bluuebunny/crossref_metadata_2025_split huggingface dataset:
An acute bleomycin inflammatory and fibrotic mouse model of morphea is dependent upon CXCL9 and CXCR3
Authors: Richmond Jillian M. , Patel Dhrumil , Watanabe Tomoya , Garelli Colton J. , Garg Madhuri , Dresser Karen , Deng April , Feghali-Bostwick Carol A. , Harris John E. , Jacobe Heidi 
Published: June 2019

AbstractMorphea, or localized scleroderma, is characterized by an inflammatory phase followed by cutaneous fibrosis, which may lead to disfigurement and/or disability. Previous work from our group showed that the CXCR3 ligands CXCL9 and CXCL10 are highly upregulated in lesional skin of morphea patients. Here, we used an acute inflammatory and fibrotic bleomycin mouse model of morphea to examine the role of the CXCR3 chemokine axis in pathogenesis. We first characterized which cells produce the CXCR3 ligands in the skin using the Reporter of Expression of CXCR3 ligands mouse (REX3). We found that fibroblasts contribute the bulk of CXCL9 and CXCL10, whereas endothelial cells are key dual chemokine producers. Macrophages, which have high MFI of chemokine expression, upregulated CXCL9 production over time, fibroblasts CXCL10 production, and T cells dual chemokine expression. To determine whether bleomycin treatment could directly induce expression of these chemokines, we treated cultured REX3 mouse dermis monolayers in vitro with bleomycin or IFNγ with TNF and found that bleomycin could induce low amounts of CXCL9 directly in fibroblasts, whereas the cytokines were required for optimal CXCL9 and CXCL10 production. To determine whether these chemokines are mechanistically involved in pathogenesis, we induced fibrosis in CXCL9, CXCL10, or CXCR3 deficient mice and found that fibrosis is dependent on CXCL9 and CXCR3. Addition of recombinant CXCL9, but not CXCL10, to cultured mouse fibroblasts induces collagen 1a1 mRNA expression, indicating the chemokine itself can contribute to fibrosis. Taken together, our studies provide evidence that acute intradermal bleomycin administration in mice can model inflammatory morphea, and that CXCL9 and its receptor CXCR3 are mechanistically involved in pathogenesis.One Sentence SummaryCXCL9 drives acute morphea pathogenesis in mice.
Current characteristics and outcomes of Cytomegalovirus Reactivation in kidney transplant seropositive recipients in the era of prophylaxis treatment. Lesson from single Moroccan center experience
Authors: Rezzouk Bouchra. , Bouattar Tarik. , Belkadi Bouchra. , Razine Rachid. , Bayahia Rabia. , Ouzeddoun Naima. , Benamar Loubna. , Rhou Hakima. , Bouihat Najat. , Ibrahimi Azeddine , Seffar Myriam. , Kabbaj Hakima. 
Published: June 2019

AbstractDespite the use of antiviral prophylaxis, the active cytomegalovirus (CMV) replication is still occurred in the seropositive kidney recipients. The aim of this study was to assess the incidence of CMV reactivation and potential risk factors associated with CMV disease. Data of sixty kidney transplant recipients who had received CMV prophylaxis were obtained between 2013 and 2017. Quantitative nucleic acid amplification testing for CMV viraemia was assessed using Abbott RealTimePolymerase Chain Reaction (PCR). Among the seropositive recipients, cumulative incidence for reactivation was 63%. In patients with quantitative viraemia, the time of active replication was significantly lower compared to those with detectable viraemia (141.5 ± 96.9vs294.1 ± 112.6 days,P< 0.001). During prophylactic treatment, 46.7% of patients with quantifiable viraemia had experienced active replication and none among patients with detectable viraemia (P= 0.017). Importantly, symptomatic reactivation was significantly observed in the younger patients with higher peak viraemia compared to those with symptoms free (28.8 ± 5.12 vs. 38.1 ± 12.34 years,P= 0.007) and 3.8 ± 1.59 vs. 2.4 ± 0. 79 log10IU/ml,P= 0.003, respectively). Furthermore, the median duration of viraemia (21.2, vs. 13.4 days,P= 0.028) and period of CMV therapy (24.3 vs 12.3 days,P<0.001) were significantly longer for this group. In addition, intercurrent infections (75% vs. 23%,P= 0.028) and acute rejection (50 % vs 0%,P= 0.003) were significantly more frequent in symptomatic reactivation group. In addition, peak viral load was a potential risk factor for development of symptomatic reactivation with odds ratio 3.39, 95%CI=1.21-9.53,P= 0.02). In conclusion, CMV reactivation remains serious problem for seropositive recipients who were expected to be on antiviral prophylaxis. Patients with high level of viraemia may be at an increased risk of progression to CMV disease and adverse outcomes.
Forecasting the impact of population ageing on tuberculosis incidence
Authors: Ku Chu-Chang , Dodd Peter J 
Published: June 2019

AbstractBackgroundTuberculosis (TB) disease reactivates from distant latent infection or recent (re)infection. Progression risks increase with age. Across the World Health Organisation Western Pacific region, many populations are ageing and have the highest per capita TB incidence rates in older age groups. However, methods for analysing age-specific TB incidence and forecasting epidemic trends while accounting for demographic change remain limited.MethodsWe applied the Lee-Carter models, which were originally developed for mortality modelling, to model the temporal trends in age-specific TB incidence data from 2005 to 2018 in Taiwan. Females and males were modelled separately. We combined our demographic forecasts, and age-specific TB incidence forecasts to project TB incidence until 2035. We compared TB incidence projections with demography fixed in 2018 to projections accounting for demographic change.ResultsOur models quantified increasing incidence rates with age and declining temporal trends. By 2035, the forecast suggests that the TB incidence rate in Taiwan will decrease by 54% (95% Prediction Interval (PI): 45%-59%) compared to 2015, while most age-specific incidence rates will reduce by more than 60%. In 2035, adults aged 65 and above will make up 78% of incident TB cases. Forecast TB incidence in 2035 accounting for demographic change will be 39% (95% PI: 36%-42%) higher than without population ageing.ConclusionsAge-specific incidence forecasts coupled with demographic forecasts can inform the impact of population ageing on TB epidemics. The TB control programme in Taiwan should develop plans specific to older age groups and their care needs.
RADICL-seq identifies general and cell type-specific principles of genome-wide RNA-chromatin interactions
Authors: Bonetti Alessandro , Agostini Federico , Suzuki Ana Maria , Hashimoto Kosuke , Pascarella Giovanni , Gimenez Juliette , Roos Leonie , Nash Alex J. , Ghilotti Marco , Cameron Christopher JF , Valentine Matthew , Medvedeva Yulia A , Noguchi Shuhei , Agirre Eneritz , Kashi Kaori , Samudyata  , Luginbuehl Joachim , Cazzoli Riccardo , Agrawal Saumya , Luscombe Nicholas M , Blanchette Mathieu , Kasukawa Takeya , De Hoon Michiel , Arner Erik , Lenhard Boris , Plessy Charles , Castelo-Branco Gonçalo , Orlando Valerio , Carninci Piero 
Published: June 2019

AbstractMammalian genomes encode tens of thousands of noncoding RNAs. Most noncoding transcripts exhibit nuclear localization and several have been shown to play a role in the regulation of gene expression and chromatin remodelling. To investigate the function of such RNAs, methods to massively map the genomic interacting sites of multiple transcripts have been developed. However, they still present some limitations. Here, we introduce RNA And DNA Interacting Complexes Ligated and sequenced (RADICL-seq), a technology that maps genome-wide RNA-chromatin interactions in intact nuclei. RADICL-seq is a proximity ligation-based methodology that reduces the bias for nascent transcription, while increasing genomic coverage and unique mapping rate efficiency compared to existing methods. RADICL-seq identifies distinct patterns of genome occupancy for different classes of transcripts as well as cell type-specific RNA-chromatin interactions, and emphasizes the role of transcription in the establishment of chromatin structure.
HiChIP-Peaks: A HiChIP peak calling algorithm
Authors: Shi Chenfu , Rattray Magnus , Orozco Gisela 
Published: June 2019

AbstractMotivationHiChIP is a powerful tool to interrogate 3D chromatin organization. Current tools to analyse chromatin looping mechanisms using HiChIP data require the identification of loop anchors to work properly. However, current approaches to discover these anchors from HiChIP data are not satisfactory, having either a very high false discovery rate or strong dependence on sequencing depth. Moreover, these tools do not allow quantitative comparison of peaks across different samples, failing to fully exploit the information available from HiChIP datasets.ResultsWe develop a new tool based on a representation of HiChIP data centred on the re-ligation sites to identify peaks from HiChIP datasets, which can subsequently be used in other tools for loop discovery. This increases the reliability of these tools and improves recall rate as sequencing depth is reduced. We also provide a method to count reads mapping to peaks across samples, which can be used for differential peak analysis using HiChIP data.AvailabilityHiChIP-Peaks is freely available at https://github.com/ChenfuShi/HiChIP_peaksContact:chenfu.shi@postgrad.manchester.ac.uk
Fitness costs of parasites explain multiple life history tradeoffs in a wild mammal
Authors: Albery Gregory F , Morris Alison , Morris Sean , Kenyon Fiona , Nussey Daniel H , Pemberton Josephine M 
Published: June 2019

SummaryReproduction in wild animals can divert limited resources away from immune defence, resulting in increased parasite burdens. A longstanding prediction of life history theory states that these parasites can harm the reproductive individual, reducing its subsequent fitness and producing reproduction-fitness tradeoffs. Here, we examined associations among reproductive allocation, immunity, parasitism, and subsequent fitness in a wild population of individually identified red deer (Cervus elaphus). Using path analysis, we investigated whether costs of lactation for downstream survival and fecundity were mediated by changes in strongyle nematode count and mucosal antibody levels. Lactating females exhibited increased parasite counts, which were in turn associated with substantially decreased fitness in the following year in terms of overwinter survival, fecundity, subsequent calf weight, and parturition date. This study offers observational evidence for parasite regulation of multiple life history tradeoffs, supporting the role of parasites as an important mediating factor in wild mammal populations.
Common genetic variation indicates separate etiologies for periventricular and deep white matter hyperintensities
Authors: Armstrong Nicola J , Mather Karen A , Sargurupremraj Muralidharan , Knol Maria J , Malik Rainer , Satizabal Claudia L , Yanek Lisa R , Wei Wen , Gudnason Vilmundur , Deuker Nicole D , Elliott Lloyd T , Hofer Edith , Jahanshad Neda , Li Shuo , Logue Mark A , Luciano Michelle , Scholz Markus , Smith Albert , Trompet Stella S , Vojinovic Dina , Xia Rui , Alfaro-Almagro Fidel , Ames David , Amin Najaf , Amouyel Philippe , Beiser Alexa S , Brodaty Henry , Deary Ian J , Fennema-Notestine Christine , Gampwar Piyush G , Gottesman Rebecca , Griffanti Ludovica , Jack Clifford R , Jenkinson Mark , Jain Jiyang , Kral Brian G , Kwok John W , Lampe Leonie , Liewald David CM , Maillard Pauline , Marchini Jonathan , Bastin Mark E , Mazoyer Bernard , Pirpamer Lukas , Romero José Rafael , Roshchupkin Gennady V , Schofield Peter R , Schroeter Matthias L , Stott David J , Thalamuth Anbupalam , Trollor Julian , Tzourio Christophe , van der Grond Jeroen , Vernooij Meike W , Witte Veronica A , Wright Maragret J , Yang Qiong , Zoe Moris , Siggurdsson Siggi , Villringer Arno , Schmidt Helena , Haberg Asta L , Van Duijn Cornelia M , Jukema J Wouter , Dichigans Martin , Sacco Ralph L , Wright Clinton B , Kremen William S , Becker Lewis C , Thompson Paul M , Launer Lenore , Mosley Thomas H , Wardlaw Joanna M , Ikram M Afran , Adams Hieab HH , Schmidt Reinhold , Smith Stephen M , Decarli Charles , Sachdev Perminder S , Fornage Myriam , Debbette Stephanie , Seshadri Sudha , Nyquist Paul A 
Published: June 2019

AbstractWe conducted a genome-wide association meta-analysis of two ischemic white matter disease subtypes in the brain, periventricular and deep white matter hyperintensities (PVWMH and DWMH). In 26,654 participants, we found 10 independent genome-wide significant loci only associated with PVWMH, four of which have not been described previously for total WMH burden (16q24.2, 17q21.31, 10q23.1, 7q36.1). Additionally, in both PVWMH and DWMH we observed the previous association of the 17q25.1 locus with total WMH. We found that both phenotypes have shared but also distinct genetic architectures, consistent with both different underlying and related pathophysiology. PVWMH had more extensive genetic overlap with small vessel ischemic stroke, and unique associations with several loci implicated in ischemic stroke. DWMH were characterized by associations with loci previously implicated in vascular as well as astrocytic and neuronal function. Our study confirms the utility of these phenotypes and identifies new candidate genes associated only with PVWMH.
funMotifs: Tissue-specific transcription factor motifs
Authors: Umer Husen M. , Smolinska-Garbulowska Karolina , Marzouka Nour-al-dain , Khaliq Zeeshan , Wadelius Claes , Komorowski Jan 
Published: June 2019

ABSTRACTTranscription factors (TF) regulate gene expression by binding to specific sequences known as motifs. A bottleneck in our knowledge of gene regulation is the lack of functional characterization of TF motifs, which is mainly due to the large number of predicted TF motifs, and tissue specificity of TF binding. We built a framework to identify tissue-specific functional motifs (funMotifs) across the genome based on thousands of annotation tracks obtained from large-scale genomics projects including ENCODE, RoadMap Epigenomics and FANTOM. The annotations were weighted using a logistic regression model trained on regulatory elements obtained from massively parallel reporter assays. Overall, genome-wide predicted motifs of 519 TFs were characterized across fifteen tissue types. funMotifs summarizes the weighted annotations into a functional activity score for each of the predicted motifs. funMotifs enabled us to measure tissue specificity of different TFs and to identify candidate functional variants in TF motifs from the 1000 genomes project, the GTEx project, the GWAS catalogue, and in 2,515 cancer samples from the Pan-cancer analysis of whole genome sequences (PCAWG) cohort. To enable researchers annotate genomic variants or regions of interest, we have implemented a command-line pipeline and a web-based interface that can publicly be accessed on: http://bioinf.icm.uu.se/funmotifs.
MAP2 is Differentially Phosphorylated in Schizophrenia, Altering its Function
Authors: Grubisha MJ , Sun X , MacDonald ML , Garver M , Sun Z , Paris KA , Patel DS , DeGiosio RA , Lewis DA , Yates NA , Camacho C , Homanics GE , Ding Y , Sweet RA 
Published: June 2019

AbstractSchizophrenia (Sz) is a highly polygenic disorder, with common, rare, and structural variants each contributing only a small fraction of overall disease risk. Thus, there is a need to identify downstream points of convergence that can be targeted with therapeutics. Reduction of Microtubule-associated Protein 2 (MAP2) immunoreactivity (MAP2-IR) is present in individuals with Sz, despite no change in MAP2 protein levels. MAP2 is phosphorylated downstream of multiple receptors and kinases identified as Sz risk genes, altering its immunoreactivity and function. Using an unbiased phosphoproteomics approach we quantified 18 MAP2 phosphopeptides, 9 of which were significantly altered in Sz subjects. Network analysis grouped MAP2 phosphopeptides into 3 modules, each with a distinct relationship to dendritic spine loss, synaptic protein levels, and clinical function in Sz subjects. We then investigated the most hyperphosphorylated site in Sz, phosphoserine1782 (pS1782). Computational modeling predicted phosphorylation of S1782 reduces binding of MAP2 to microtubules, which was confirmed experimentally. We generated a transgenic mouse containing a phosphomimetic mutation at S1782 (S1782E) and found reductions in basilar dendritic length and complexity along with reduced spine density. Because only a limited number of MAP2 interacting proteins have been previously identified, we combined co-immunoprecipitation with mass spectrometry to characterize the MAP2 interactome in mouse brain. The MAP2 interactome was enriched for proteins involved in protein translation. These associations were shown to be functional as overexpression of wildtype and phosphomimetic MAP2 reduced protein synthesisin vitro. Finally, we found that Sz subjects with low MAP2-IR had reductions in the levels of synaptic proteins relative to nonpsychiatric control (NPC) subjects and to Sz subjects with normal and MAP2-IR, and this same pattern was recapitulated in S1782E mice. These findings suggest a new conceptual framework for Sz - that a large proportion of individuals have a “MAP2opathy” - in which MAP function is altered by phosphorylation, leading to impairments of neuronal structure, synaptic protein synthesis, and function.
Asymmetric, dynamic adaptation in prefrontal cortex during dichotic listening tasks
Authors: Fisher J. A. N. , Gumenchuk I. , Rogovin O. , Yodh A. G. , Busch D. R. 
Published: June 2019

AbstractSpeech comprehension relies on highly distributed, dynamically interconnected neuroanatomical loci. Accordingly, performance on complex speech processing tasks such as dichotic listening can be used to assess the integrity and health of many functional and structural aspects of the brain. Despite the potential merits as a clinical assessment tool, however, the neural substrates activated during dichotic listening remain relatively opaque at higher processing levels. Ultimately, this knowledge gap limits diagnostic use of the task. At the level of the prefrontal cortex, dichotic listening induces an asymmetric response wherein regions on the right hemisphere exhibit a higher functional activation than on the left. Superficially, this finding is counterintuitive given the left hemisphere’s dominance for speech and language. To obtain a more in-depth perspective on the potentially distinct roles of the right and left prefrontal cortex, we optically monitored cerebral blood flow in the dorsolateral prefrontal cortex (DLPFC) during dichotic listening tasks in human subjects. The method permitted us to avoid systematic experimental confounds that functional magnetic resonance imaging (fMRI) measurements suffer from, namely the influence of scanner noise. In addition to reproducing the documented larger activation amplitude in the right hemisphere, we also found that repeated listening task blocks were associated with altered kinetics of blood flow in the right, but not the left DLPFC. Interestingly, subjects with the most prominent regional blood flow changes in the right hemisphere also displayed large distortion product otoacoustic emissions (DPOAEs) in the left ear, possibly signaling a correlation between prefrontal activity and top-down listening control infrastructure through medial olivocochlear efferent projections to the inner ear. Overall, our results suggest that the right prefrontal cortical regions play an active role in optimizing task performance.
Invariants of Frameshifted Variants
Authors: Bartonek Lukas , Braun Daniel , Zagrovic Bojan 
Published: June 2019

AbstractFrameshifts in protein coding sequences are widely perceived as resulting in either non-functional or even deleterious protein products. Indeed, frameshifts typically lead to markedly altered protein sequences and premature stop codons. By analyzing complete proteomes from all three domains of life, we demonstrate that, in contrast, several key physicochemical properties of protein sequences exhibit significant robustness against +1 and −1 frameshifts in their mRNA coding sequences. In particular, we show that hydrophobicity profiles of many protein sequences remain largely invariant upon frameshifting. For example, over 2900 human proteins exhibit a Pearson correlation coefficient between the hydrophobicity profiles of the original and the +1-frameshifted variants greater than 0.7, despite a median sequence identity between the two of only 6.5% in this group. We observe a similar effect for protein sequence profiles of affinity for certain nucleobases, their matching with the cognate mRNA nucleobase-density profiles as well as protein sequence profiles of intrinsic disorder. Finally, we show that frameshift invariance is directly embedded in the structure of the universal genetic code and may have contributed to shaping it. Our results suggest that frameshifting may be a powerful evolutionary mechanism for creating new proteins with vastly different sequences, yet similar physicochemical properties to the proteins they originate from.Significance StatementGenetic information stored in DNA is transcribed to messenger RNAs and then read in the process of translation to produce proteins. A frameshift in the reading frame at any stage of the process typically results in a significantly different protein sequence being produced and is generally assumed to be a source of detrimental errors that biological systems need to control. Here, we show that several essential properties of many protein sequences, such as their hydrophobicity profiles, remain largely unchanged upon frameshifts. This finding suggests that frameshifting could be an effective evolutionary strategy for generating novel protein sequences, which retain the functionally relevant physicochemical properties of the sequences they derive from.
Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior
Authors: Yu Xiao , Ba Wei , Zhao Guangchao , Ma Ying , Harding Edward C. , Yin Lu , Wang Dan , Shi Youran , Vyssotski Alexei L. , Dong Hailong , Franks Nicholas P. , Wisden William 
Published: June 2019

AbstractThe ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTAVgat) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTAVgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleep-deprived baseline, suggesting that the sleep homeostasis process was bypassed. The mania-like behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTAVgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTAVgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTAVgat neurons are centrally positioned to help set an animal’s (and human’s) level of mental and physical activity. Inputs that inhibit VTAVgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTAVgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).