bluuebunny/crossref_metadata_2025_split huggingface dataset:
The organization of intracortical connections by layer and cell class in the mouse brain
Authors: Harris Julie A. , Mihalas Stefan , Hirokawa Karla E. , Whitesell Jennifer D. , Knox Joseph E. , Bernard Amy , Bohn Phillip , Caldejon Shiella , Casal Linzy , Cho Andrew , Feng David , Gaudreault Nathalie , Gerfen Charles R. , Graddis Nile , Groblewski Peter A. , Henry Alex , Ho Anh , Howard Robert , Kuan Leonard , Lecoq Jerome , Luviano Jennifer , McConoghy Stephen , Mortrud Marty T. , Naeemi Maitham , Ng Lydia , Oh Seung W. , Ouellette Benjamin , Sorensen Staci A. , Wakeman Wayne , Wang Quanxin , Williford Ali , Phillips John W. , Jones Allan , Koch Christof , Zeng Hongkui 
Published: April 2018

AbstractThe mammalian cortex is a laminar structure composed of many cell types densely interconnected in complex ways. Recent systematic efforts to map the mouse mesoscale connectome provide comprehensive projection data on interareal connections, but not at the level of specific cell classes or layers within cortical areas. We present here a significant expansion of the Allen Mouse Brain Connectivity Atlas, with ∼1,000 new axonal projection mapping experiments across nearly all isocortical areas in 49 Cre driver lines. Using 13 lines selective for cortical layer-specific projection neuron classes, we identify the differential contribution of each layer/class to the overall intracortical connectivity patterns. We find layer 5 (L5) projection neurons account for essentially all intracortical outputs. L2/3, L4, and L6 neurons contact a subset of the L5 cortical targets. We also describe the most common axon lamination patterns in cortical targets. Most patterns are consistent with previous anatomical rules used to determine hierarchical position between cortical areas (feedforward, feedback), with notable exceptions. While diverse target lamination patterns arise from every source layer/class, L2/3 and L4 neurons are primarily associated with feedforward type projection patterns and L6 with feedback. L5 has both feedforward and feedback projection patterns. Finally, network analyses revealed a modular organization of the intracortical connectome. By labeling interareal and intermodule connections as feedforward or feedback, we present an integrated view of the intracortical connectome as a hierarchical network.
Manipulation of the unfolded protein response: a pharmacological strategy against coronavirus infection
Authors: Echavarría-Consuegra Liliana , Cook Georgia M. , Busnadiego Idoia , Lefèvre Charlotte , Keep Sarah , Brown Katherine , Doyle Nicole , Dowgier Giulia , Franaszek Krzysztof , Moore Nathan A. , Siddell Stuart G. , Bickerton Erica , Hale Benjamin G. , Firth Andrew E. , Brierley Ian , Irigoyen Nerea 
Published: April 2018

AbstractCoronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV-2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1α and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release ∼1,000-fold. Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection.Author SummarySARS-CoV-2 is the novel coronavirus responsible for the COVID-19 pandemic which has resulted in over 100 million cases since the end of 2019. Most people infected with the virus will experience mild to moderate respiratory illness and recover without any special treatment. However, older people, and those with underlying medical problems like chronic respiratory disease are more likely to develop a serious illness. So far, more than 2 million people have died of COVID-19. Unfortunately, there is no specific medication for this viral disease.In order to produce viral proteins and to replicate their genetic information, all coronaviruses use a cellular structure known as the endoplasmic reticulum or ER. However, the massive production and modification of viral proteins stresses the ER and this activates a compensatory cellular response that tries to reduce ER protein levels. This is termed the unfolded protein response or UPR. We believe that coronaviruses take advantage of the activation of the UPR to enhance their replication.The UPR is also activated in some types of cancer and neurodegenerative disorders and UPR inhibitor drugs have been developed to tackle these diseases. In this work, we have tested some of these compounds in human lung cells infected with SARS-CoV-2 and found that virus production was reduced 1000-fold in human lung cells.
Leveraging chromatin accessibility for transcriptional regulatory network inference in T Helper 17 Cells
Authors: Miraldi Emily R. , Pokrovskii Maria , Watters Aaron , Castro Dayanne M. , Veaux Nicholas De , Hall Jason A. , Lee June-Yong , Ciofani Maria , Madar Aviv , Carriero Nick , Littman Dan R. , Bonneau Richard 
Published: April 2018

AbstractTranscriptional regulatory networks (TRNs) provide insight into cellular behavior by describing interactions between transcription factors (TFs) and their gene targets. The Assay for Transposase Accessible Chromatin (ATAC)-seq, coupled with transcription-factor motif analysis, provides indirect evidence of chromatin binding for hundreds of TFs genome-wide. Here, we propose methods for TRN inference in a mammalian setting, using ATAC-seq data to influence gene expression modeling. We rigorously test our methods in the context of T Helper Cell Type 17 (Th17) differentiation, generating new ATAC-seq data to complement existing Th17 genomic resources (plentiful gene expression data, TF knock-outs and ChIP-seq experiments). In this resource-rich mammalian setting, our extensive benchmarking provides quantitative, genome-scale evaluation of TRN inference combining ATAC-seq and RNA-seq data. We refine and extend our previous Th17 TRN, using our new TRN inference methods to integrate all Th17 data (gene expression, ATAC-seq, TF KO, ChIP-seq). We highlight newly discovered roles for individual TFs and groups of TFs (“TF-TF modules”) in Th17 gene regulation. Given the popularity of ATAC-seq, which provides high-resolution with low sample input requirements, we anticipate that application of our methods will improve TRN inference in new mammalian systems, especially in vivo, for cells directly from humans and animal models.
CD56 expression of intravascular trophoblasts defines a class of vasculopathy in preeclampsia and other pregnancy complications
Authors: Zhang Peilin 
Published: April 2018

AbstractWe have discovered the expression of CD56 on the intravascular trophoblasts in the maternal spiral artery at implantation sites, and we have also found the similar phenotypic switch of intravascular trophoblasts in the decidual vasculopathy in preeclampsia. Currently we have examined 124 placentas from the patients with preeclampsia and 84 placentas from patients with other pregnancy associated complications without preeclampsia. CD56 expression on the intravascular trophoblasts can be seen in classic decidual vasculopathy such as fibrinoid medial necrosis and acute atherosis. In addition, partial involvement of the decidual vessels with classic vasculopathy can also be identified by CD56 expression. The cellular components of the classic vasculopathy in preeclampsia showed immunoreactivity to cytokeratin and CD68, in addition to CD56 expression, indicating the fetal trophoblastic cell origin. The classic decidual vasculopathy including acute atherosis and fibrinoid medial necrosis can be unified and designated as CD56-related vasculopathy. The CD56 related vasculopathy is associated not only to preeclampsia but also to other pregnancy related complications, such as gestational diabetes, placental infarcts, intervillous thrombosis and other fetal distress syndromes. Our study defined a spectrum of decidual vasculopathy spanning from the classic preeclampsia to other complications important to pregnancy that can be highlighted by CD56 expression, pointing to different direction of pathogenesis of preeclampsia and other pregnancy associated complications.
NRG1-mediated recognition of HopQ1 reveals a link between PAMP- and Effector-triggered Immunity
Authors: Brendolise Cyril , Martinez-Sanchez Marcela , Morel Arry , Chen Ronan , Dinis Romain , Deroles Simon , Peeters Nemo , Rikkerink Erik H. A. , Montefiori Mirco 
Published: April 2018

SummaryMembers of the hopQ1/XopQ family of effectors are conserved amongst pathogenic bacteria suggesting an important function in virulence. Therefore, the identification of R proteins recognising members of this family is potentially of high value to achieve broad-spectrum resistance in crops.Recent studies demonstrated that HopQ1/XopQ recognition is EDS1-dependant and is mediated by the TIR-NB-LRR protein Roq1. Using our recently described R gene RNAi library, we have investigated the mechanism of HopQ1 recognition and the other components of its signalling network.We show that silencing of the CCR-NB-LRR helper protein N Requirement Gene 1 (NRG1) prevents HopQ1 recognition in N. benthamiana and that NRG1 expression confers recognition of HopQ1 and restricts Pto DC3000 proliferation in the otherwise susceptible host Arabidopsis. Moreover NRG1 expression is briefly but strongly induced at a very early stage of the plant innate response, establishing a strong dependency link between PAMP-triggered immunity (PTI) and effector-triggered immunity (ETI).Overall we demonstrate that in addition to Roq1, HopQ1 recognition in N. benthamiana requires the CCR-NB-LRR protein NRG1 and propose a model based on the dual requirement of a CCR-NB-LRR and a TIR-NB-LRR that could extend beyond HopQ1 detection and possibly be used to recognize other pathogen effectors.
Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells induces dedifferentiated liposarcoma potency
Authors: Kim Yu Jin , Sung Minjung , Yu Dan Bi , Kim Mingi , Song Ji-Young , Song Kyoung , Jung Kyungsoo , Choi Yoon-La 
Published: April 2018

AbstractAmplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria of well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, it remains unclear whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis. We examined whether MDM2 and/or CDK4 produce WDLPS/DDLPS using transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that co-overexpression of MDM2 and CDK4 plays key roles in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency compared to sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can develop proliferative DDLPS in vivo. Our results suggest that co-overexpression of MDM2 and CDK4 induces DDLPS tumour potency in transformed human BMSCs by accelerating cell growth and migration and blocking adipogenetic potential incooperation with multiple genetic factors.
Chronic exposure to a neonicotinoid pesticide and a synthetic pyrethroid in full-sized honey bee colonies
Authors: Odemer Richard , Rosenkranz Peter 
Published: April 2018

ABSTRACTIn the last decade, the use of neonicotinoid insecticides increased significantly in the agricultural landscape and meanwhile considered a risk to honey bees. Besides the exposure to pesticides, colonies are treated frequently with various acaricides that beekeepers are forced to use against the parasitic mite Varroa destructor. Here we have analyzed the impact of a chronic exposure to sublethal concentrations of the common neonicotinoid thiacloprid (T) and the widely used acaricide τ-fluvalinate (synthetic pyrethroid, F) - applied alone or in combination - to honey bee colonies under field conditions. The population dynamics of bees and brood were assessed in all colonies according to the Liebefeld method. Four groups (T, F, F+T, control) with 8-9 colonies each were analyzed in two independent replications, each lasting from spring/summer until spring of the consecutive year. In late autumn, all colonies were treated with oxalic acid against Varroosis. We could not find a negative impact of the chronic neonicotinoid exposure on the population dynamics or overwintering success of the colonies, irrespective of whether applied alone or in combination with τ-fluvalinate. This is in contrast to some results obtained from individually treated bees under laboratory conditions and confirms again an effective buffering capacity of the honey bee colony as a superorganism. Yet, the underlying mechanisms for this social resilience remain to be fully understood.
Native DNA electronics: the Nuclear Aggregates of Polyamines possible role
Authors: D’Agostino L. 
Published: April 2018

ABSTRACTThe genomic DNA is enveloped by nanotubes formed by the Nuclear Aggregates of Polyamines (NAPs) that induce DNA conformational changes, and provides protection and increased interactive abilities for the double strands. In a physiologic environment, the nanotube arrangement initiates with the spontaneous interaction among the terminal amino groups of polyamines and the phosphate ions, with the consequent formation of cyclic monomers that hook at DNA grooves. The polymer thus formed has the morphological features of an organic semiconductor and, therefore, can be considered able to conduce electric charges. Phosphate ions positioned on NAP external surface could regulate, as in a physical electric circuit, both protein linear and rotational (histones) motion, in accordance with the basilar principles of the electronics. A model of a carrier system for proteins motion along the polymer wrapping the DNA strands, based on the phosphate-phosphate complexation, is proposed.
Toward a model-free feedback control synthesis for treating acute inflammation
Authors: Bara Ouassim , Fliess Michel , Join Cédric , Day Judy , Djouadi Seddik M. 
Published: April 2018

AbstractAn effective and patient-specific feedback control synthesis for inflammation resolution is still an ongoing research area. A strategy consisting of manipulating a pro and anti-inflammatory mediator is considered here as used in some promising model-based control studies. These earlier studies, unfortunately, suffer from the difficultly of calibration due to the heterogeneity of individual patient responses even under similar initial conditions. We exploit a new model-free control approach and its corresponding “intelligent” controllers for this biomedical problem. A crucial feature of the proposed control problem is as follows: the two most important outputs which must be driven to their respective desired states are sensorless. This difficulty is overcome by assigning suitable reference trajectories to the other two outputs that do have sensors. A mathematical model, via a system of ordinary differential equations, is nevertheless employed as a “virtual” patient forin silicotesting. We display several simulation results with respect to the most varied situations, which highlight the effectiveness of our viewpoint.
Visualizing conformational dynamics of proteins in solution and at the cell membrane
Authors: Gordon Sharona E. , Munari Mika , Zagotta William N. 
Published: April 2018

AbstractConformational dynamics underlie enzyme function, yet are generally inaccessible via traditional structural approaches. FRET has the potential to measure conformational dynamicsin vitroand in intact cells, but technical barriers have thus far limited its accuracy, particularly in membrane proteins. Here, we combine amber codon suppression to introduce a donor fluorescent noncanonical amino acid with a new, biocompatible approach for labeling proteins with acceptor transition metals in a method called ACCuRET (Anap Cyclen-Cu2+resonance energy transfer). We show that ACCuRET measures absolute distances and distance changes with high precision and accuracy using maltose binding protein as a benchmark. Using cell unroofing, we show that ACCuRET can accurately measure rearrangements of proteins in native membranes. Finally, we implement a computational method for correcting the measured distances for the distance distributions observed in proteins. ACCuRET thus provides a flexible, powerful method for measuring conformational dynamics in both soluble proteins and membrane proteins.
GET_PHYLOMARKERS, a software package to select optimal orthologous clusters for phylogenomics and inferring pan-genome phylogenies, used for a critical geno-taxonomic revision of the genusStenotrophomonas
Authors: Vinuesa Pablo , Ochoa-Sánchez Luz Edith , Contreras-Moreira Bruno 
Published: April 2018

AbstractThe massive accumulation of genome-sequences in public databases promoted the proliferation of genome-level phylogenetic analyses in many areas of biological research. However, due to diverse evolutionary and genetic processes, many loci have undesirable properties for phylogenetic reconstruction. These, if undetected, can result in erroneous or biased estimates, particularly when estimating species trees from concatenated datasets. To deal with these problems, we developed GET_PHYLOMARKERS, a pipeline designed to identify high-quality markers to estimate robust genome phylogenies from the orthologous clusters, or the pan-genome matrix (PGM), computed by GET_HOMOLOGUES. In the first context, a set of sequential filters are applied to exclude recombinant alignments and those producing anomalous or poorly resolved trees. Multiple sequence alignments and maximum likelihood (ML) phylogenies are computed in parallel on multi-core computers. A ML species tree is estimated from the concatenated set of top-ranking alignments at the DNA or protein levels, using either FastTree or IQ-TREE (IQT). The latter is used by default due to its superior performance revealed in an extensive benchmark analysis. In addition, parsimony and ML phylogenies can be estimated from the PGM.We demonstrate the practical utility of the software by analyzing 170Stenotrophomonasgenome sequences available in RefSeq and 10 new complete genomes of environmentalS. maltophiliacomplex (Smc) isolates reported herein. A combination of core-genome and PGM analyses was used to revise the molecular systematics of the genus. An unsupervised learning approach that uses a goodness of clustering statistic identified 20 groups within the Smc at a core-genome average nucleotide identity of 95.9% that are perfectly consistent with strongly supported clades on the core- and pan-genome trees. In addition, we identified 14 misclassified RefSeq genome sequences, 12 of them labeled asS. maltophilia, demonstrating the broad utility of the software for phylogenomics and geno-taxonomic studies. The code, a detailed manual and tutorials are freely available for Linux/UNIX servers under the GNU GPLv3 license athttps://github.com/vinuesa/get_phylomarkers. A docker image bundling GET_PHYLOMARKERS with GET_HOMOLOGUES is available athttps://hub.docker.com/r/csicunam/get_homologues/, which can be easily run on any platform.
CagY-dependent regulation of type IV secretion inHelicobacter pyloriis associated with alterations in integrin binding
Authors: Skoog Emma C. , Morikis Vasilios A. , Martin Miriam E. , Foster Greg A. , Cai Lucy P. , Hansen Lori M. , Li Beibei , Gaddy Jennifer A. , Simon Scott I. , Solnick Jay V. 
Published: April 2018

ABSTRACTStrains ofHelicobacter pylorithat cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by thecagpathogenicity island (PAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4+ T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density. Since CagY is known to bind human α5β1integrin, we tested the hypothesis that recombination in the CagY MRR regulates T4SS function by modulating binding to α5β1integrin. Using a cell-free microfluidic assay, we found thatH. pyloribinding to α5β1integrin under shear flow is dependent on the CagY MRR, but independent of the presence of the T4SS pili, which are only formed whenH. pyloriis in contact with host cells. Similarly, expression of CagY in the absence of other T4SS genes was necessary and sufficient for whole bacterial cell binding to α5β1integrin. Bacteria with variantcagYalleles that reduced T4SS function showed comparable reduction in binding to α5β1integrin, though CagY was still expressed on the bacterial surface. We speculate thatcagY-dependent modulation ofH. pyloriT4SS function is mediated by alterations in binding to α5β1integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection.IMPORTANCEInfection withH. pylorican cause peptic ulcers, and is the most important risk factor for gastric cancer, the third most common cause of cancer death worldwide. The majorH. pylorivirulence factor that determines whether infection causes disease or asymptomatic colonization is the type IV secretion system (T4SS), a sort of molecular syringe that injects bacterial products into gastric epithelial cells and alters host cell physiology. We previously showed that recombination in CagY, an essential T4SS component, modulates the function of the T4SS. Here we found that these recombination events produce parallel changes in specific binding to α5β1integrin, a host cell receptor that is essential for T4SS-dependent translocation of bacterial effectors. We propose that CagY-dependent binding to α5β1integrin acts like a molecular rheostat that alters T4SS function and modulates the host immune response to promote persistent infection.