bluuebunny/crossref_metadata_2025 huggingface dataset:
State-Based Delay Representation and Its Transfer from a Game of Pong to Reaching and Tracking
Authors: Avraham Guy , Leib Raz , Pressman Assaf , Simo Lucia S. , Karniel Amir , Shmuelof Lior , Mussa-Ivaldi Ferdinando A. , Nisky Ilana
Published: September 2017

To accurately estimate the state of the body, the nervous system needs to account for delays between signals from different sensory modalities. To investigate how such delays may be represented in the sensorimotor system, we asked human participants to play a virtual pong game in which the movement of the virtual paddle was delayed with respect to their hand movement. We tested the representation of this new mapping between the hand and the delayed paddle by examining transfer of adaptation to blind reaching and blind tracking tasks. These blind tasks enabled to capture the representation in feedforward mechanisms of movement control. A Time Representation of the delay is an estimation of the actual time lag between hand and paddle movements. A State Representation is a representation of delay using current state variables: the distance between the paddle and the ball originating from the delay may be considered as a spatial shift; the low sensitivity in the response of the paddle may be interpreted as a minifying gain; and the lag may be attributed to a mechanical resistance that influences paddle’s movement. We found that the effects of prolonged exposure to the delayed feedback transferred to blind reaching and tracking tasks and caused participants to exhibit hypermetric movements. These results, together with simulations of our representation models, suggest that delay is not represented based on time, but rather as a spatial gain change in visuomotor mapping.

Significance Statement

It is known that the brain copes with sensory feedback delays to control movements, but it is unclear whether it does so using a representation of the actual time lag. We addressed this question by exposing participants to a visuomotor delay during a dynamic game of pong. Following the game, participants exhibited hypermetric reaching and tracking movements that indicate that delay is represented as a visuomotor gain rather than as a temporal shift.
Embryonic and postnatal neurogenesis produce functionally distinct subclasses of dopaminergic neuron
Authors: Galliano Elisa , Franzoni Eleonora , Breton Marine , Chand Annisa N. , Byrne Darren J. , Murthy Venkatesh N. , Grubb Matthew S.
Published: September 2017

Most neurogenesis in the mammalian brain is completed embryonically, but in certain areas the production of neurons continues throughout postnatal life. The functional properties of mature postnatally-generated neurons often match those of their embryonically-produced counterparts. However, we show here that in the olfactory bulb (OB), embryonic and postnatal neurogenesis produce functionally distinct subpopulations of dopaminergic (DA) neurons. We define two subclasses of OB DA neuron by the presence or absence of a key subcellular specialisation: the axon initial segment (AIS). Large AIS-positive axon-bearing DA neurons are exclusively produced during early embryonic stages, leaving small anaxonic AIS-negative cells as the only DA subtype generated via adult neurogenesis. These populations are functionally distinct: large DA cells are more excitable, yet display weaker and – for certain long-latency or inhibitory events – more broadly-tuned responses to odorant stimuli. Embryonic and postnatal neurogenesis can therefore generate distinct neuronal subclasses, placing important constraints on the functional roles of adult-born neurons in sensory processing.
Music training improves the ability to understand speech-in-noise in older adults
Authors: Zendel Benjamin Rich , West Greg , Belleville Sylvie , Peretz Isabelle
Published: September 2017

It is well known that hearing abilities decline with age, and one of the most commonly reported hearing difficulties reported in older adults is a reduced ability to understand speech in noisy environments. Older musicians have an enhanced ability to understand speech in noise, and this has been associated with enhanced brain responses related to both speech processing and the deployment of attention, however the causal impact of music lessons in older adults is poorly understood. A sample of older adults was randomly assigned to learn to play piano (Mus), to learn to play a visuo-spatially demanding video-game (Vid), or to serve as a no-contact control (Nocon).After 6 months, the Mus group improved their ability to understand a word presented in loud background noise. This improvement was related to an earlier N100, enhanced P250 (P2/P3) and a reduced N600 (N400). These findings support the idea that music lessons provide a causal benefit to hearing abilities, and that this benefit is due to both enhanced encoding of speech stimuli, and enhanced deployment of attentional mechanisms towards the speech stimuli. Importantly, these findings suggest that music training could be used as a foundation to develop auditory rehabilitation programs for older adults.
Genetic pleiotropy between mood disorders, metabolic, and endocrine traits in a multigenerational pedigree
Authors: Kember Rachel L. , Hou Liping , Ji Xiao , Andersen Lars H. , Ghorai Arpita , Estrella Lisa N. , Almasy Laura , McMahon Francis J. , Brown Christopher , Bućan Maja
Published: September 2017

Bipolar disorder (BD) is a mental disorder characterized by alternating periods of depression and mania. Individuals with BD have higher levels of early mortality than the general population, and a substantial proportion of this may be due to increased risk for comorbid diseases. Recent evidence suggests that pleiotropy, either in the form of a single risk-allele or the combination of multiple loci genome-wide, may underlie medical comorbidity between traits and diseases. To identify the molecular events that underlie BD and related medical comorbidities, we generated imputed whole genome sequence (WGS) data using a population specific reference panel, for an extended multigenerational Old Order Amish pedigree (400 family members) segregating BD and related disorders. First, we investigated all putative disease-causing variants at known Mendelian disease loci present in this pedigree. Second, we performed genomic profiling using polygenic risk scores to establish each individual's risk for several complex diseases. To explore the contribution of disease genes to BD we performed gene-based and variant-based association tests for BD, and found that Mendelian disease genes are enriched in the top results from both tests (OR=20.3, p=1×10−3; OR=2.2, p=1×10−2). We next identified a set of Mendelian variants that co-occur in individuals with BD more frequently than their unaffected family members, including the R3527Q mutation inAPOBassociated with hypercholesterolemia. Using polygenic risk scores, we demonstrated that BD individuals from this pedigree were enriched for the same common risk-alleles for BD as in the general population (β=0.416, p=6×10−4). Furthermore, in the extended Amish family we find evidence for a common genetic etiology between BD and clinical autoimmune thyroid disease (p=1×10−4), diabetes (p=1×10−3), and lipid traits such as triglyceride levels (p=3×10−4). We identify genomic regions that contribute to the differences between BD individuals and unaffected family members by calculating local genetic risk for independent LD blocks. Our findings provide evidence for the extensive genetic pleiotropy that can drive epidemiological findings of comorbidities between diseases and other complex traits. Identifying such patterns may enable the subtyping of complex diseases and facilitate our understanding of the genetic mechanisms underlying phenotypic heterogeneity.
Improving the Generation and Selection of Virtual Populations in Quantitative Systems Pharmacology Models
Authors: Rieger Theodore R. , Allen Richard J. , Bystricky Lukas , Chen Yuzhou , Colopy Glen Wright , Cui Yifan , Gonzalez Angelica , Liu Yifei , White R. D. , Everett R. A. , Banks H. T. , Musante Cynthia J.
Published: September 2017

Quantitative systems pharmacology (QSP) models aim to describe mechanistically the pathophysiology of disease and predict the effects of therapies on that disease. For most drug development applications, it is important to predict not only the mean response to an intervention but also the distribution of responses, due to inter-patient variability. Given the necessary complexity of QSP models, and the sparsity of relevant human data, the parameters of QSP models are often not well determined. One approach to overcome these limitations is to develop alternative virtual patients (VPs) and virtual populations (Vpops), which allow for the exploration of parametric uncertainty and reproduce inter-patient variability in response to perturbation. Here we evaluated approaches to improve the efficiency of generating Vpops. We aimed to generate Vpops without sacrificing diversity of the VPs’ pathophysiologies and phenotypes. To do this, we built upon a previously published approach (Allen, Rieger et al. 2016) by (a) incorporating alternative optimization algorithms (genetic algorithm and Metropolis-Hastings) or alternatively (b) augmenting the optimized objective function. Each method improved the baseline algorithm by requiring significantly fewer plausible patients (precursors to VPs) to create a reasonable Vpop. #ddct #qsp
A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β
Authors: Malley Konstantin R. , Koroleva Olga , Miller Ian , Sanishvili Ruslan , Jenkins Christopher M. , Gross Richard W. , Korolev Sergey
Published: September 2017

Calcium-independent phospholipase A2β (iPLA2β) regulates several physiological processes including inflammation, calcium homeostasis and apoptosis. It is linked genetically to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underlying pathologic phenotypes remain unknown. Here, we present the first crystal structure of iPLA2β that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. The ankyrin repeat domains wrap around the catalytic domains in an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. A single calmodulin binds and allosterically inhibits both catalytic domains. These unique structural features identify the molecular interactions that can regulate iPLA2β activity and its cellular localization, which can be targeted to identify novel inhibitors for therapeutic purposes. The structure provides a well-defined framework to investigate the role of neurodegenerative mutations and the function of iPLA2β in the brain.
Measuring nonapoptotic caspase activity with a transgenic reporter in mice
Authors: Nicholls P. J. , Pack Thomas F. , Urs Nikhil M. , Kumar Sunil , Zhou Yang , Ichim Gabriel , Ginzel Joshua D. , Turu Gabor , Calabrese Evan , Roberts Wendy L. , Fan Ping , Ostapchenko Valeriy G. , Lenis Monica S. Guzman , Beraldo Flavio , Hatina Jiri , Prado Vania F. , Prado Marco A. M. , Spasojevic Ivan , Snyder Joshua C. , Dzirasa Kafui , Johnson G. Allan , Caron Marc G.
Published: September 2017

The protease caspase-3 is a key mediator of apoptotic programmed cell death. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no simple method for mapping and quantifying nonapoptotic caspase activity in rodent brains. We therefore generated a transgenic mouse expressing a highly sensitive and specific fluorescent reporter of caspase activity, with peak signal localized to the nucleus. As a proof of concept, we first obtained evidence that nonapoptotic caspase activity influences neurophysiology in an amygdalar circuit. Then focusing on the amygdala, we were able to quantify a sex-specific persistent elevation in caspase activity in females after restraint stress. This simplein vivocaspase activity reporter will facilitate systems-level studies of apoptotic and nonapoptotic phenomena in behavioral and pathological models.

Significance Statement

Caspase-3 is an enzyme that can cause cell death when highly active but can also perform important cellular functions, such as maturation and structural changes, when only weakly or transiently active. Despite the importance of this nonlethal type of caspase activity, there is no straightforward method to measure it in live rodents. We therefore developed mice that have a fluorescent reporter that is sensitive enough to detect nonlethal caspase activity. Surprisingly, we found that weak caspase activity influences the synchrony of neuronal firing across different brain regions. We also observed increased caspase activity in female mice after severe stress. This simple caspase activity reporter can subserve multiple applications in behavior and pathology research.
indCAPS: A tool for designing screening primers for CRISPR/Cas9 mutagenesis events
Authors: Hodgens Charles , Nimchuk Zachary L. , Kieber Joseph J.
Published: September 2017

Genetic manipulation of organisms using CRISPR/Cas9 technology generally produces small insertions/deletions (indels) that can be difficult to detect. Here, we describe a technique to easily and rapidly identify such indels. Sequence-identified mutations that alter a restriction enzyme recognition site can be easily distinguished from wild-type alleles using a cleaved amplified polymorphic sequence (CAPS) technique. If a restriction site is created or altered by the mutation such that only one allele contains the restriction site, a polymerase chain reaction (PCR) followed by a restriction digest can be used to distinguish the two alleles. However, in the case of most CRISPR-induced alleles, no such restriction sites are present in the target sequences. In this case, a derived CAPS (dCAPS) approach can be used in which mismatches are purposefully introduced in the oligonucleotide primers to create a restriction site in one, but not both, of the amplified templates. Web-based tools exist to aid dCAPS primer design, but when supplied sequences that include indels, the current tools often fail to suggest appropriate primers. Here, we report the development of a Python-based, species-agnostic web tool, called indCAPS, suitable for the design of PCR primers used in dCAPS assays that is compatible with indels. This tool should have wide utility for screening editing events following CRISPR/Cas9 mutagenesis as well as for identifying specific editing events in a pool of CRISPR-mediated mutagenesis events. This tool was field-tested in a CRISPR mutagenesis experiment targeting a cytokinin receptor (AHK3) inArabidopsis thaliana. The tool suggested primers that successfully distinguished between wild-type and edited alleles of a target locus and facilitated the isolation of two novelahk3null alleles. Users can access indCAPS and design PCR primers to employ dCAPS to identify CRISPR/Cas9 alleles athttp://indcaps.kieber.cloudapps.unc.edu/.
Spatial RNA proximities reveal a bipartite nuclear transcriptome and territories of differential density and transcription elongation rates
Authors: Morf Jörg , Wingett Steven W. , Farabella Irene , Cairns Jonathan , Furlan-Magaril Mayra , Liu Xin , Craig Frank F. , Andrews Simon , Marti-Renom Marc A. , Fraser Peter
Published: September 2017

Spatial transcriptomics aims to understand how the ensemble of RNA molecules in tissues and cells is organized in 3D space. Here we introduce Proximity RNA-seq, which enriches for nascent transcripts, and identifies contact preferences for individual RNAs in cell nuclei. Proximity RNA-seq is based on massive-throughput RNA-barcoding of sub-nuclear particles in water-in-oil emulsion droplets, followed by sequencing. We show a bipartite organization of the nuclear transcriptome in which compartments of different RNA density correlate with transcript families, tissue specificity and extent of alternative splicing. Integration of proximity measurements at the DNA and NA level identify transcriptionally active genomic regions with increased nucleic acid density and faster RNA polymerase II elongation located close to compact chromatin.
CYK-4 functions independently of its centralspindlin partner ZEN-4 to cellularize oocytes in germline syncytia
Authors: Lee Kian-Yong , Green Rebecca A. , Gutierrez Edgar , Sebastian Gomez-Cavazos J. , Kolotuev Irina , Wang Shaohe , Desai Arshad , Groisman Alex , Oegema Karen
Published: September 2017

Throughout metazoans, germ cells undergo incomplete cytokinesis to form syncytia connected by intercellular bridges. Formation of gametes ultimately requires bridge closure. Here, we investigate the contribution of the conserved bridge component centralspindlin to oocyte production inC. elegans. Centralspindlin is composed of the Rho family GTPase-activating protein (GAP) CYK-4/MgcRacGAP and the microtubule motor ZEN-4/kinesin-6, which are both essential for cytokinesis. In contrast, we show that oocyte production by the syncytial germline requires CYK-4 but not ZEN-4. Longitudinal imaging after conditional CYK-4 inactivation revealed a role in oocyte cellularization, rather than in generation of syncytial compartments. CYK-4’s lipid-binding C1 domain and the GTPase-binding interface of its GAP domain were individually important for oocyte cellularization and for targeting CYK-4 to bridges, where it contributes to enrichment of active RhoA. These results identify a C1-GAP module in CYK-4 that recruits it to bridges in the germline and directs their closure to produce oocytes.

IMPACT STATEMENT

The CYK-4 subunit of centralspindlin, a broadly conserved component of intercellular bridges across metazoa, is required for the cytokinesis-like closure of intercellular bridges that cellularizes oocytes to separate them from germline syncytia.

MAJOR SUBJECT AREAS

Cell Biology, Developmental Biology & Stem Cells
Nicotine increases apoptosis in HUVECs cultured in high glucose/high fat via Akt ubiquitination and degradation
Authors: Cao Xiaofang , Han Chunling , Wen Jinsuo , Guo Xiaokun , Zhang Kejian
Published: September 2017

It is well‐documented that nicotine, the main active ingredient in cigarettes, results in endothelial cell injury in numerous diseases. However, whether nicotine plays a crucial role in endothelial cell injury in diabetes and the exact molecular mechanism that mediates this process have not been fully elucidated. The current study aimed to investigate the effects of nicotine on endothelial cell injury in diabetes and the specific molecular mechanism by which it plays a role. Human umbilical vein endothelial cells (HUVECs) were incubated in HG/HF media and treated with nicotine, PYR‐41 (a selective ubiquitin E1 inhibitor), Akt‐overexpressing adenovirus, or TTC3 and MUL1 shRNA adenovirus. Cell viability was subsequently detected by the CCK8 assay, and apoptosis was examined by caspase‐3 cleavage and activity analysis. Compared to the HG/HF incubated group, nicotine incubation significantly decreased cell survival and increased apoptosis. Moreover, nicotine induced Akt degradation via UPS, and Akt overexpression blocked nicotine‐induced apoptosis in HUVECs cultured in HG/HF media. Furthermore, the TTC3 and MUL1 shRNA adenovirus dramatically decreased the Akt ubiquitination and apoptosis induced by nicotine. These results indicate that nicotine‐induced Akt ubiquitination and degradation occurs through TTC3 and MUL1 and results in a dramatic increase in apoptosis in HUVECs cultured in HG/HF media.
MicroRNAs mir‐184 and let‐7 alter Drosophila metabolism and longevity
Authors: Gendron Christi M. , Pletcher Scott D.
Published: September 2017

MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression associated with many complex biological processes. By comparing miRNA expression between long‐lived cohorts of Drosophila melanogaster that were fed a low‐nutrient diet with normal‐lived control animals fed a high‐nutrient diet, we identified miR‐184, let‐7, miR‐125, and miR‐100 as candidate miRNAs involved in modulating aging. We found that ubiquitous, adult‐specific overexpression of these individual miRNAs led to significant changes in fat metabolism and/or lifespan. Most impressively, adult‐specific overexpression of let‐7 in female nervous tissue increased median fly lifespan by ~22%. We provide evidence that this lifespan extension is not due to alterations in nutrient intake or to decreased insulin signaling.
The effect of a behavioral activation treatment for substance use on post‐treatment abstinence: a randomized controlled trial
Authors: Daughters Stacey B. , Magidson Jessica F. , Anand Deepika , Seitz‐Brown C. J. , Chen Yun , Baker Sydney
Published: September 2017

Aims

To compare outcomes for a behavioral activation group treatment for substance use [life enhancement treatment for substance use (LETS ACT)] versus a time and group size‐matched control condition delivered in a residential treatment setting.

Design

Single‐site two‐arm parallel‐group randomized clinical trial with follow‐up assessment at 3, 6 and 12 months post‐treatment.

Setting

Residential substance use treatment facility in the United States.

Participants

Participants were 263 adults [mean age 42.7 (11.8); 29.5% female; 95.4% African American; 73.2% court mandated] whose insurance dictated 30‐day (65.9%) or 90‐day (34.1%) treatment duration.

Intervention and comparator

LETS ACT (n = 142) is a treatment developed originally for depression and modified for substance use. It teaches participants to increase positively reinforcing value‐driven activities in order to counter depression and relapse. The control group [supportive counseling (SC); n = 121] received time and group size‐matched supportive counseling. Treatment was delivered in five or eight 1‐hour sessions depending on patient length of stay.

Measurements

Percentage abstinent at follow‐up, percentage of substance use days among those reporting use, depressive symptoms [Beck Depression Inventory (BDI)] and adverse consequences of drug use [Short Inventory of Problems—Alcohol and Drug (SIP‐AD)].

Findings

LETS ACT had significantly higher abstinence rates at 3 months [odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.3–3.7], 6 months (OR = 2.6, 95% CI= 1.3–5.0) and 12 months (OR = 2.9, 95% CI = 1.3–6.1) post‐treatment compared with SC. LETS ACT participants reported significantly fewer adverse consequences from substance use at 12 months post‐treatment [B = 4.50, standard error (SE) = 2.17, 95% CI = 0.22–8.78]. Treatment condition had no effect on percentage substance use days among those who resumed use or on change in depressive symptoms; the latter decreased over time only in those who remained abstinent after residential treatment irrespective of condition (B = 0.43, SE = 0.11, 95% confidence interval = 0.22–0.65).

Conclusions

A behavioral activation group treatment for substance use (LETS ACT) appears to increase the likelihood of abstinence and reduce adverse consequences from substance use up to 12 months post‐treatment.
Dwarf shrub and grass vegetation resistant to long‐term experimental warming while microarthropod abundance declines on the Falkland Islands
Authors: Bokhorst S. , Convey P. , Huiskes A. , Aerts R.
Published: September 2017

Dwarf shrubs are a dominant plant type across many regions of the Earth and have hence a large impact on carbon and nutrient cycling rates. Climate change impacts on dwarf shrubs have been extensively studied in the Northern Hemisphere, and there appears to be large variability in response between ecosystem types and regions. In the Southern Hemisphere, less data are available despite dwarf shrub vegetation being a dominant feature of southern South America and mountainous regions of the Southern Hemisphere. Here, we present the response of anEmpetrum rubrumdwarf shrub and aPoagrass community to 12 years of experimental climate manipulation achieved using open top chambers on the Falkland Islands, a cold temperate island group in the South Atlantic. The dwarf shrub and grass vegetation did not change significantly in cover, biomass or species richness over the 12 years period in response to climate warming scenarios of up to 1°C reflecting annual warming levels predicted in this region for the coming decades. The soil microarthropod community, however, responded with declines in abundance (37%) under warming conditions in the grass community, but no such changes were observed in the dwarf shrub community. Overall, our data indicate that dwarf shrub communities are resistant to the levels of climate warming predicted over the coming decades in the southern South America region and will, therefore, remain a dominant driver of local ecosystem properties.
The complexity of forest borders determines the understorey vegetation
Authors: Lindgren Jessica , Kimberley Adam , Cousins Sara A. O.
Published: September 2017

Questions

What are the most important drivers of plant species richness (gamma‐diversity) and species turnover (beta‐diversity) in the field layer of a forest edge? Does the tree and shrub species richness structure and complexity affect the richness of forest and grassland specialist species?

Location

Southeast Sweden.

Methods

We sampled 50 forest edges with different levels of structural complexity in agricultural landscapes. In each border we recorded trees, shrubs and herb layer species in a 50‐m transect parallel with the forest. We investigated species composition and species turnover in relation to the proportions of gaps in the border and the diversity of trees and shrubs.

Results

Total plant species richness in the field layer was mainly explained by the proportion of gaps to areas with full canopy cover and tree diversity. Increasing number of gaps promoted higher diversity of grassland specialist species within the field layer, resulting in open forest borders with the highest overall species richness. Gaps did however have a negative impact on forest species richness. Conversely, increasing forest species richness was positively related to tree diversity, but the number of grassland specialist species was negatively affected by tree diversity.

Conclusions

Managing forest borders, and therefore increasing the area of semi‐open habitats in fragmented agricultural landscapes, provides future opportunities to create a network of suitable habitats for both grassland and deciduous forest specialist species. Such measures therefore have the potential to increase functional connectivity and support dispersal of species in homogeneous forest/agricultural landscapes.
Is acetaminophen associated with a risk of Stevens–Johnson syndrome and toxic epidermal necrolysis? Analysis of the French Pharmacovigilance Database
Authors: Lebrun‐Vignes Bénédicte , Guy Claire , Jean‐Pastor Marie‐Josèphe , Gras‐Champel Valérie , Zenut Marie ,   The French Network of Regional Centres of Pharmacovigilance and the French Investigators for Adverse Skin Reactions to Drugs
Published: September 2017

Aim

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe mostly drug‐induced cutaneous reactions. Acetaminophen is an over‐the‐counter drug used worldwide to treat pain and reduce fever. In 2013, the US Food and Drug Administration informed the public that acetaminophen was associated with a rare risk of SJS/TEN. The aim of the present retrospective study was to analyse reports of acetaminophen as a possible suspect in the development of SJS/TEN from the French Pharmacovigilance Database (FPDB).

Methods

Cases of TEN/SJS with acetaminophen as a suspect drug registered in the FPDB, collected from January 2002 to December 2013, were analysed by an expert group. The algorithm of drug causality for epidermal necrolysis (ALDEN) was used as a reference tool for SJS/TEN to assess the causality of each suspect drug.

Results

After exclusion of 16 nonvalidated cases, 112 cases (47 TEN, 51 SJS, 14 SJS/TEN overlaps) involving 574 suspected drugs (5⋅1/case) were analysed. In 80 cases, the acetaminophen ALDEN score was inferior or equal to that of other drugs, associated with a higher suspicion for causality. In 32 cases, acetaminophen had the highest score but matched with a ‘very unlikely’ or ‘unlikely’ causality in 12 cases. For the 20 remaining cases with a ‘possible’ or ‘ probable’ causality, a protopathic or a confounding bias was likely in 14 cases.

Conclusions

After analysis of the French pharmacovigilance data using the ALDEN algorithm, we found no obvious SJS/TEN risk related to the use of acetaminophen in this large national series.
Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period
Authors: Schwarz J , Scheckenbach V , Kugel H , Spring B , Pagel J , Härtel C , Pauluschke-Fröhlich J , Peter A , Poets C F , Gille C , Köstlin N
Published: September 2017

Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal–fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.
The anti-CD6 antibody itolizumab provides clinical benefit without lymphopenia in rheumatoid arthritis patients: results from a 6-month, open-label Phase I clinical trial
Authors: Rodríguez P C , Prada D M , Moreno E , Aira L E , Molinero C , López A M , Gómez J A , Hernández I M , Martínez J P , Reyes Y , Milera J M , Hernández M V , Torres R , Avila Y , Barrese Y , Viada C , Montero E , Hernández P
Published: September 2017

Itolizumab is a humanized anti-CD6 monoclonal antibody (mAb) that has previously shown encouraging results, in terms of safety and positive clinical effects, in a 6-week monotherapy clinical trial conducted in rheumatoid arthritis (RA) patients. The current Phase I study evaluated the safety and clinical response for a longer treatment of 12 itolizumab intravenous doses in subjects with active RA despite previous disease-modifying anti-rheumatic drug (DMARD) therapy. Twenty-one subjects were enrolled into four dosage groups (0·1, 0·2, 0·4 and 0·8 mg/kg). Efficacy end-points including American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates and disease activity score in 28 joints (DAS28) were monitored at baseline and at specific time-points during a 10-week follow-up period. Itolizumab was well tolerated up to the highest tested dose. No related serious adverse events were reported and most adverse events were mild. Remarkably, itolizumab treatment did not produce lymphopenia and, therefore, was not associated with infections. All patients achieved a clinical response (ACR20) at least once during the study. Eleven subjects (55%) achieved at least a 20% improvement in ACR just 1 week after the first itolizumab administration. The clinical response was observed from the beginning of the treatment and was sustained during 24 weeks. The efficacy profile of this 12-week treatment was similar to that of the previous study (6-week treatment). These results reinforce the safety profile of itolizumab and provide further evidence on the clinical benefit from the use of this anti-CD6 mAb in RA patients.
Factors associated with low anterior resection syndrome after surgical treatment of rectal cancer
Authors: Jimenez‐Gomez L. M. , Espin‐Basany E. , Trenti L. , Martí‐Gallostra M. , Sánchez‐García J. L. , Vallribera‐Valls F. , Kreisler E. , Biondo S. , Armengol‐Carrasco M.
Published: September 2017

Aim

The aim was to assess factors independently associated with low anterior resection syndrome (LARS) following resection for rectal cancer.

Method

This was a cross‐sectional study carried out in two acute‐care teaching hospitals in Barcelona, Spain. Patients who had undergone sphincter‐preserving low anterior resection with curative intent with total or partial mesorectal excision (with and without protective ileostomy) between January 2001 and December 2009 completed a self‐administered questionnaire to assess bowel dysfunction after rectal cancer surgery. Predictors of LARS were assessed by univariate and multivariate analyses.

Results

The questionnaire was sent to 329 patients (response rate 57.7%). Six cases of incomplete questionnaires were excluded. The study population included 184 patients (66.8% men) with a mean age of 63 years. There were 44 (23.9%) patients with no LARS, 36 (19.6%) with minor LARS and 104 (56.2%) with major LARS. In the univariate analysis, total mesorectal excision (P = 0.0008), protective ileostomy (P = 0.002), preoperative and postoperative radiotherapy (P = 0.0000), postoperative chemotherapy (P = 0.0046) and age (P = 0.035) were significantly associated with major LARS, whereas in the multivariate analysis total mesorectal excision (OR 2.18, 95% CI: 1.02–4.65), preoperative radiotherapy (OR 4.33, 95% CI: 2.03–9.27) and postoperative radiotherapy (OR 9.52, 95% CI: 1.74–52.24) were independent risk factors for major LARS.

Conclusions

In this study, the risk of having major LARS increases with total mesorectal excision and both neoadjuvant and adjuvant radiotherapy.
The relationship between quality of life and health‐related quality of life in young males with Duchenne muscular dystrophy
Authors: Wei Yi , Speechley Kathy Nixon , Zou Guangyong , Campbell Craig
Published: September 2017

Aim

This study investigated the relationship between quality of life (QoL) and health‐related quality of life (HRQoL) and assessed factors other than health that contribute to differences in QoL in young males with Duchenne muscular dystrophy (DMD).

Method

In this cross‐sectional study, QoL and HRQoL measures were completed by 98 parents and 85 children. The Quality of My Life (QoML) questionnaire measured QoL and HRQoL as single‐items, and the Pediatric Quality of Life 4.0 Generic Core (PedsQL) questionnaire was used as a multidimensional measure of HRQoL. Simple regression was used to examine the relationship between single‐item measures of HRQoL and QoL. Multivariable regression was used to investigate factors that may contribute to difference in QoL and HRQoL.

Results

While ratings of QoL and HRQoL were significantly correlated with one another, HRQoL only accounted for 21% and 44% of the variability in QoL by child‐ and parent‐reports respectively. None of the factors measured contributed ratings of the child's QoL to be much higher than HRQoL.

Interpretation

QoL and HRQoL are related but distinct constructs as rated by children with DMD and their parents. Further research is needed to elucidate factors outside HRQoL that contribute to QoL.

What this paper adds

Quality of life (QoL) and health‐related quality of life are distinct concepts rated by young males with Duchenne muscular dystrophy (DMD) and their parents.

Factors outside of ‘health’ contribute to overall QoL in the paediatric population with DMD.

This article's abstract has been translated into Spanish and Portuguese.

Follow the links from the abstract to view the translations.
Community Health Centre‐Based Outreach Clinic for undergraduate dental education: Experience in Helsinki over 8 years
Authors: Goswami S. , Karaharju‐Suvanto T. , Kaila M. , Tseveenjav B.
Published: September 2017

Introduction

The University Dental Clinic of the City of Helsinki (UDC) developed a Community Health Centre‐Based Outreach Clinic, with emphasis on paediatric dentistry. This study aimed to summarise the experiences and explore the student perspectives of the health centre‐based outreach teaching clinic.

Methods

The study data were from the years 2010 to 2016. The dental procedures carried out by the third‐ to fifth‐year dental students were based on electronic health record of patients. The students’ self‐perceived benefits and free‐text comments on the outreach training were collected as part of a yearly questionnaire survey.

Results

A vast majority of the paediatric dental procedures that are required for competencies of dental students were performed in the outreach clinic. The most common procedures were fillings with local anaesthesia followed by preventive procedures. The majority of the students were very motivated to participate in the outreach training and reported that it was a useful educational approach to broaden their understanding of oral diseases and clinical experience.

Conclusion

The outreach clinic gives dental students a chance to gain valuable clinical experience through the number and diversity of the dental procedures they carry out. They gain confidence and get an opportunity to get acquainted with the primary healthcare system and social determinants of oral diseases. Outreach appears to provide complementary clinical experiences that fulfil learning outcomes. Learning objectives should be taken into account when planning the outreach programme in order to offer meaningful and motivating education.
Assessing the potential of genotyping‐by‐sequencing‐derived single nucleotide polymorphisms to identify the geographic origins of intercepted gypsy moth (Lymantria dispar) specimens: A proof‐of‐concept study
Authors: Picq Sandrine , Keena Melody , Havill Nathan , Stewart Don , Pouliot Esther , Boyle Brian , Levesque Roger C. , Hamelin Richard C. , Cusson Michel
Published: September 2017

Forest invasive alien species are a major threat to ecosystem stability and can have enormous economic and social impacts. For this reason, preventing the introduction of Asian gypsy moths (AGM; Lymantria dispar asiatica and L. d. japonica) into North America has been identified as a top priority by North American authorities. The AGM is an important defoliator of a wide variety of hardwood and coniferous trees, displaying a much broader host range and an enhanced dispersal ability relative to the already established European gypsy moth (L. d. dispar). Although molecular assays have been developed to help distinguish gypsy moth subspecies, these tools are not adequate for tracing the geographic origins of AGM samples intercepted on foreign vessels. Yet, this type of information would be very useful in characterizing introduction pathways and would help North American regulatory authorities in preventing introductions. The present proof‐of‐concept study assessed the potential of single nucleotide polymorphism (SNP) markers, obtained through genotyping by sequencing (GBS), to identify the geographic origins of gypsy moth samples. The approach was applied to eight laboratory‐reared gypsy moth populations, whose original stocks came from locations distributed over the entire range of L. dispar, comprising representatives of the three recognized subspecies. The various analyses we performed showed strong differentiation among populations (FST ≥ 0.237), enabling clear distinction of subspecies and geographic variants, while revealing introgression near the geographic boundaries between subspecies. This strong population structure resulted in 100% assignment success of moths to their original population when 2,327 SNPs were used. Although the SNP panels we developed are not immediately applicable to contemporary, natural populations because of distorted allele frequencies in the laboratory‐reared populations we used, our results attest to the potential of genomewide SNP markers as a tool to identify the geographic origins of intercepted gypsy moth samples.
Placental alterations in structure and function in intra‐uterine growth‐retarded horses
Authors: Robles M. , Peugnet P. M. , Valentino S. A. , Dubois C. , Dahirel M. , Aubrière M.‐C. , Reigner F. , Serteyn D. , Wimel L. , Couturier‐Tarrade A. , Chavatte‐Palmer P.
Published: September 2017

Background

Following embryo transfer (ET), the size and breed of the recipient mare can affect fetal development and subsequent post natal growth rate and insulin sensitivity in foals.

Objectives

To investigate placental adaptation in pregnancies where increased or restricted fetal growth was induced through ET between Pony, Saddlebred and Draught horses.

Study design

In vivo experiment.

Methods

Control Pony (P, n = 21) and Saddlebred (S, n = 28) pregnancies were obtained by artificial insemination. Increased pregnancies were obtained by transferring Pony (P‐D, n = 6) and Saddlebred (S‐D, n = 8) embryos into Draught mares. Restricted pregnancies were obtained by transferring Saddlebred embryos into Pony mares (S‐P, n = 6). Placental weight and surface were recorded and samples collected for stereology and analysis of expression of genes involved in placental growth, vascularisation and nutrient transport. Data were analysed by linear model.

Results

S‐P foals were growth retarded when compared with controls despite increased gestational length. Placental weight was reduced but placental surface density and volume fraction were increased. Placental expression of genes involved in growth and development and nutrient transfer was strongly reduced. In contrast, placental size and weight were increased in enhanced growth P‐D and S‐D foals. The trophoblastic surface density and the allantoic vessels surface density were decreased in P‐D and S‐D, respectively, both with very few modifications in gene expression.

Main limitations

Control embryos were produced by artificial insemination whereas experimental embryos were produced by ET.

Conclusions

Placental structure and gene expression are modified after ET into a smaller or larger breed than that of the embryo. These adaptations contribute to the observed phenotype of foal growth restriction or enhanced growth at birth.
A circadian clock gene, PER2, activates HIF‐1 as an effector molecule for recruitment of HIF‐1α to promoter regions of its downstream genes
Authors: Kobayashi Minoru , Morinibu Akiyo , Koyasu Sho , Goto Yoko , Hiraoka Masahiro , Harada Hiroshi
Published: September 2017

Hypoxia‐inducible factor 1 (HIF‐1) is a transcription factor functioning in cellular adaptive responses to hypoxia. Recent studies have suggested that HIF‐1 activity is upregulated by one of the important circadian clock genes, period circadian clock 2 (PER2); however, its underlying mechanism remains unclear. Here, we show that PER2 functions as an effector protein for the recruitment of HIF‐1α to its cognate enhancer sequence, the hypoxia‐response element (HRE). We found that the forced expression of PER2 enhanced HIF‐1 activity without influencing expression levels of the regulatory subunit of HIF‐1, HIF‐1α, at either mRNA or protein levels. A series of coimmunoprecipitation‐based experiments revealed that PER2 interacted with HIF‐1α and facilitated the recruitment of HIF‐1α to HRE derived from vascular endothelial growth factor (VEGF) promoter. The PER2‐mediated activation of HIF‐1 was observed only when the asparagine residue at position 803 of HIF‐1α (HIF‐1α N803) was kept unhydroxylated by hypoxic stimulation, by introducing an N803A point mutation, or by an inhibitor of N803‐dioxygenase, deferoxamine. However, the extent of PER‐2‐HIF‐1α interaction was equivalent regardless of the N803 hydroxylation status. Taken together, these results suggest that, with the help of an unknown sensor molecule for the N803 hydroxylation status, PER2 functions as an effector molecule for the recruitment of HIF‐1 to promoter regions of its downstream genes. Our findings reveal a novel regulatory step in the activation of HIF‐1, which can be targeted to develop therapeutic strategies against HIF‐1‐related diseases, such as cancers.
Unfolded protein exhibits antiassociation activity toward the 50S subunit facilitating 70S ribosome dissociation
Authors: Pathak Bani K. , Banerjee Senjuti , Mondal Surojit , Chakraborty Biprashekhar , Sengupta Jayati , Barat Chandana
Published: September 2017

The ability of the ribosome to assist in the folding of proteins both in vitro and in vivo is well documented. The interaction of an unfolded protein with the peptidyltransferase center of the bacterial large ribosomal subunit is followed by release of the protein in a folding‐competent state and rapid dissociation of ribosome into its subunits. Our studies demonstrate that the 50S subunit‐associated antiassociation ability of an unfolded protein might contribute significantly to its ability to mediate energy‐independent and stable dissociation of the ribosome into its subunits. The stoichiometry of the protein present with respect to the ribosome is an important factor in determining whether the ribosome has a chaperoning effect on protein folding or if the protein acts as a 50S subunit antiassociation factor. Sustained interaction of the protein with the ribosome at higher protein concentrations and the hindrance in the formation of the central intersubunit bridge B2a could underlie the antiassociation activity of unfolded proteins. The ribosome dissociation and antiassociation activity of unfolded proteins could make the ribosome susceptible to cellular ribonucleases, thereby initiating ribosome degradation, which is a well‐documented phenomenon under nutrient deprivation conditions.
Fighting talk: complex song elicits more aggressive responses in a vocally complex songbird
Authors: Hill Samuel D. , Brunton Dianne H. , Anderson Michael G. , Ji Weihong
Published: September 2017

Song complexity in many songbirds is a trait subject to sexual selection. It is often associated with male territorial defence. Empirical studies testing differential male responses to rival song in vocally complex songbirds have, however, been scarce. We conducted playback experiments of the endemic New Zealand TuiProsthemadera novaeseelandiaeto test the aggressive response of territorial male Tui to rival songs with differing complexity levels. Overall, complex songs evoked significantly stronger responses from territorial males than did simple songs. Following playback of complex songs, focal males approached the playback more closely and rapidly, and responded with songs of higher complexity than they did to playback of simple songs. This suggests males could both distinguish between different levels of complexity within the Tui repertoire, and perceive a more complex song as a greater territorial threat. Our study is one of the first to demonstrate strong aggressive responses to increased levels of song complexity in a songbird species with highly complex vocalizations.