bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centenarian Hotspots in Denmark
Authors: Hansen Anne Vinkel , Mortensen Laust Hvas , Westendorp Rudi 
Published: August 2017

AbstractBackground:The study of regions with high prevalence of centenarians is motivated by a desire to find determinants of healthy ageing. While existing research has focused on selected candidate geographical regions, we explore the existence of hotspots in the whole the Denmark, which is a small and homogeneous country.Methods:We performed a Kulldorff spatial scan across the whole of Denmark, searching for regions of birth, and regions of residence at age 71, where a significantly increased percentage of the cohort born 1906-1915 became centenarians. Next we compared mortality hazards for the identified regions to the rest of the country by sex and residence at age 71.Results:We found a birth hotspot of 222 centenarians, 1.37 times more than the expected number, centered on a group of fairly remote rural islands. Significantly lower mortality hazards from age 71 onwards were confined to those who were born within the hotspot and persisted over a period of at least 30 years. At age 71, we found two residence-based hotspots of 348 respectively 238 centenarians, equaling 1.46- and 1.44 times the expected number. One is located in the high-income suburbs of the Danish capital and here the lower mortality hazard was confined to those who moved into the hotspot. In the second residence-based hotspot, both those who were born, and those who moved into the hotspot, showed significant lower mortality hazards.Conclusion:Within the whole of Denmark, we identified several centenarian hotspots that have different biological underpinnings. These outcomes point to complex gene-environmental interactions explaining a variety of longevity trajectories.
Targeting Vaccinations for the Licensed Dengue Vaccine: Considerations for Serosurvey Design
Authors: Imai N , Ferguson NM 
Published: August 2017

AbstractObjectiveWHO recommends countries consider dengue vaccination in geographic settings only where epidemiological data indicate a high burden of disease. In defining target populations, WHO recommend that prior infection with any dengue serotype should be >70% seroprevalence. Here we address considerations for serosurvey design in the context of the newly licensed CYD-TDV vaccine.MethodsTo explore how the design of seroprevalence surveys (age range, survey size) would affect estimates of the force of infection, for every combination of age range, total survey size, transmission setting, and test sensitivity/specificity, 100 age-specific seroprevalence surveys were simulated using a beta-binomial distribution and a simple catalytic model. The transmission intensity was then re-estimated using a Metropolis-Hastings Markov Chain Monte-Carlo algorithm.FindingsSampling from a wide age range led to more accurate estimates than having a larger sample size. This finding was consistent across all transmission settings. The optimal age range to sample from differed by transmission intensity, with younger and older ages being important in high and low transmission settings respectively. The optimum test sensitivity and specificity given an imperfect test also differed by transmission setting with high sensitivity being important in high transmission settings and high specificity important in low transmission settings.ConclusionsWhen assessing the suitability for vaccination by seroprevalence surveys, countries should ensure that an appropriate age range is sampled, taking into account epidemiological evidence about the local burden of dengue.
Regulation of mesenchymal stem cell function by TGFβ-1 on mast cell extracellular vesicles – role of endosomal retention
Authors: Yin Yanan , Shelke Ganesh Vilas , Jang Su Chul , Lässer Cecilia , Wennmalm Stefan , Hoffmann Hans Jürgen , Nilsson Jonas , Li Li , Gho Yong Song , Lötvall Jan 
Published: August 2017

AbstractExtracellular vesicles (EVs) convey biological messages between cells, either by surface-to-surface interaction, or by shuttling of bioactive molecules to a recipient cell cytoplasm. Here we show that EVs released by human primary mast cells or transformed human mast cells (HMC1), carry TGFβ-1 on their surface. EV-associated TGFβ-1 enhance the migratory activity of human mesenchymal stem cells (MSCs) compared to free TGFβ-1, as both knockdown of TGFβ, or a TGFβ-antibody, attenuate the effect. The MSCs respond by increasing matrix metalloproteinase-2 and −9 (MMP) activity. Further, EVs given to MSCs are retained in the endosomal compartments at a time of biological function, prolonging EV-associated TGFβ-1 signaling vs free TGFβ-1. When exposed to EVs, MSCs home more toward allergen-exposed lung in a mouse allergen model, resulting in attenuated allergic inflammation. Our results show that mast cell-EVs are decorated with TGFb-1, are retained in endosomes, which influences both MSC phenotype and function.
Capture-based DNA methylation sequencing facilitates diagnosis and reveals potential pathogenic mechanisms in teratogenic diabetes exposure
Authors: Schulze Katharina V. , Bhatt Amit , Azamian Mahshid S. , Sundgren Nathan C. , Zapata Gladys , Hernandez Patricia , Fox Karin , Kaiser Jeffrey R. , Belmont John W. , Hanchard Neil A. 
Published: August 2017

ABSTRACTDiabetic embryopathy (DE) describes a spectrum of birth defects associated with a teratogenic exposure to maternal diabetesin utero.These defects strongly overlap the phenotypes of known genetic syndromes; however, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests that distinguish the diagnosis. Here, we explore the potential of DNA methylation as both a diagnostic biomarker and a means of informing disease pathogenesis in DE. Capture-based bisulfite sequencing was used to compare patterns of DNA methylation at 2,800,516 sites genome-wide in seven DE neonates and 11 healthy neonates, including five within uterodiabetes exposure. DE infants had significantly lower global DNA methylation (ANOVA, Tukey HSDp=0.045) than diabetes-unexposed, healthy controls (UH), with multiple sites showing large (mean methylation difference = 16.6%) and significant (p<0.001) differential methylation between the two groups. We found that a subset of 237 highly differentially methylated loci could accurately distinguish DE infants from both UH and diabetes-exposed healthy infants (sensitivity 80% -100%). Differentially methylated sites were enriched in intergenic (p<3.52×10-15) and intronic (p<0.001) regions found proximal to genes either associated with Mendelian syndromes that overlap the DE phenotype (e.g.TRIO,ANKRD11), or known to influence early organ development (e.g.BRAX1,RASA3). Further, by integrating information oncis-sequence variation, we found that 39.3% of loci with evidence for allele-specific methylation also showed differential methylation between DE and controls. Our study suggests a role for aberrant DNA methylation andcis-sequence variation in the pathogenesis of DE, and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.
Cortical interneurons ensure maintenance of frequency tuning following adaptation
Authors: Natan Ryan G. , Rao Winnie , Geffen Maria N. 
Published: August 2017

AbstractNeurons throughout the sensory pathway are tuned to specific aspects of stimuli. This selectivity is shaped by feedforward and recurrent excitatory-inhibitory interactions. In the auditory cortex (AC), two large classes of interneurons, parvalbumin- (PVs) and somatostatin- positive (SOMs) interneurons, differentially modulate frequency-dependent responses across the frequency response function of excitatory neurons. At the same time, the responsiveness of neurons in AC to sounds is dependent on the temporal context, with the majority of neurons exhibiting adaptation to repeated sounds. Here, we asked whether and how inhibitory neurons shape the frequency response function of excitatory neurons as a function of adaptation to temporal repetition of tones. The effects of suppressing both SOMs and PVs diverged for responses to preferred versus non-preferred frequencies following adaptation. Prior to adaptation, suppressing either SOM or PV inhibition drove both increases and decreases in spiking activity among cortical neurons. After adaptation, suppressing SOM activity caused predominantly disinhibitory effects, whereas suppressing PV activity still evoked bi-directional changes. SOM, but not PV-driven inhibition dynamically modulated frequency tuning as a function of adaptation. Additionally, testing across frequency tuning revealed that, unlike PVs, SOM-driven inhibition exhibited gain-like increases reflective of adaptation. Our findings suggest that distinct cortical interneurons differentially shape tuning to sensory stimuli across the neuronal receptive field, maintaining frequency selectivity of excitatory neurons during adaptation.
Very high density EEG elucidates spatiotemporal aspects of early visual processing
Authors: Robinson Amanda K , Venkatesh Praveen , Boring Matthew J. , Tarr Michael J. , Grover Pulkit , Behrmann Marlene 
Published: August 2017

AbstractStandard human EEG systems based on spatial Nyquist estimates suggest that 20-30 mm electrode spacing suffices to capture neural signals on the scalp, but recent studies posit that increasing sensor density can provide higher resolution neural information. Here, we compared “super-Nyquist” density EEG (“SND”) with Nyquist density (“ND”) arrays for assessing the spatiotemporal aspects of early visual processing. EEG was measured from 128 electrodes arranged over occipitotemporal brain regions (14 mm spacing) while participants viewed flickering checkerboard stimuli. Analyses compared SND with ND-equivalent subsets of the same electrodes. Frequency-tagged stimuli were classified more accurately with SND than ND arrays in both the time and the frequency domains. Representational similarity analysis revealed that a computational model of V1 correlated more highly with the SND than the ND array. Overall, SND EEG captured more neural information from visual cortex, arguing for increased development of this approach in basic and translational neuroscience.AbbreviationsSND“super-Nyquist” density EEG (smaller than 20-30 mm electrode spacing)NDNyquist density EEG (20-30 mm electrode spacing)
Mixed Effects Association of Single Cells Identifies an Expanded Th1-Skewed Cytotoxic Effector CD4+ T Cell Subset in Rheumatoid Arthritis
Authors: Fonseka Chamith Y. , Rao Deepak A. , Teslovich Nikola C. , Hannes Susan K. , Slowikowsi Kamil , Gurish Michael F. , Donlin Laura T. , Weinblatt Michael E. , Massarotti Elena M. , Coblyn Jonathan S. , Helfgott Simon M. , Todd Derrick J. , Bykerk Vivian P. , Karlson Elizabeth W. , Ermann Joerg , Lee Yvonne C. , Brenner Michael B. , Raychaudhuri Soumya 
Published: August 2017

AbstractHigh dimensional single-cell analyses have dramatically improved the ability to resolve complex mixtures of cells from human disease samples; however, identifying disease-associated cell types or cell states in patient samples remains challenging due to technical and inter-individual variation. Here we present Mixed effects modeling of Associations of Single Cells (MASC), a novel reverse single cell association strategy for testing whether case-control status influences the membership of single cells in any of multiple cellular subsets while accounting for technical confounds and biological variation. Applying MASC to mass cytometry analyses of CD4+ T cells from blood of rheumatoid arthritis (RA) patients and controls revealed a significantly expanded population of CD4+ T cells, identified as CD27- HLA-DR+ effector memory cells, in RA patients (OR = 1.7; p = 1.1 × 10−3). The frequency of CD27- HLA-DR+ cells was similarly elevated in blood samples from a second RA patient cohort, and CD27- HLA-DR+ cell frequency decreased in RA patients who respond to immunosuppressive therapy. Compared to peripheral blood, synovial fluid and synovial tissue samples from RA patients contained ∼5-fold higher frequencies of CD27- HLA-DR+ cells, which comprised ∼10% of synovial CD4+ T cells. We find that CD27- HLA-DR+ cells are abundant producers of IFN-γ and also express perforin and granzyme A at elevated levels. Thus MASC identified the expansion of a unique Th1 skewed effector T cell population with cytotoxic capacity in RA. We propose that MASC is a broadly applicable method to identify disease-associated cell populations in high-dimensional single cell data.OneSentenceSummaryMixed-effects regression of single cells identifies a cytotoxic Th1-like CD4+ T cell subset while accounting for inter-individual and technical variation.
Domain-General and Domain-Specific Patterns of Activity Supporting Metacognition in Human Prefrontal Cortex
Authors: Morales Jorge , Lau Hakwan , Fleming Stephen M. 
Published: August 2017

AbstractMetacognition is the capacity to evaluate the success of one’s own cognitive processes in various domains, e.g. memory and perception. It remains controversial whether metacognition relies on a domain-general resource that is applied to different tasks, or whether self-evaluative processes are domain-specific. Here we directly investigated this issue by examining the neural substrates engaged when metacognitive judgments were made by human participants during perceptual and memory tasks matched for stimulus and performance characteristics. By comparing patterns of functional magnetic resonance imaging (fMRI) activity while subjects evaluated their performance, we revealed both domain-specific and domain-general metacognitive representations. Multi-voxel activity patterns in anterior prefrontal cortex predicted levels of confidence in a domain-specific fashion, whereas domain-general signals predicting confidence and accuracy were found in a widespread network in the frontal and posterior midline. The demonstration of domain-specific metacognitive representations suggests the presence of a content-rich mechanism available to introspection and cognitive control.SignificancestatementWe use human neuroimaging to investigate processes supporting memory and perceptual metacognition. It remains controversial whether metacognition relies on a global resource that is applied to different tasks, or whether self-evaluative processes are specific to particular tasks. Using multivariate decoding methods, we provide evidence that perceptual- and memory-specific metacognitive representations cortex co-exist with generic confidence signals. Our findings reconcile previously conflicting results on the domain-specificity/generality of metacognition, and lay the groundwork for a mechanistic understanding of metacognitive judgments.
Mineral analysis of complete dog and cat foods in the UK and compliance with European guidelines
Authors: M. Davies , L. Jones , R. Alborough , C. Davis , C. Williams , D.S. Gardner 
Published: August 2017

AbstractThe mineral content of complete pet food is regulated to ensure health of the companion animal population. A comprehensive analysis of adherence to these regulatory guidelines has not been conducted. We measured mineral composition of a range of complete wet (n=97) and dry (n=80) canine and feline pet food sold in the UK to assess compliance with EU guidelines. While a majority of foods complied with ≥8 of 11 guidelines (99% and 83% for dry and wet food, respectively), many failed to provide nutritional minimum (e.g. Cu, 20 % of wet food) or exceeded nutritional maximum (e.g. Se, 76% of wet food). Only 6% (6/97) of wet and 39% (34/80) of dry food were fully compliant. Some foods (20-30% of all analysed) had mineral imbalances such as not having the recommended balance of Ca:P (between 1:1 to 2:1). Foods with high fish content had high levels of undesirable metal elements such as arsenic. The study highlights broad non-compliance of a range of popular pet foods sold in the UK with EU guidelines (95% and 61% of wet and dry foods, respectively). If fed exclusively and over an extended period, a number of these pet foods could impact the general health of companion animals.
Integrator Subunit 4 is a ‘Symplekin-like’ Scaffold that Associates with INTS9/11 to Form the Integrator Cleavage Module
Authors: Albrecht Todd R. , Shevtsov Sergey P. , Mascibroda Lauren G. , Peart Natoya J. , Sawyer Iain A. , Dundr Miroslav , Wagner Eric J. 
Published: August 2017

AbstractIntegrator (INT) is a transcriptional regulatory complex associated with RNA polymerase II that is required for the 3’-end processing of both UsnRNAs and enhancer RNAs. Integrator subunits 9 (INTS9) and INTS11 constitute the catalytic core of INT and are paralogues of the cleavage and polyadenylation specificity factors CPSF100 and CPSF73. While CPSF73/100 are known to associate with a third protein called Symplekin, there is no paralog of Symplekin within INT raising the question of how INTS9/11 associate with the other INT subunits. Here, we have identified that INTS4 is a specific and conserved interaction partner of INTS9/11 that does not interact with either subunit individually. Although INTS4 has no significant homology with Symplekin, it possesses N-terminal HEAT repeats similar to Symplekin but also contains a β-sheet rich C-terminal region, both of which are important to bind INTS9/11. We assess three functions of INT including UsnRNA 3’-end processing, maintenance of Cajal body integrity, and formation of histone locus bodies to conclude that INTS4/9/11 are the most critical of the INT subunits for UsnRNA biogenesis. Altogether, these results indicate that INTS4/9/11 compose a heterotrimeric complex that likely represents the Integrator ‘cleavage module’ responsible for its endonucleolytic activity.
Nonconsumptive predator effects on prey demography: Dogwhelk cues decrease benthic mussel recruitment
Authors: Ehlers Sonja M. , Scrosati Ricardo A. , Ellrich Julius A. 
Published: August 2017

AbstractPredators have often been shown to have nonconsumptive effects (NCEs) on prey behaviour, but the demographic consequences for prey remain poorly known. This is important to understand because demography influences the impact of a species in its community. We used an intertidal predator–prey system to investigate predator NCEs on prey recruitment, a key demographic process for population persistence. Pelagic mussel larvae are known to avoid waterborne cues from dogwhelks, which prey on intertidal mussels. Through a field experiment done in Atlantic Canada, we manipulated the presence of dogwhelks in intertidal habitats during the mussel recruitment season. We measured mussel recruitment in collectors that could be reached by waterborne dogwhelk cues but not by dogwhelks themselves. We found that the nearby presence of dogwhelks significantly decreased mussel recruit density. A previous study done in the same habitats under the same experimental conditions showed that dogwhelk cues also limit the recruitment of barnacles, another prey item for dogwhelks. However, such NCEs were four times stronger than those observed for mussel recruitment. This difference relates well to the higher ability of mussels to escape predation, as mussels can relocate while barnacles cannot. Therefore, basic features of natural history may be useful to predict predator NCEs on prey recruitment.
Integrative DNA copy number detection and genotyping from sequencing and array-based platforms
Authors: Zhou Zilu , Wang Weixin , Wang Li-San , Zhang Nancy Ruonan 
Published: August 2017

AbstractMotivationCopy number variations (CNVs) are gains and losses of DNA segments and have been associated with disease. Many large-scale genetic association studies are performing CNV analysis using whole exome sequencing (WES) and whole genome sequencing (WGS). In many of these studies, previous SNP-array data are available. An integrated cross-platform analysis is expected to improve resolution and accuracy, yet there is no tool for effectively combining data from sequencing and array platforms. The detection of CNVs using sequencing data alone can also be further improved by the utilization of allele-specific reads.ResultsWe propose a statistical framework, integrated Copy Number Variation detection algorithm (iCNV), which can be applied to multiple study designs: WES only, WGS only, SNP array only, or any combination of SNP and sequencing data. iCNV applies platform specific normalization, utilizes allele specific reads from sequencing and integrates matched NGS and SNP-array data by a Hidden Markov Model (HMM). We compare integrated two-platform CNV detection using iCNV to naive intersection or union of platforms and show that iCNV increases sensitivity and robustness. We also assess the accuracy of iCNV on WGS data only, and show that the utilization of allele-specific reads improve CNV detection accuracy compared to existing methods.Availabilityhttps://github.com/zhouzilu/iCNVContactnzh@wharton.upenn.edu,zhouzilu@mail.med.upenn.eduSupplementary informationSupplementary data are available atBioinformaticsonline.
GTP Hydrolysis by eIF5B in the Last Step of Translation Initiation Is Activated by a Rotation of the Small Ribosomal Subunit
Authors: Fernández Israel S. , Ramakrishnan V. 
Published: August 2017

AbstractPlacement of an initiator aminoacyl-tRNA [(f)Met-tRNAi(f)Met] base paired with the AUG initiation codon of a messenger RNA (mRNA) is the first step of translation. The eukaryotic translation factor eIF5B or its bacerial homologue IF2 facilitate the correct positioning of initiator tRNA in the P site of the ribosome. We report the electron cryomicroscopy (cryoEM) structure of a stabilized intermediate state of a yeast 80S/tRNAiMet/eIF5B complex at 3.6 Å resolution. The structure shows how a universally conserved tyrosine couples the rotational state of the small ribosomal subunit with GTP hydrolysis.
Measuring treatment outcomes in gambling disorders: a systematic review
Authors: Pickering Dylan , Keen Brittany , Entwistle Gavin , Blaszczynski Alex 
Published: August 2017

AbstractBackground and AimsConsiderable variation of outcome variables used to measure recovery in the gambling treatment literature has precluded effective cross‐study evaluations and hindered the development of best‐practice treatment methodologies. The aim of this systematic review was to describe current diffuse concepts of recovery in the gambling field by mapping the range of outcomes and measurement strategies used to evaluate treatments, and to identify more commonly accepted indices of recovery.MethodsA systematic search of six academic databases for studies evaluating treatments (psychological and pharmacological) for gambling disorders with a minimum 6‐month follow‐up. Data from eligible studies were tabulated and analysis conducted using a narrative approach. Guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) were adhered to.ResultsThirty‐four studies were reviewed systematically (RCTs = 17, comparative designs = 17). Sixty‐three different outcome measures were identified: 25 (39.7%) assessed gambling‐specific constructs, 36 (57.1%) assessed non‐gambling specific constructs, and two instruments were used across both categories (3.2%). Self‐report instruments ranged from psychometrically validated to ad‐hoc author‐designed questionnaires. Units of measurement were inconsistent, particularly in the assessment of gambling behaviour. All studies assessed indices of gambling behaviour and/or symptoms of gambling disorder. Almost all studies (n = 30; 88.2%) included secondary measures relating to psychiatric comorbidities, psychological processes linked to treatment approach, or global functioning and wellbeing.ConclusionsIn research on gambling disorders, the incorporation of broader outcome domains that extend beyond disorder‐specific symptoms and behaviours suggests a multi‐dimensional conceptualization of recovery. Development of a single comprehensive scale to measure all aspects of gambling recovery could help to facilitate uniform reporting practices across the field.