bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal Analysis of Regulatory T Cell Defect in Patients with Autoimmune Polyendocrine Syndrome Type 1 Suggests Intrathymic Impairment
Authors: Koivula T.‐T. , Laakso S. M. , Niemi H. J. , Kekäläinen E. , Laine P. , Paulin L. , Auvinen P. , Arstila T. P. 
Published: July 2017

AbstractMutations in the autoimmune regulator gene disrupt thymic T cell development and negative selection, leading to the recessively inherited polyendocrine autoimmune disease autoimmune polyendocrine syndrome type 1 (APS‐1). The patients also have a functional defect in the FOXP3+ regulatory T cell population, but its origin is unclear. Here, we have used T cell receptor sequencing to analyse the clonal relationship of major CD4+ T cell subsets in three patients and three healthy controls. The naive regulatory T cells showed little overlap with helper T cell subsets, supporting divergence in the thymus. The activated/memory regulatory T cell subset displayed more sharing with helper T cells, but was mainly recruited from the naive regulatory T cell population. These clonal patterns were very similar in both patients and controls. However, naive regulatory T cells isolated from the patients had a significantly longer T cell receptor complementarity‐determining region 3 than any other population, suggesting failure of thymic selection. These data indicate that the peripheral differentiation of regulatory T cells in APS‐1 patients is not different from that in healthy controls. Rather, the patients' naive regulatory T cells may have an intrinsic defect imprinted already in the thymus.
Association of Toxoplasma gondii infection with schizophrenia and its relationship with suicide attempts in these patients
Authors: Ansari‐Lari Maryam , Farashbandi Hassan , Mohammadi Fahimeh 
Published: July 2017

AbstractObjectivesTo investigate the association between schizophrenia and Toxoplasma gondii, and to assess the association of infection with suicide attempts and age of onset of schizophrenia in these patients.MethodsCase–control study Fars Province, southern Iran. Cases were individuals with psychiatric diagnosis of schizophrenia as per Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) criteria. Controls were healthy blood donors, frequency‐matched with patients according to age and sex. For the detection of IgG antibodies, enzyme‐linked immunosorbent assay (ELISA) was used. Data about demographic information in all subjects and duration of illness and history of suicide attempts in patients with schizophrenia were collected using a brief questionnaire and hospital records. Chi‐square test and multivariable logistic regression were used for statistical analyses.ResultsAmong 99 cases, 42 individuals (42%) were positive for T. gondii antibody, vs. 41 (27%) among 152 controls (OR = 2, 95% CI: 1.2–3.4, P = 0.012). We compared the suicide attempts in patients with schizophrenia based on their T. gondii serologic status. There was a lower rate of suicide attempts in seropositive male patients than seronegative ones (OR = 0.3, 95% CI: 0.1–0.97, P = 0.04). Age of onset of schizophrenia did not differ between T. gondii‐infected and non‐infected patients.ConclusionsThese findings may have implications for schizophrenia and suicide prevention programmes. However, clearly further studies are required to confirm them.
ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey
Authors: Cinelli Elenia , Iovino Ludovica , Mutolo Donatella 
Published: July 2017

Key points
The paratrigeminal respiratory group (pTRG) is responsible for the respiratory pattern generation in the lamprey.
The role of ATP and astrocytes, known to control respiratory activity in mammals, was investigated in the lamprey respiratory network.
ATP microinjected into the pTRG induces a biphasic response consisting of marked increases in respiratory frequency mediated by P2X receptors followed by a decrease in the respiratory motor output due to the ATP metabolite adenosine.
We provide evidence that astrocytes are involved in the genesis of the normal respiratory pattern, ATP‐induced responses and acidification‐induced increases of the respiratory activity.
The function of astrocytes in rhythmic networks appears to be phylogenetically conserved.
AbstractThe role of ATP and astrocytes in respiratory rhythm modulation has been recently investigated in neonatal rodents. However, no information on the role of ATP and astrocytes within the respiratory network of the lamprey is available, particularly within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator. To address these issues, the present study was carried out on isolated brainstems of the adult lamprey. Bath application of ATP caused marked increases in respiratory frequency followed by decreases in the respiratory motor output, mediated by the ATP metabolite adenosine at the level of the pTRG. Bath applications and microinjections of agonists and antagonists of purinergic receptors showed that ATP increased respiratory activity through an action on pTRG P2X receptors. To disclose the respiratory role of astrocytes, we used bath application of the gliotoxin aminoadipic acid, which dramatically depressed the respiratory motor output that, however, promptly recovered following glutamine application. Furthermore, the excitatory responses to ATP‐γ‐S (a non‐hydrolysable ATP analogue), but not to substance P, microinjected into the pTRG, were abolished. Finally, we also demonstrated that acidification‐induced increases in respiratory activity were ATP‐independent, but mediated by the astrocytes’ glutamate–glutamine cycle. The results show for the first time that ATP and especially astrocytes strongly contribute to the modulation of the lamprey respiratory pattern. Their role in the modulation or maintenance of rhythmic neuronal activities appears to be phylogenetically conserved.
Specific Signatures of the Gut Microbiota and Increased Levels of Butyrate in Children Treated with Fermented Cow's Milk Containing Heat-Killed Lactobacillus paracasei CBA L74
Authors: Berni Canani Roberto , De Filippis Francesca , Nocerino Rita , Laiola Manolo , Paparo Lorella , Calignano Antonio , De Caro Carmen , Coretti Lorena , Chiariotti Lorenzo , Gilbert Jack A. , Ercolini Danilo 
Published: July 2017

ABSTRACTWe recently demonstrated that cow's milk fermented with the probioticLactobacillus paracaseiCBA L74 (FM-CBAL74) reduces the incidence of respiratory and gastrointestinal tract infections in young children attending school. This effect apparently derives from a complex regulation of non-immune and immune protective mechanisms. We investigated whether FM-CBAL74 could regulate gut microbiota composition and butyrate production. We randomly selected 20 healthy children (12 to 48 months) from the previous randomized controlled trial, before (t0) and after 3 months (t3) of dietary treatment with FM-CBAL74 (FM) or placebo (PL). Fecal microbiota was profiled using 16S rRNA gene amplicon sequencing, and the fecal butyrate concentration was also measured. Microbial alpha and beta diversities were not significantly different between groups prior to treatment. FM-CBAL74 but not PL treatment increased the relative abundance ofLactobacillus. IndividualBlautia,Roseburia, andFaecalibacteriumoligotypes were associated with FM-CBAL74 treatment and demonstrated correlative associations with immune biomarkers. Accordingly, PICRUSt analysis predicted an increase in the proportion of genes involved in butyrate production pathways, consistent with an increase in fecal butyrate observed only in the FM group. Dietary supplementation with FM-CBAL74 induces specific signatures in gut microbiota composition and stimulates butyrate production. These effects are associated with changes in innate and acquired immunity.IMPORTANCEThe use of a fermented milk product containing the heat-killed probiotic strainLactobacillus paracaseiCBAL74 induces changes in the gut microbiota, promoting the development of butyrate producers. These changes in the gut microbiota composition correlate with increased levels of innate and acquired immunity biomarkers.
Structural and Mechanistic Insights into the Improvement of the Halotolerance of a Marine Microbial Esterase by Increasing Intra- and Interdomain Hydrophobic Interactions
Authors: Li Ping-Yi , Zhang Yi , Xie Bin-Bin , Zhang Yan-Qi , Hao Jie , Wang Yue , Wang Peng , Li Chun-Yang , Qin Qi-Long , Zhang Xi-Ying , Su Hai-Nan , Shi Mei , Zhang Yu-Zhong , Chen Xiu-Lan 
Published: July 2017

ABSTRACT

Halotolerant enzymes are beneficial for industrial processes requiring high salt concentrations and low water activity. Most halophilic proteins are evolved to have reduced hydrophobic interactions on the surface and in the hydrophobic cores for their haloadaptation. However, in this study, we improved the halotolerance of a thermolabile esterase, E40, by increasing intraprotein hydrophobic interactions. E40 was quite unstable in buffers containing more than 0.3 M NaCl, and its
k
cat
and substrate affinity were both significantly reduced in 0.5 M NaCl. By introducing hydrophobic residues in loop 1 of the CAP domain and/or α7 of the catalytic domain in E40, we obtained several mutants with improved halotolerance, and the M3 S202W I203F mutant was the most halotolerant. (“M3” represents a mutation in loop 1 of the CAP domain in which residues R22-K23-T24 of E40 are replaced by residues Y22-K23-H24-L25-S26 of Est2.) Then we solved the crystal structures of the S202W I203F and M3 S202W I203F mutants to reveal the structural basis for their improved halotolerance. Structural analysis revealed that the introduction of hydrophobic residues W202 and F203 in α7 significantly improved E40 halotolerance by strengthening intradomain hydrophobic interactions of F203 with W202 and other residues in the catalytic domain. By further introducing hydrophobic residues in loop 1, the M3 S202W I203F mutant became more rigid and halotolerant due to the formation of additional interdomain hydrophobic interactions between the introduced Y22 in loop 1 and W204 in α7. These results indicate that increasing intraprotein hydrophobic interactions is also a way to improve the halotolerance of enzymes with industrial potential under high-salt conditions.

IMPORTANCE
Esterases and lipases for industrial application are often subjected to harsh conditions such as high salt concentrations, low water activity, and the presence of organic solvents. However, reports on halotolerant esterases and lipases are limited, and the underlying mechanism for their halotolerance is still unclear due to the lack of structures. In this study, we focused on the improvement of the halotolerance of a salt-sensitive esterase, E40, and the underlying mechanism. The halotolerance of E40 was significantly improved by introducing hydrophobic residues. Comparative structural analysis of E40 and its halotolerant mutants revealed that increased intraprotein hydrophobic interactions make these mutants more rigid and more stable than the wild type against high concentrations of salts. This study shows a new way to improve enzyme halotolerance, which is helpful for protein engineering of salt-sensitive enzymes.
Construction and Optimization of a Heterologous Pathway for Protocatechuate Catabolism in Escherichia coli Enables Bioconversion of Model Aromatic Compounds
Authors: Clarkson Sonya M. , Giannone Richard J. , Kridelbaugh Donna M. , Elkins James G. , Guss Adam M. , Michener Joshua K. 
Published: July 2017

ABSTRACT

The production of biofuels from lignocellulose yields a substantial lignin by-product stream that currently has few applications. Biological conversion of lignin-derived compounds into chemicals and fuels has the potential to improve the economics of lignocellulose-derived biofuels, but few microbes are able both to catabolize lignin-derived aromatic compounds and to generate valuable products. While
Escherichia coli
has been engineered to produce a variety of fuels and chemicals, it is incapable of catabolizing most aromatic compounds. Therefore, we engineered
E. coli
to catabolize protocatechuate, a common intermediate in lignin degradation, as the sole source of carbon and energy via heterologous expression of a nine-gene pathway from
Pseudomonas putida
KT2440. We next used experimental evolution to select for mutations that increased growth with protocatechuate more than 2-fold. Increasing the strength of a single ribosome binding site in the heterologous pathway was sufficient to recapitulate the increased growth. After optimization of the core pathway, we extended the pathway to enable catabolism of a second model compound, 4-hydroxybenzoate. These engineered strains will be useful platforms to discover, characterize, and optimize pathways for conversions of lignin-derived aromatics.

IMPORTANCE
Lignin is a challenging substrate for microbial catabolism due to its polymeric and heterogeneous chemical structure. Therefore, engineering microbes for improved catabolism of lignin-derived aromatic compounds will require the assembly of an entire network of catabolic reactions, including pathways from genetically intractable strains. Constructing defined pathways for aromatic compound degradation in a model host would allow rapid identification, characterization, and optimization of novel pathways. We constructed and optimized one such pathway in
E. coli
to enable catabolism of a model aromatic compound, protocatechuate, and then extended the pathway to a related compound, 4-hydroxybenzoate. This optimized strain can now be used as the basis for the characterization of novel pathways.
Feral Swine in the United States Have Been Exposed to both Avian and Swine Influenza A Viruses
Authors: Martin Brigitte E. , Sun Hailiang , Carrel Margaret , Cunningham Fred L. , Baroch John A. , Hanson-Dorr Katie C. , Young Sean G. , Schmit Brandon , Nolting Jacqueline M. , Yoon Kyoung-Jin , Lutman Mark W. , Pedersen Kerri , Lager Kelly , Bowman Andrew S. , Slemons Richard D. , Smith David R. , DeLiberto Thomas , Wan Xiu-Feng 
Published: July 2017

ABSTRACT
Influenza A viruses (IAVs) in swine can cause sporadic infections and pandemic outbreaks among humans, but how avian IAV emerges in swine is still unclear. Unlike domestic swine, feral swine are free ranging and have many opportunities for IAV exposure through contacts with various habitats and animals, including migratory waterfowl, a natural reservoir for IAVs. During the period from 2010 to 2013, 8,239 serum samples were collected from feral swine across 35 U.S. states and tested against 45 contemporary antigenic variants of avian, swine, and human IAVs; of these, 406 (4.9%) samples were IAV antibody positive. Among 294 serum samples selected for antigenic characterization, 271 cross-reacted with ≥1 tested virus, whereas the other 23 did not cross-react with any tested virus. Of the 271 IAV-positive samples, 236 cross-reacted with swine IAVs, 1 with avian IAVs, and 16 with avian and swine IAVs, indicating that feral swine had been exposed to both swine and avian IAVs but predominantly to swine IAVs. Our findings suggest that feral swine could potentially be infected with both avian and swine IAVs, generating novel IAVs by hosting and reassorting IAVs from wild birds and domestic swine and facilitating adaptation of avian IAVs to other hosts, including humans, before their spillover. Continued surveillance to monitor the distribution and antigenic diversities of IAVs in feral swine is necessary to increase our understanding of the natural history of IAVs.

IMPORTANCE
There are more than 5 million feral swine distributed across at least 35 states in the United States. In contrast to domestic swine, feral swine are free ranging and have unique opportunities for contact with wildlife, livestock, and their habitats. Our serological results indicate that feral swine in the United States have been exposed to influenza A viruses (IAVs) consistent with those found in both domestic swine and wild birds, with the predominant infections consisting of swine-adapted IAVs. Our findings suggest that feral swine have been infected with IAVs at low levels and could serve as hosts for the generation of novel IAVs at the interface of feral swine, wild birds, domestic swine, and humans.
Is more research always needed? Estimating optimal sample sizes for trials of retention in care interventions for HIV-positive East Africans
Authors: Uyei Jennifer , Li Lingfeng , Braithwaite R Scott 
Published: July 2017

IntroductionGiven the serious health consequences of discontinuing antiretroviral therapy, randomised control trials of interventions to improve retention in care may be warranted. As funding for global HIV research is finite, it may be argued that choices about sample size should be tied to maximising health.MethodsFor an East African setting, we calculated expected value of sample information and expected net benefit of sampling to identify the optimal sample size (greatest return on investment) and to quantify net health gains associated with research. Two hypothetical interventions were analysed: (1) one aimed at reducing disengagement from HIV care and (2) another aimed at finding/relinking disengaged patients.ResultsWhen the willingness to pay (WTP) threshold was within a plausible range (1–3 × GDP; US$1377–4130/QALY), the optimal sample size was zero for both interventions, meaning that no further research was recommended because the pre-research probability of an intervention's effectiveness and value was sufficient to support a decision on whether to adopt the intervention and any new information gained from additional research would likely not change that decision. In threshold analyses, at a higher WTP of $5200 the optimal sample size for testing a risk reduction intervention was 2750 per arm. For the outreach intervention, the optimal sample size remained zero across a wide range of WTP thresholds and was insensitive to variation. Limitations, including not varying all inputs in the model, may have led to an underestimation of the value of investing in new research.ConclusionIn summary, more research is not always needed, particularly when there is moderately robust prestudy belief about intervention effectiveness and little uncertainty about the value (cost-effectiveness) of the intervention. Users can test their own assumptions athttp://torchresearch.org.
Does expanding primary healthcare improve hospital efficiency? Evidence from a panel analysis of avoidable hospitalisations in 5506 municipalities in Brazil, 2000–2014
Authors: Silva Everton Nunes da , Powell-Jackson Timothy 
Published: July 2017

BackgroundHospitals account for the major share of health expenditure. Primary healthcare may improve efficiency at the hospital level by reducing avoidable admissions. We examined whether rapid expansion of primary healthcare in the context of Brazil’s Family Health Strategy (FHS) was associated with a reduction in avoidable hospitalisations.MethodsWe constructed panel data for 5506 municipalities over 2000–2014. Our primary outcome was the rate of avoidable hospitalisations, defined with reference to the official list of ambulatory care sensitive conditions (ACSC). The exposure variable was FHS coverage. We used first-difference models at the municipality level, controlling for municipality characteristics and confounding trends. We ran similar models for each of the 19 diseases in the list of ACSCs.FindingsFHS coverage expanded from 14% to 64% of the population between 2000 and 2014. Over the same period, the rate of avoidable hospitalisations fell from 17 to 10 per 1000 population. Results from the econometric analysis show that the FHS at full coverage was associated with an increase of 0.6 (95% CI 0.3 to 0.9; p<0.001) in the rate of avoidable hospital admissions. Expansion of the FHS was associated with an increase of 866 (95% CI 762 to 970; p<0.001) in the rate of primary care consultations. The FHS was not significantly associated with a reduction in hospitalisations for any of the 19 conditions.ConclusionsWhile high-quality primary healthcare can deliver considerable health benefits to the population, it may not always be effective in addressing inefficiencies at the hospital level due to avoidable admissions.
Implementation of effective practices in health facilities: a systematic review of cluster randomised trials
Authors: Allanson Emma R , Tunçalp Özge , Vogel Joshua P , Khan Dina N , Oladapo Olufemi T , Long Qian , Gülmezoglu Ahmet Metin 
Published: July 2017

BackgroundThe capacity for health systems to support the translation of research in to clinical practice may be limited. The cluster randomised controlled trial (cluster RCT) design is often employed in evaluating the effectiveness of implementation of evidence-based practices. We aimed to systematically review available evidence to identify and evaluate the components in the implementation process at the facility level using cluster RCT designs.MethodsAll cluster RCTs where the healthcare facility was the unit of randomisation, published or written from 1990 to 2014, were assessed. Included studies were analysed for the components of implementation interventions employed in each. Through iterative mapping and analysis, we synthesised a master list of components used and summarised the effects of different combinations of interventions on practices.ResultsForty-six studies met the inclusion criteria and covered the specialty groups of obstetrics and gynaecology (n=9), paediatrics and neonatology (n=4), intensive care (n=4), internal medicine (n=20), and anaesthetics and surgery (n=3). Six studies included interventions that were delivered across specialties. Nine components of multifaceted implementation interventions were identified: leadership, barrier identification, tailoring to the context, patient involvement, communication, education, supportive supervision, provision of resources, and audit and feedback. The four main components that were most commonly used were education (n=42, 91%), audit and feedback (n=26, 57%), provision of resources (n=23, 50%) and leadership (n=21, 46%).ConclusionsFuture implementation research should focus on better reporting of multifaceted approaches, incorporating sets of components that facilitate the translation of research into practice, and should employ rigorous monitoring and evaluation.
Circum-Arctic Lithosphere Evolution (CALE) Transect C: displacement of the Arctic Alaska–Chukotka microplate towards the Pacific during opening of the Amerasia Basin of the Arctic
Authors: Miller Elizabeth L. , Meisling Kristian E. , Akinin Vyacheslav V. , Brumley Kelley , Coakley Bernard J. , Gottlieb Eric S. , Hoiland Carl W. , O'Brien Timothy M. , Soboleva Anna , Toro Jaime 
Published: July 2017

Abstract
This paper synthesizes the framework and geological evolution of the Arctic Alaska–Chukotka microplate (AACM), from its origin as part of the continental platform fringing Baltica and Laurentia to its southward motion during the formation of the Amerasia Basin (Arctic Ocean) and its progressive modification as part of the dynamic northern palaeo-Pacific margin. A synthesis of the available data refines the crustal identity, limits and history of the AACM and, together with regional geological constraints, provides a tectonic framework to aid in its pre-Cretaceous restoration. Recently published seismic reflection data and interpretations, integrated with regional geological constraints, provide the basis for a new crustal transect (the Circum-Arctic Lithosphere Evolution (‘CALE’) Transect C) linking the Amerasia Basin and the Pacific margin along two paths that span 5100 km from the Lomonosov Ridge (near the North Pole), across the Amerasia Basin, Chukchi Sea and Bering Sea, and ending at the subducting Pacific plate margin in the Aleutian Islands. We propose a new plate tectonic model in which the AACM originated as part of a re-entrant in the palaeo-Pacific margin and moved to its present position during slab-related magmatism and the southward retreat of palaeo-Pacific subduction, largely coeval with the rifting and formation of the Amerasia Basin in its wake.