bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease
Authors: Sasaki Takanori , Yajima Taiki , Shimaoka Tatsuro , Ogawa Shuhei , Saito Takashi , Yamaoka Kunihiro , Takeuchi Tsutomu , Kubo Masato 
Published: November 2019

AbstractIgG4-related disease (IgG4-RD) is characterized by multi-organ irreversible damage resulting from tissue-specific infiltration of IgG4+ plasma cells and cytotoxic T lymphocytes (CTLs). However, whether IgG4 antibody contributes to the inflammation remains unclear. In this study, we established a mouse model that enabled us to evaluate the pathogenic function of IgG4 antibodies in response to a tissue-specific autoantigen using recombinant ovalbumin (OVA)-specific human IgG4 monoclonal antibody (rOVA-hIgG4 mAb) and the mice expressing OVA of the pancreatic islets (RIP-mOVA mice). We found no inflammatory effect of rOVA-hIgG4 mAb transfer alone; however, co-transfer with OVA-specific CD8 CTLs (OT-I T cells) induced tissue damage with dense lymphocytic inflammation in the pancreas of RIP-mOVA mice. rOVA-hIgG4 mAb caused accumulation of conventional DC1 cells (cDC1s) in the lymphoid tissues, and the dendritic cells (DCs) activated the OT-I T cells via cross-presentation. We also revealed that the synergistic effects of CTLs and antibodies were observed in the other subclasses including endogenous antibodies if they recognized the same antigen. The transfer of OVA-specific CD4 helper T cells (OT-II T cells) into RIP-mOVA mice induced the production of anti-OVA antibody, which had a synergistic effect, through acquisition of a T follicular helper (TFH) phenotype. Moreover, using OT-II T cells deficient in Bcl6 caused lower anti-OVA antibody production and inflammation with OT-I T cells. Our results indicated that autoreactive IgG4 antibodies play an important role of the tissue-specific CTL response in IgG4-RD.
Selective suppression of oral allergen-induced anaphylaxis by Allergin-1 on basophils in mice
Authors: Lin Yu-Hsien , Tahara-Hanaoka Satoko , Nagai Kei , Yoshikawa Soichiro , Kubo Masato , Shibayama Shiro , Karasuyama Hajime , Shibuya Akira 
Published: November 2019

Abstract
Mast cells (MCs) play a critical role in oral allergen-induced anaphylaxis. However, the contribution of basophils to the anaphylaxis remains unclear. The inhibitory immunoreceptor Allergin-1 is highly expressed on MCs and basophils and inhibits FcεRI-mediated signaling in MCs. Here, we show that Allergin-1-deficient (Milr1−/−) mice developed more severe hypothermia, a higher mortality rate and a greater incidence of diarrhea than did wild-type (WT) mice in an oral ovalbumin (OVA)-induced food allergy model. MC-deficient Mas–TRECK mice, which had been reconstituted with either WT or Milr1−/− bone marrow-derived cultured MCs, did not develop hypothermia in this food allergy model. On the other hand, depletion of basophils by injection of anti-CD200R3 antibody rescued Milr1−/− mice from lethal hypothermia but not from diarrhea. In vitro analyses demonstrated that Allergin-1 inhibits IgE-dependent activation of both human and mouse basophils. Thus, Allergin-1 on basophils selectively suppresses oral allergen-induced anaphylaxis.
Did a quality improvement intervention improve quality of maternal health care? Implementation evaluation from a cluster-randomized controlled study
Authors: Larson Elysia , Mbaruku Godfrey M , Cohen Jessica , Kruk Margaret E 
Published: November 2019

Abstract

Objective
To test the success of a maternal healthcare quality improvement intervention in actually improving quality.

Design
Cluster-randomized controlled study with implementation evaluation; we randomized 12 primary care facilities to receive a quality improvement intervention, while 12 facilities served as controls.

Setting
Four districts in rural Tanzania.

Participants
Health facilities (24), providers (70 at baseline; 119 at endline) and patients (784 at baseline; 886 at endline).

Interventions
In-service training, mentorship and supportive supervision and infrastructure support.

Main outcome measures
We measured fidelity with indictors of quality and compared quality between intervention and control facilities using difference-in-differences analysis.

Results
Quality of care was low at baseline: the average provider knowledge test score was 46.1% (range: 0–75%) and only 47.9% of women were very satisfied with delivery care. The intervention was associated with an increase in newborn counseling (β: 0.74, 95% CI: 0.13, 1.35) but no evidence of change across 17 additional indicators of quality. On average, facilities reached 39% implementation. Comparing facilities with the highest implementation of the intervention to control facilities again showed improvement on only one of the 18 quality indicators.

Conclusions
A multi-faceted quality improvement intervention resulted in no meaningful improvement in quality. Evidence suggests this is due to both failure to sustain a high-level of implementation and failure in theory: quality improvement interventions targeted at the clinic-level in primary care clinics with weak starting quality, including poor infrastructure and low provider competence, may not be effective.
Isolation of Metrosideros (ʻOhiʻa) Taxa on Oʻahu Increases with Elevation and Extreme Environments
Authors: Stacy Elizabeth A , Sakishima Tomoko , Tharp Heaven , Snow Neil 
Published: November 2019

AbstractSpecies radiations should be facilitated by short generation times and limited dispersal among discontinuous populations. Hawaii’s hyper-diverse, landscape-dominant tree, Metrosideros, is unique among the islands’ radiations for its massive populations that occur continuously over space and time within islands, its exceptional capacity for gene flow by both pollen and seed, and its extended life span (ca. &gt;650 years). Metrosideros shows the greatest phenotypic and microsatellite DNA diversity on Oʻahu, where taxa occur in tight sympatry or parapatry in mesic and montane wet forest on 2 volcanoes. We document the nonrandom distributions of 12 taxa (including unnamed morphotypes) along elevation gradients, measure phenotypes of ~6-year-old common-garden plants of 8 taxa to verify heritability of phenotypes, and examine genotypes of 476 wild adults at 9 microsatellite loci to compare the strengths of isolation across taxa, volcanoes, and distance. All 8 taxa retained their diagnostic phenotypes in the common garden. Populations were isolated by taxon to a range of degrees (pairwise FST between taxa: 0.004–0.267), and there was no pattern of isolation by distance or by elevation; however, significant isolation between volcanoes was observed within monotypic species, suggesting limited gene flow between volcanoes. Among the infraspecific taxa of Metrosideros polymorpha, genetic diversity and isolation significantly decreased and increased, respectively, with elevation. Overall, 5 of the 6 most isolated taxa were associated with highest elevations or otherwise extreme environments. These findings suggest a principal role for selection in the origin and maintenance of the exceptional diversity that occurs within continuous Metrosideros stands on Oʻahu.
MC1R and KIT Haplotypes Associate With Pigmentation Phenotypes of North American Yak (Bos grunniens)
Authors: Petersen Jessica L , Kalbfleisch Theodore S , Parris Morgan , Tietze Shauna M , Cruickshank Jenifer 
Published: November 2019

AbstractSmall numbers of domestic yak (Bos grunniens) were imported to North America in the late 19th century indirectly from the Qinghai-Tibetan Plateau. Coat color of yak is of interest for fiber production, aesthetics, and as a potential indicator of recent hybridization with cattle. North American yak are classified into 3 major coat color patterns depending upon the presence and extent of white markings. They are further classified by nose pigmentation (black or gray). The aim of this study was to identify loci involved in white patterning and nose pigmentation of North American yak. Genotyping by mass spectrometry of markers identified through Sanger and whole-genome sequencing revealed a 388 kb haplotype of KIT associated in a semi-dominant manner with white coloration in this population of yak. This KIT haplotype is similar to both a haplotype found in white-faced Chinese yak and to haplotypes found in cattle but is divergent from other Bos species such as bison, gaur, and banteng. Melanocortin 1 receptor (MC1R) was implicated as a dominant determinant of black nose color with a single haplotype containing 2 missense mutations perfectly associated with the phenotype. The MC1R haplotype associated with black nose pigment is also similar to cattle haplotypes. No cattle studied, however, shared either of the 2 haplotypes associated with color in yak, suggesting these alleles were introgressed into yak before they were imported to North America. These results provide molecular insight into the history of North American yak and information from which breeders can determine possible color outcomes of matings.
Chromogranin A pathway: from pathogenic molecule to renal disease
Authors: Mir Saiful A. , Biswas Nilima , Cheung Wai , Wan Ji , Webster Nicholas , Macedo Etienne , O’Connor Daniel T. , Vaingankar Sucheta M. 
Published: November 2019

Background:
Chromogranin A (CHGA) is an index granin protein critical for biogenesis and exocytotic release of catecholamine storage granules. It is elevated in plasma of patients with sympathetic over-activity and kidney dysfunction. Several CHGA polymorphisms are associated with hypertensive kidney disease. Previously, we unraveled the molecular mechanism by which CHGA expression is regulated in African Americans carrying a genetic variation associated with hypertensive chronic kidney disease (CKD).

Method:
Experimental CKD mouse model were created by 5/6th nephrectomy (Npx) using wild-type and Chga−/− knockout mouse strains to delineate the role of CHGA in CKD.

Result:
Wild-type-Npx mice expressing Chga developed exacerbated azotemia and fibrosis as compared with their knockout-Npx counterparts. Gene expression profiling revealed downregulation of mitochondrial respiratory complexes genes consistent with maladaptive mitochondria in wild-type-Npx mice, contrasted to knockout-Npx. In healthy individuals, an inverse relationship between circulating CHGA levels and glomerular function was observed. In vitro, mesangial cells treated with CHGA-triggered nitric oxide release by a signaling mechanism involving scavenger receptor SR-A. The CHGA-treated and untreated mesangial cells displayed differential expression of cytokine, chemokine, complement, acute phase inflammatory and apoptotic pathway genes. Thus, build-up of plasma CHGA because of kidney injury served as an insult to the mesangial cells resulting in expression of genes promoting inflammation, fibrosis, and progression of CKD.

Conclusion:
These findings improve understanding of the role of elevated CHGA in the progression of CKD and reveal novel pathways that could be exploited for therapeutic strategies in hypertensive kidney disease.
Depression and Fatigue in Patients With Multiple Sclerosis Have No Influence on the Parameters of Cognitive Evoked Potentials
Authors: Lazarevic Snezana , Azanjac Arsic Ana , Aleksic Dejan , Toncev Gordana , Miletic-Drakulic Svetlana 
Published: November 2019

Purpose:
The purpose of this study was to examine if depression and fatigue affect event-related brain potentials (ERPs) in patients with relapsing–remitting multiple sclerosis, and to assess the significance of ERP as an indicator of cognitive impairment.

Methods:
A total of 81 relapsing–remitting multiple sclerosis patients and 32 healthy control subjects participated in the study. Cognitive functions were evaluated using a standard PASAT, the symbol digit modality test, and ERP. The degrees of depressive symptomatology and fatigue were assessed with Beck Depression Inventory, the Fatigue Severity Scale, and the Fatigue Impact Scale.

Results:
Fatigue and depression had a negative effect on the cognitive functions examined by neuropsychological tests. Depression and fatigue did not influence ERP amplitude and latency findings. Depression level was negatively correlated with symbol digit modality test score (r = −0.135, P < 0.05). Fatigue level was negatively correlated with the results for PASAT A (r = −0.225, P < 0.05) and PASAT B (r = −0.342, P < 0.01). Reaction time was positively associated with depression (r = 0.246, P = 0.01) and fatigue (r = 0.281, P = 0.01).

Conclusions:
Depression and fatigue have no effect on ERP amplitude and latency, so they cannot participate in risk assessment for the development of cognitive impairment in patients with relapsing–remitting multiple sclerosis.
Persistent loss of biologically-rich tropical forests in the Indian Eastern Himalaya
Authors: Sheth Chintan , Datta Aparajita , Parashuram Devathi 
Published: November 2019

AbstractDeforestation is a major cause of biodiversity loss in Asia. Using fine-resolution satellite imagery we assessed the change in forest cover of a state-managed Reserved Forest located in India’s Eastern Himalaya biodiversity hot-spot. Thirty-two square kilometers of forest cover was lost from 2013 and 2017 with a 5% decline in total forest area over four years. Hornbills are a key functionally important species found in the area. We therefore assessed the habitat around 29 hornbill nest trees in this Reserved Forest and estimated that there was a loss of 35% of forest cover from 2011 to 2019. We identify illegal logging (despite a ban by the Supreme Court of India) as the main driver that is depleting forest cover within this important area. Our results highlight the ongoing threats to biologically-rich forests and the need for urgent measures to halt this loss. We suggest that this study has practical implications for the governance of non-PA state-managed forests in Arunachal Pradesh. The ongoing deforestation appears to be due to organized crime, institutional inadequacy from a combination of limited resources, bureaucratic apathy, and/or ambiguity in use and ownership of forest land compared to other community forests which appear to have robust governance systems.
Mapping the growth effect of previously hidden ubiquitin alleles using an overexpression based mutational scan
Authors: Mavor David , Bolon Daniel N. A. , Mishra Parul 
Published: November 2019

AbstractDeep mutational scanning has emerged as a powerful, high throughput approach to determine the growth effect of thousands of alleles at once in bulk competition. However, to date only the growth effect of mutant alleles in isolation has been determined. Building off previous work, we have created a library of all possible single point mutations in ubiquitin and determined the growth effect of mutants overexpressed in the presence of a wild type allele. Using this scan, we explained over half of the previously missing mutants in the single allele scan by showing that they exhibit deleterious effects when co-expressed with wild type ubiquitin. Additionally, unlike the single allele growth effect, these overexpression growth effects were distributed across the entire protein. This overexpression scan methodology can identify likely dominant mutant effects in any essential gene and is highly complementary with traditional deep mutational scanning approaches.
Poly-Exposure and Poly-Genomic Scores Implicate Prominent Roles of Non-Genetic and Demographic Factors in Four Common Diseases in the UK
Authors: He Yixuan , Lakhani Chirag M , Manrai Arjun K , Patel Chirag J 
Published: November 2019

ABSTRACTWhile polygenic risk scores (PRSs) have been shown to identify a small number of individuals with increased clinical risk for several common diseases, non-genetic factors that change during a lifetime, such as lifestyle, employment, diet, and pollution, have a larger role in clinical prediction. We analyzed data from 459,613 participants of the UK Biobank to investigate the independent and combined roles of demographics (e.g., sex and age), 96 environmental exposures, and common genetic variants in atrial fibrillation, coronary artery disease, inflammatory bowel disease, and type 2 diabetes. We develop an additive modelling approach to estimate and validate a poly-exposure score (PXS) that goes beyond consideration of a handful of factors such as smoking and pollution. PXS is able to identify groups with high prevalence of the four common disease comparable to, if not better, than the PRS. Type 2 diabetes has the largest discrepancy in PXS and PRS performance, defined as the maximum area under the receiver-operator curve (AUC) (PXS AUC of 0.828 [0.821-0.836], PRS AUC of 0.711 [0.702-0.720]). Most importantly, we show that PXS identifies individuals that have low genetic risk but high overall risk for disease. While PRS is useful for screening genetically exceptional individuals in a time-invariant way, broader consideration of multiple non-genetic and modifiable factors is required to fully translate risk scores to the bedside for precision medicine. All results and the PXS calculator can be found in our web applicationhttp://apps.chiragjpgroup.org/pxs/.
Primate homologs of mouse cortico-striatal circuits
Authors: Balsters Joshua H. , Zerbi Valerio , Sallet Jérôme , Wenderoth Nicole , Mars Rogier B. 
Published: November 2019

AbstractWith the increasing necessity of animal models in biomedical research, there is a vital need to harmonise findings across species by establishing similarities and differences in rodent and primate neuroanatomy. Using a connectivity fingerprint matching approach, we compared cortico-striatal circuits across humans, non-human primates, and mice using resting state fMRI data in all species. Our results suggest that the connectivity patterns for both the nucleus accumbens and cortico-striatal motor circuits (posterior/lateral putamen) were conserved across species, making them reliable targets for cross-species comparisons. However, a large number of human and macaque striatal voxels were not matched to any mouse cortico-striatal circuit (mouse->human: 85% unassigned; mouse->macaque 69% unassigned; macaque->human; 31% unassigned). These unassigned voxels were largely localised to the caudate nucleus and anterior putamen, overlapping with executive function and social/language regions of the striatum, and connected to prefrontal-projecting cerebellar lobules and anterior prefrontal cortex, forming circuits that seem to be unique for non-human primates and humans. Our results demonstrate the potential of connectivity fingerprint matching to bridge the gap between rodent and primate neuroanatomy.
Spatial regulation of clathrin-mediated endocytosis through position-dependent site maturation
Authors: Pedersen Ross TA , Hassinger Julian E , Marchando Paul , Drubin David G 
Published: November 2019

AbstractDuring clathrin-mediated endocytosis (CME), over 50 different proteins assemble on the plasma membrane to reshape it into a cargo-laden vesicle. It has long been assumed that cargo triggers local CME site assembly in Saccharomyces cerevisiae based on the discovery that cortical actin patches clustered near exocytic sites are CME sites. Quantitative imaging data reported here lead to a radically different view of which CME steps are regulated and which steps are deterministic. We quantitatively and spatially describe progression through the CME pathway and pinpoint a cargo-sensitive regulatory transition point that governs progression from the initiation phase of CME to the internalization phase. Thus, site maturation, rather than site initiation, accounts for the previously observed polarized distribution of actin patches in this organism. While previous studies suggested that cargo ensures its own internalization by regulating either CME initiation rates or frequency of abortive events, our data instead identify maturation through a checkpoint in the pathway as the cargo-sensitive step.SummaryPedersen, Hassinger, et al. investigate steps of the clathrin-mediated endocytosis pathway that are subject to regulation. They report position-dependent differences in endocytic site maturation rates in polarized cells and suggest that cargo controls endocytic internalization through tuning site maturation rather than site initiation.
Multiple evidences suggest sox2 as the main driver of a young and complex sex determining ZW/ZZ system in turbot (Scophthalmus maximus)
Authors: Martínez Paulino , Robledo Diego , Taboada Xoana , Blanco Andrés , Gómez-Tato Antonio , Álvarez-Blázquez Blanca , Cabaleiro Santiago , Piferrer Francesc , Bouza Carmen , Viñas Ana M. 
Published: November 2019

ABSTRACTA major challenge in evolutionary biology is to find an explanation for the variation in sex-determining (SD) systems across taxa and to understand the mechanisms driving sex chromosome differentiation. We studied the turbot, holding a ZW/ZZ SD system and no sex chromosome heteromorphism, by combining classical genetics and genomics approaches to disentangle the genetic architecture of this trait. RAD-Seq was used to genotype 18,214 SNPs on 1,135 fish from 36 families and a genome wide association study (GWAS) identified a ∼ 6 Mb region on LG5 associated with sex (P < 0.05). The most significant associated markers were located close to sox2, dnajc19 and fxr1 genes. A segregation analysis enabled narrowing down the associated region and evidenced recombination suppression in a region overlapping the candidate genes. A Nanopore/Illumina assembly of the SD region using ZZ and WW individuals identified a single SNP fully associated with Z and W chromosomes. RNA-seq from 5-90 day-old fish detected the expression along the gonad differentiation period of a short non-coding splicing variant (ncRNA) included in a vertebrate-conserved long non-coding RNA overlapping sox2. qPCR showed that sox2 was the only differentially expressed gene between males and females at 50-55 days post fertilization, just prior the beginning of gonad differentiation. More refined information on the involvement of secondary genetic and environmental factors and their interactions on SD was gathered after the analysis of a broad sample of families. Our results confirm the complex nature of SD in turbot and support sox2 as its main driver.
Boosting Brain Signal Variability Underlies Liberal Shifts in Decision Bias
Authors: Kloosterman Niels A. , Kosciessa Julian Q. , Lindenberger Ulman , Fahrenfort Johannes Jacobus , Garrett Douglas D. 
Published: November 2019

AbstractStrategically adopting decision biases allows organisms to tailor their choices to environmental demands. For example, a liberal response strategy pays off when target detection is crucial, whereas a conservative strategy is optimal for avoiding false alarms. Using conventional time-frequency analysis of human electroencephalographic (EEG) activity, we previously showed that bias setting entails adjustment of evidence accumulation in sensory regions (Kloosterman et al., 2019), but the presumed prefrontal signature of a strategic conservative-to-liberal bias shift has remained elusive. Here, we show that a liberal bias shift relies on frontal regions adopting a more unconstrained neural regime (boosted entropy) that is suited to the detection of unpredictable events. Overall EEG variation, spectral power and event-related potentials could not explain this relationship, highlighting the unique contribution of moment-to-moment neural variability to bias shifts. Neural variability modulation through prefrontal cortex appears instrumental for permitting an organism to tailor its decision bias to environmental demands.Impact statementMoment-to-moment variability is a prominent feature of neural activity. Rather than representing mere noise, this variability might enable us to flexibly adapt our decision biases to the environment.