bare (10S). Mulch decreased soil penetration resistance and increased to 4 days the favourable time for root development in drying soil. Relative to bare soil, mulch with a 6‐day irrigation interval almost doubled nitrogen uptake post‐tasselling, which decreased nitrogen remobilization and increased the crop growth rate during this stage. These conditions had a positive effect on the transpiration rate and stomatal conductance as well as on the growth and yield of maize. A 6‐day irrigation interval with mulch compared to 4 days with bare soil resulted in similar conditions for root development, but greater uptake of nitrogen (102.73–78.70 kg/ha) and better yield (6.2–5.3 t/ha), which means greater efficiency in nitrogen and water use.
Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients
Authors: Michelakis Evangelos D. , Gurtu Vikram , Webster Linda , Barnes Gareth , Watson Geoffrey , Howard Luke , Cupitt John , Paterson Ian , Thompson Richard B. , Chow Kelvin , O’Regan Declan P. , Zhao Lan , Wharton John , Kiely David G. , Kinnaird Adam , Boukouris Aristeidis E. , White Chris , Nagendran Jayan , Freed Darren H. , Wort Stephen J. , Gibbs J. Simon R. , Wilkins Martin R.
Published: October 2017

Metabolic modulation with dichloroacetate improves hemodynamics in genetically susceptible patients with idiopathic pulmonary arterial hypertension.
Through the smoke lies a further threat
Authors: Christenson Stephanie A.
Published: October 2017

CD4
+
lymphocyte differentiation is enhanced in patients with concomitant COPD and lung cancer, improving responses to immune checkpoint inhibition.
Core Genome Multilocus Sequence Typing: a Standardized Approach for Molecular Typing of Mycoplasma gallisepticum
Authors: Ghanem Mostafa , Wang Leyi , Zhang Yan , Edwards Scott , Lu Amanda , Ley David , El-Gazzar Mohamed
Published: October 2017

Mycoplasma gallisepticum
is the most virulent and economically important
Mycoplasma
species for poultry worldwide. Currently,
M. gallisepticum
strain differentiation based on sequence analysis of 5 loci remains insufficient for accurate outbreak investigation. Recently, whole-genome sequences (WGS) of many human and animal pathogens have been successfully used for microbial outbreak investigations. However, the massive sequence data and the diverse properties of different genes within bacterial genomes results in a lack of standard reproducible methods for comparisons among
M. gallisepticum
whole genomes. Here, we proposed the development of a core genome multilocus sequence typing (cgMLST) scheme for
M. gallisepticum
strains and field isolates. For development of this scheme, a diverse collection of 37
M. gallisepticum
genomes was used to identify cgMLST targets. A total of 425
M. gallisepticum
conserved genes (49.85% of
M. gallisepticum
genome) were selected as core genome targets. A total of 81
M. gallisepticum
genomes from 5 countries on 4 continents were typed using
M. gallisepticum
cgMLST. Analyses of phylogenetic trees generated by cgMLST displayed a high degree of agreement with geographical and temporal information. Moreover, the high discriminatory power of cgMLST allowed differentiation between
M. gallisepticum
strains of the same outbreak.
M. gallisepticum
cgMLST represents a standardized, accurate, highly discriminatory, and reproducible method for differentiation among
M. gallisepticum
isolates. cgMLST provides stable and expandable nomenclature, allowing for comparison and sharing of typing results among laboratories worldwide. cgMLST offers an opportunity to harness the tremendous power of next-generation sequencing technology in applied avian mycoplasma epidemiology at both local and global levels.
Plague: Recognition, Treatment, and Prevention
Authors: Yang Ruifu
Published: October 2017

Plague is caused by
Yersinia pestis
and is not commonly encountered in clinics, although natural plague foci are widely distributed around the world.
Y. pestis
has been listed as a category A bioterrorism agent. A neglected diagnosis will cause severe consequences. Therefore, this minireview briefly introduces the current understanding on
Y. pestis
and then focuses on practical aspects of plague, including clinical manifestations, diagnosis, treatment, and prevention, to alert clinicians about this notorious disease.
Emergence and Adaptation of a Novel Highly Pathogenic H7N9 Influenza Virus in Birds and Humans from a 2013 Human-Infecting Low-Pathogenic Ancestor
Authors: Qi Wenbao , Jia Weixin , Liu Di , Li Jing , Bi Yuhai , Xie Shumin , Li Bo , Hu Tao , Du Yingying , Xing Li , Zhang Jiahao , Zhang Fuchun , Wei Xiaoman , Eden John-Sebastian , Li Huanan , Tian Huaiyu , Li Wei , Su Guanming , Lao Guangjie , Xu Chenggang , Xu Bing , Liu Wenjun , Zhang Guihong , Ren Tao , Holmes Edward C. , Cui Jie , Shi Weifeng , Gao George F. , Liao Ming
Published: October 2017

Since its emergence in 2013, the H7N9 low-pathogenic avian influenza virus (LPAIV) has been circulating in domestic poultry in China, causing five waves of human infections. A novel H7N9 highly pathogenic avian influenza virus (HPAIV) variant possessing multiple basic amino acids at the cleavage site of the hemagglutinin (HA) protein was first reported in two cases of human infection in January 2017. More seriously, those novel H7N9 HPAIV variants have been transmitted and caused outbreaks on poultry farms in eight provinces in China. Herein, we demonstrate the presence of three different amino acid motifs at the cleavage sites of these HPAIV variants which were isolated from chickens and humans and likely evolved from the preexisting LPAIVs. Animal experiments showed that these novel H7N9 HPAIV variants are both highly pathogenic in chickens and lethal to mice. Notably, human-origin viruses were more pathogenic in mice than avian viruses, and the mutations in the PB2 gene associated with adaptation to mammals (E627K, A588V, and D701N) were identified by next-generation sequencing (NGS) and Sanger sequencing of the isolates from infected mice. No polymorphisms in the key amino acid substitutions of PB2 and HA in isolates from infected chicken lungs were detected by NGS. In sum, these results highlight the high degree of pathogenicity and the valid transmissibility of this new H7N9 variant in chickens and the quick adaptation of this new H7N9 variant to mammals, so the risk should be evaluated and more attention should be paid to this variant.

IMPORTANCE
Due to the recent increased numbers of zoonotic infections in poultry and persistent human infections in China, influenza A(H7N9) virus has remained a public health threat. Most of the influenza A(H7N9) viruses reported previously have been of low pathogenicity. Now, these novel H7N9 HPAIV variants have caused human infections in three provinces and outbreaks on poultry farms in eight provinces in China. We analyzed the molecular features and compared the relative characteristics of one H7N9 LPAIV and two H7N9 HPAIVs isolated from chickens and two human-origin H7N9 HPAIVs in chicken and mouse models. We found that all HPAIVs both are highly pathogenic and have valid transmissibility in chickens. Strikingly, the human-origin viruses were more highly pathogenic than the avian-origin viruses in mice, and dynamic mutations were confirmed by NGS and Sanger sequencing. Our findings offer important insight into the origin, adaptation, pathogenicity, and transmissibility of these viruses to both poultry and mammals.
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

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

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

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

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

Objectives

To 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 participants

The 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 variables

Early initiation of breast feeding, exclusive breast feeding, predominant breast feeding and bottle feeding.

Results

The 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.

Conclusions

West 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

Background

Prevalence 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.

Method

Data 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.

Results

Of 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.

Conclusion

People 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

Background

Development 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 results

Among 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.

Conclusions

This 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

Objectives

External 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.

Methods

A 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.

Results

A 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.

Conclusions

In 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

Introduction

We 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).

Methods

In 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.

Results

Seven 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.

Conclusions

Our 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/Purpose

Serositis 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.

Methods

2,390 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.

Results

43% 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.

Conclusion

Our 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.
Detection of Neisseria gonorrhoeae and Chlamydia trachomatis from pooled rectal, pharyngeal and urine specimens in men who have sex with men
Authors: Speers David John , Chua I-Ly Joanna , Manuel Justin , Marshall Lewis
Published: October 2017

Objectives

Screening of men who have sex with men (MSM) for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) requires sampling from anorectal and pharyngeal sites in addition to urogenital sampling. Due to the cost of testing multiple anatomical sites individually testing of pooled specimens has potential merit. The Cepheid GeneXpert CT/NG assay (GeneXpert), which also has potential for point-of-care nucleic acid testing in the sexual health clinic, has not been assessed for pooled specimen testing.

Methods

We prospectively compared GeneXpert testing of pooled pharyngeal and rectal swabs with urine samples to standard of care testing of individual specimens from 107 participants using the Roche cobas 4800 CT/NG assay (cobas) for CT and NG in high-risk MSM attending an inner city sexual health clinic.

Results

We found testing of pooled pharyngeal, rectal and urine samples by the GeneXpert to have 100% agreement for NG and 94% overall agreement for CT when compared with individual specimen testing by cobas. For CT testing, 14 cases were detected for both tests, 4for cobas only, 2 for GeneXpert only and 89 participants were negative for both tests.

Conclusions

Pooled specimen CT and NG testing by the GeneXpert was accurate when compared with single specimen testing and has potential for screening MSM for CT and NG. The role of pooled specimen testing with the GeneXpert as a point-of-care nucleic acid test in MSM requires further investigation.