bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two Nimrod receptors, NimC1 and Eater, synergistically contribute to bacterial phagocytosis inDrosophila melanogaster
Authors: Melcarne Claudia , Ramond Elodie , Dudzic Jan , Bretscher Andrew J , Kurucz Éva , Andó István , Lemaitre Bruno 
Published: November 2018

AbstractEater and NimC1 are transmembrane receptors of theDrosophilaNimrod family, specifically expressed in hemocytes, the insect blood cells. Previousex vivoandin vivoRNAi studies have pointed to their role in the phagocytosis of bacteria. Here, we have created a novel null mutant in NimC1 to re-evaluate the role of NimC1, alone or in combination with Eater, in the cellular immune response. We show that NimC1 functions as an adhesion moleculeex vivo, but in contrast to Eater is not required for hemocyte sessilityin vivo.Ex vivophagocytosis assays and electron microscopy experiments confirmed that Eater is the main phagocytic receptor for Gram-positive, but not Gram-negative bacteria, and contributes to microbe tethering to hemocytes. Surprisingly, theNimC1deletion did not impair phagocytosis of bacteria, nor their adhesion to the hemocytes. However, phagocytosis of both types of bacteria was almost abolished inNimC11;eater1hemocytes. This indicates that both receptors contribute synergistically to the phagocytosis of bacteria, but that Eater can bypass the requirement for NimC1. Finally, we uncovered that NimC1, but not Eater, is essential for uptake of latex beads and zymosan particles. We conclude that Eater and NimC1 are the two main receptors for phagocytosis of bacteria inDrosophila,and that each receptor likely plays distinct roles in microbial uptake.
Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland
Authors: Arnau-Soler Aleix , Macdonald-Dunlop Erin , Adams Mark J. , Clarke Toni-Kim , MacIntyre Donald J. , Milburn Keith , Navrady Lauren , Scotland Generation ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hayward Caroline , McIntosh Andrew M. , Thomson Pippa A. 
Published: November 2018

ABSTRACTStress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77×10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53kb downstream PIWIL4; p = 4.95×10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46×10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00×10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77×10-6). Polygenic risk scores (PRS) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91×10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
The Participation and Motivations of Grant Peer Reviewers: A Comprehensive Survey
Authors: Gallo Stephen A , Thompson Lisa A , Schmaling Karen B , Glisson Scott R 
Published: November 2018

AbstractScientific peer reviewers play an integral role in the grant selection process, yet very little has been reported on the levels of participation or the motivations of scientists to take part in peer review. AIBS developed a comprehensive peer review survey that examined the motivations and levels of participation of grant reviewers. The survey was disseminated to 13,091 scientists in AIBS’s proprietary database. Of the 874 respondents, 76% indicated they had reviewed grant applications in the last 3 years; however, the number of reviews was unevenly distributed across this sample. Higher review loads were associated with respondents who had submitted more grant proposals over this time period, some of whom were likely to be study section members for large funding agencies. The most prevalent reason to participate in a review was to give back to the scientific community (especially among frequent grant submitters) and the most common reason to decline an invitation to review was lack of time. Interestingly, few suggested that expectation from the funding agency was a motivation to review. Most felt that review participation positively influenced their careers through improving grantsmanship and exposure to new scientific ideas. Of those who reviewed, respondents reported dedicating 2-5% of their total annual work time to grant review and, based on their self-reported maximum review loads, it is estimated they are participating at 56%-89% of their capacity, which may have important implications regarding the sustainability of the system. Overall, it is clear that participation in peer review is uneven and in some cases near capacity, and more needs to be done to create new motivations and incentives to increase the future pool of reviewers.
Nucleoid size scaling and intracellular organization of translation across bacteria
Authors: Gray William T. , Govers Sander K. , Xiang Yingjie , Parry Bradley R. , Campos Manuel , Kim Sangjin , Jacobs-Wagner Christine 
Published: November 2018

SummaryThe scaling of organelles with cell size is thought to be exclusive to eukaryotes. Here, we demonstrate that similar scaling relationships hold for the nucleoid in bacteria. Despite the absence of a nuclear membrane, nucleoid size strongly correlates with cell size, independent of changes in DNA amount and across various nutrient conditions. This correlation is observed in diverse bacteria, revealing a near-constant ratio between nucleoid and cell size for a given species. As in eukaryotes, the nucleocytoplasmic ratio in bacteria varies greatly among species. This spectrum of nucleocytoplasmic ratios is independent of genome size, and instead appears linked to the average cell size of the population. Bacteria with different nucleocytoplasmic ratios have different biophysical properties of the cytoplasm, impacting the mobility and localization of ribosomes. Together, our findings identify new organizational principles and biophysical features of bacterial cells, implicating the nucleocytoplasmic ratio and cell size as determinants of the intracellular organization of translation.
Limits to a classic paradigm: Most transcription factors regulate genes in multiple biological processes
Authors: Ledezma-Tejeida Daniela , Altamirano-Pacheco Luis , Fajardo Vicente , Collado-Vides Julio 
Published: November 2018

ABSTRACTTranscription factors (TFs) are important drivers of cellular decision-making. When bacteria encounter a change in the environment, transcription factors alter the expression of a defined set of genes in order to adequately respond. It is commonly assumed that genes regulated by the same TF should be involved in the same biological process. Examples of this are methods that rely on coregulation to infer function of not yet annotated genes. We have previously shown that only 21% of TFs regulate functionally homogeneous genes based on the proximity of their catalyzed reactions in the metabolic network. Here, we provide more evidence to support the claim that a one TF/one process relationship is not a general property. We show that the observed functional heterogeneity of regulons is not a result of the quality of the annotation of regulatory interactions, or the absence of protein-metabolite interactions, and is also present when function is defined by Gene Ontology terms. Furthermore, the observed functional heterogeneity is different from the one expected by chance, supporting the notion that it is a biological property. To further explore the relationship between transcriptional regulation and metabolism, we analyze 5 other types of regulatory groups and identify complex regulons (i.e. genes regulated by the same combination of TFs) as the most functionally homogeneous, which is supported by coexpression data. Whether higher levels of related functions exist beyond metabolism and current functional annotations, remains an open question.
Isolation and Identification of Enterovirus D111 in a Child with Acute Flaccid Paralysis in Nigeria
Authors: Faleye T.O.C. , Adewumi M.O. , Olayinka O.T. , Adeniji J.A 
Published: November 2018

ABSTRACTThe WHO recommended cell-culture-based algorithm requires enterovirus (EV) isolates to produce reproducible cytopathic effect (R-CPE) in RD and/or L20b cell lines. Samples with non-reproducible CPE (NR-CPE) are considered negative for EVs. We investigated whether there could be EVs lurking in samples with NR-CPE.Fifty-nine (59) cell culture supernatants (CCS) (collected between 2016 and 2017) recovered from RD and L20b cell culture tubes with NR-CPE, were analyzed in this study. The tubes had been previously inoculated with stool suspension from children (<15 years) in Nigeria with acute flaccid paralysis (AFP). All CCS were screened for Enteric Adenoviruses and group A Rotavirus using a rapid immunochromatographic test kit. Subsequently, they were passaged in HEp-2 cell line. All isolates were subjected to RNA extraction, cDNA synthesis, three (5l-UTR, VP1 and EV Species C [EV-C]) different PCR assays and sequencing of amplicons. EVs were further subjected to Illumina sequencing.All CCS were negative for Adenoviruses and group A Rotaviruses. Four CCS produced R-CPE in HEp-2 cell line, three of which were positive for the 5l-UTR assay. Of the 3 isolates two and none were positive for the VP1 and EV-C assays, respectively. One of the two VP1 amplicons was successfully sequenced and identified as Echovirus 1(E1). Illumina sequencing of the three 5l- UTR positive isolates confirmed the E1 isolate and typed the remaining two as EV-Ds (94 and 111).We describe the first EV-D94 and 111 isolates of Nigerian origin. We also show that NR-CPE could sometimes be caused by EVs that do not produce R-CPE in RD and L20b cell lines but do so in other cell lines like HEp-2.
Modelling conduction delays in the corpus callosum using MRI-measured g-ratio
Authors: Berman S. , Filo S. , Mezer A. A. 
Published: November 2018

AbstractConduction of action potentials along myelinated axons is affected by their structural features, such as the axonal g-ratio, the ratio between the inner and outer diameters of the myelin sheath surrounding the axon. The effect of g-ratio variance on conduction properties has been quantitatively evaluated using single-axon models. It has recently become possible to estimate a g-ratio weighted measurementin vivousing quantitative MRI. Nevertheless, it is still unclear whether the variance in the g-ratio in the healthy human brain leads to significant differences in conduction velocity. In this work we tested whether the g-ratio MRI measurement can be used to predict conduction delays in the corpus callosum.We present a novel framework in which the structural properties of fibers (i.e. length and g-ratio, measured using MRI), are incorporated in a biophysical model of axon conduction, to predict conduction delays of long-range white matter fibers. We applied this framework to the corpus callosum, and found conduction delay estimates that are compatible with previously estimated values of conduction delays. We account for the variance in the velocity given the axon diameter distribution in the splenium, mid-body and genu, to further compare the fibers within the corpus callosum.Conduction delays have been suggested to increase with age. Therefore, we investigated whether there are differences in the g-ratio and the fiber length between young and old adults, and whether this leads to a difference in conduction speed and delays. We found small but significant differences between the predicted delays of the two groups in the motor fibers of the corpus callosum. We also found that the motor fibers of the corpus callosum have the fastest conduction estimates. Using the axon diameter distributions, we found that the occipital fibers have the slowest estimations, while the frontal and motor fiber tracts have similar estimates.Our study provides a framework for predicting conduction latenciesin vivo. The framework could have major implications for future studies of white matter diseases and large range network computations. Our results highlight the need for improving additionalin vivomeasurements of white matter microstructure.
DYT1 dystonia patient-derived fibroblasts have increased deformability and susceptibility to damage by mechanical forces
Authors: Gill Navjot Kaur , Ly Chau , Kim Paul H. , Saunders Cosmo A. , Fong Loren G. , Young Stephen G. , Luxton G.W. Gant , Rowat Amy C. 
Published: November 2018

AbstractDYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the DYT1/TOR1A gene, which encodes torsinA, the luminal ATPase-associated (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown. Here, we define the mechanotype of mouse fibroblasts lacking functional torsinA as well as human fibroblasts isolated from DYT1 dystonia patients. We find that the deletion of torsinA or the expression of torsinA containing the DYT1 dystonia-causing ΔE302/303 (ΔE) mutation results in a more deformable cellular mechanotype. We observe a similar increased deformability of mouse fibroblasts that lack lamina-associated polypeptide 1 (LAP1), which interacts with and stimulates the ATPase activity of torsinA in vitro; as well as with depletion of the LINC complex proteins, Sad1/UNC-84 (SUN)1 and SUN2, lamin A/C, or lamin B1. Moreover, we report that DYT1 dystonia patient-derived fibroblasts are more compliant than fibroblasts isolated from unafflicted individuals. DYT1 fibroblasts also exhibit increased nuclear strain and decreased viability following mechanical stretch. Taken together, our results support a model where the physical connectivity between the cytoskeleton and nucleus contributes to cellular mechanotype. These findings establish the foundation for future mechanistic studies to understand how altered cellular mechanotype may contribute to DYT1 dystonia pathogenesis; this may be particularly relevant in the context of how neurons sense and respond to mechanical forces during traumatic brain injury, which is known to be a major cause of acquired dystonia.
Cross-reactivity reduced dengue virus serotype 2 vaccine does not confer cross-protection against other serotypes of dengue viruses
Authors: Galula Jedhan Ucat , Yang Chung-Yu , Davis Brent S. , Chang Gwong-Jen J. , Chao Day-Yu 
Published: November 2018

AbstractThe four serotypes of dengue virus (DENV) cause the most important rapidly emerging arthropod-borne disease globally. The humoral immune response to DENV infection is predominantly directed against the immunodominant cross-reactive weakly neutralizing epitopes located in the highly conserved fusion peptide of ectodomain II of envelope (E) protein (EDIIFP). Antibodies recognizing EDIIFP have been shown to associate with immune enhancement in an ex vivo animal model. In this study, we explored how prime-boost strategies influence the immunogenicity of a cross-reactivity reduced (CRR) DENV-2 vaccine with substitutions in EDIIFP residues (DENV-2 RD) and found that mice in various DENV-2 RD prime-boost immunizations had significantly reduced levels of EDIIFP antibodies. In addition, heterologous DENV-2 RD DNA-VLP prime-boost immunization induced higher and broader levels of total IgG and neutralizing antibodies (NtAbs) although IgG titers to DENV-2 and 3 were statistically significant. Consistently, mice from DENV-2 RD DNA-VLP prime-boost immunization were fully protected from homologous DENV-2 lethal challenge and partially protected (60% survival rate) from heterologous lethal DENV-3 challenge. Our results conclude that the CRR DENV-2 RD vaccine requires a multivalent format to effectively elicit a balanced and protective immunity across all four DENV serotypes.ImportanceThe low vaccine efficacy of the live-attenuated chimeric yellow fever virus-DENV tetravalent dengue vaccine (CYD-TDV) is unexpected and there is an urgent need to develop a next generation of dengue vaccine. Antibodies against the fusion peptide in envelope protein (E) ectodomain II (EDIIFP) can potentially induce a severe disease via antibody-dependent enhancement (ADE) of infection. This study evaluated different formats of an EDIIFP-modified DENV-2 vaccine (DENV-2 RD) in its capability of inducing a reduced EDIIFP antibodies, and sculpting the immune response towards an increased DENV complex-reactive neutralizing antibodies (CR NtAb). The results from this study confirmed the poor correlate of neutralizing assay with protection as suggested by the results of CYD-TDV clinical trials. There is a urgent need to develop a biological correlate with protection while evaluating the efficacy of the next generation dengue vaccine.
Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet IGF-1
Authors: Nackiewicz D. , Dan M. , Speck M. , Chow S. Z. , Chen Y.C. , Pospisilik J. A. , Verchere C. B. , Ehses J. A. 
Published: November 2018

SummaryMacrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages expressed increasedIgf1, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet IGF-1 production. Adoptive transfer experiments showed that macrophages can maintain insulin secretionin vivofollowing beta-cell death with no effects on islet-cell turnover. IGF-1 neutralization during STZ-treatment decreased insulin secretion without affecting islet-cell apoptosis or proliferation. Interestingly, high fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages fromdb/dbmice also expressed decreased proinflammatory cytokines and increasedIgf1mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia.
Mismatch repair disturbs meiotic class I crossover control
Authors: Cooper Tim J. , Crawford Margaret R. , Hunt Laura J. , Marsolier-Kergoat Marie-Claude , Llorente Bertrand , Neale Matthew J. 
Published: November 2018

SummarySequence divergence, mediated by the anti-recombinogenic activity of mismatch repair (MMR), forms a barrier to meiotic recombination and in turn the formation of viable gametes. However, rather than MMR acting as a non-specific impediment to meiotic recombination, here we provide evidence that at regions of greater sequence divergence MMR preferentially suppresses interfering (class I) crossovers (COs). Specifically, as measured in twoSaccharomyces cerevisiaehybrids containing thousands of DNA-sequence polymorphisms, removal of MMR components increases both the frequency of CO formation and the uniformity of the observed CO distribution. At fine scale, CO positions are skewed away from polymorphic regions in MMR-proficient cells, but, critically, not when members of the class I CO pathway,MSH4orZIP3, are inactivated. These findings suggest that class I COs are more sensitive to heteroduplex DNA arising during recombination. Simulations and analysis of Zip3 foci on meiotic chromosomes support roles for Msh2 both early and late in the class I CO maturation process. Collectively, our observations highlight an unexpected interaction between DNA sequence divergence, MMR, and meiotic class I CO control, thereby intimately linking the regulation of CO numbers and their distribution to pathways contributing to reproductive isolation and eventual speciation.
Millimetre wave radiation activates leech nociceptors via TRPV1-like receptor sensitisation
Authors: Romanenko S. , Harvey A. R. , Hool L , Begley R. , Fan S. , Wallace V. P. 
Published: November 2018

AbstractDue to new applications such as wireless communications, security scanning, and imaging the presence of artificially generated high frequency (30-300 GHz) millimetre-wave (MMW) signals in the environment is increasing. Although safe exposure levels have been set by studies involving direct thermal damage to tissue, there is evidence that MMWs can have an impact on cellular function, including neurons. Earlier in vitro studies have shown that exposure levels well below the recommended safe limit of 1mW/cm2 cause changes in the action potential (AP) firing rate, resting potential, and AP pulse shape of sensory neurons in leech preparations, as well as alter neuronal properties in rat cortical brain slices; these effects differ from changes induced by direct heating. In this paper we examine continuous MMW power (up to 80 mW/cm2 at 60 GHz) and evaluate the responses in the thermosensitive primary nociceptors of the medicinal leech (genus Richardsonianus Australis). The results show that MMW exposure causes an almost two-fold decrease in the threshold for activation of the AP compared with conductive heating (3.6±0.4 mV vs. 6.5±0.4 mV respectively). Our analysis suggests that MMW exposure mediated threshold alterations are not caused by enhancement of voltage gated sodium and potassium conductance. Moreover, it appears that MMW exposure has a modest suppressing effect on membrane excitability. We propose that the reduction in AP threshold can be attributed to sensitization of the TRPV1-like receptor in the leech nociceptor. In silico modelling supported the experimental findings. Our results provide evidence that MMW exposure stimulates specific receptor responses that differ from direct conductive heating, fostering the need for additional studies.