bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDR1-INDUCED NEUTROPHIL EXTRACELLULAR TRAPS DRIVE PANCREATIC CANCER METASTASIS
Authors: Deng Jenying , Kang Yaan , Cheng Chien-Chia , Li Xinqun , Dai Bingbing , Katz Matthew H. , Men Taoyan , Kim Michael P. , Koay Eugene A. , Huang Huocong , Brekken Rolf A. , Fleming Jason B. 
Published: August 2020

AbstractPancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction and dense collagen that is known to promote cancer progression. A central mediator of pro-tumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 prevents PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell non-autonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs) and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1-PKCθ-SYK-NFκB signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.SummaryDeng et al find that collagen signaling via DDR1 on human pancreatic cancer cells drives production and release of the cytokine, CXCL5, into systemic circulation. CXCL5 then triggers infiltration of neutrophils into the tumor where they promote cancer cell progression.
Neuron-intrinsic NF-κB Signaling Mediates Reovirus Virulence
Authors: Pruijssers Andrea J. , Taylor Gwen , Brigleb Pamela , Shang Pengcheng , Urbanek Kelly , Brown Judy J. , Dermody Terence S. 
Published: August 2020

ABSTRACTPathological effects of apoptosis associated with viral infections of the central nervous system are an important cause of morbidity and mortality. Reovirus is a neurotropic virus that causes apoptosis in neurons, leading to lethal encephalitis in newborn mice. Reovirus-induced encephalitis is diminished in mice with germline ablation of NF-κB subunit p50. It is not known whether the pro-apoptotic function of NF-κB is mediated by neuron-intrinsic processes, NF-κB-regulated cytokine production by inflammatory cells, or a combination of both. To determine the contribution of cell type-specific NF-κB signaling in reovirus-induced neuronal injury, we established mice that lack NF-κB p65 expression in neurons using theCre/loxPrecombination system. Following intracranial inoculation of reovirus, 50% of wild-type (WT) mice succumbed to infection, whereas more than 90% of mice lacking neural NF-κB p65 (Nsp65−/−) mice survived. While viral loads in brains of WT and Nsp65−/−were comparable, histological analysis revealed that reovirus antigen-positive areas in the brain of WT mice displayed enhanced cleaved caspase-3 immunoreactivity, a marker of apoptosis, compared with Nsp65−/−mice. These data suggest that neuron-intrinsic NF-κB-dependent factors are essential mediators of reovirus neurovirulence. RNA sequencing analysis of reovirus-infected cortices of WT and Nsp65−/−mice suggests that NF-κB activation in neurons upregulates genes involved in innate immunity, inflammation, and cell death following reovirus infection. A better understanding of the contribution of cell type-specific NF-κB-dependent signaling to viral neuropathogenesis could inform development of new therapeutics that target and protect highly vulnerable cell populations
Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration kinetics in the zebrafish retina
Authors: Emmerich Kevin B. , White David T. , Kambhampati Siva P. , Lee Grace Y. , Fu Tian-Ming , Sahoo Arpan , Saxena Meera T. , Betzig Eric , Kannan Rangaramanujam M. , Mumm Jeff S. 
Published: August 2020

AbstractMüller glia (MG) function as injury-induced retinal stem cells in zebrafish but not mammals. Insights from zebrafish, however, have been used to stimulate limited regenerative responses from mammalian MG. Microglia/macrophages regulate MG stem cell activity in the chick, zebrafish and mouse. We previously showed that dexamethasone can accelerate retinal regeneration in zebrafish. Similarly, microglia ablation enhances regenerative outcomes in the mouse retina. Targeted immunomodulation may therefore enhance the regenerative potential of human MG. Nanoparticle-based immunomodulation is an emerging field with immense therapeutic potential. Here, we investigated how regeneration-enhancing dexamethasone treatments alter microglia behavior and how dendrimer-based targeting of dexamethasone to reactive microglia impact retinal regeneration kinetics. Intravital time-lapse imaging revealed specific dexamethasone-induced changes in microglia reactivity. Dendrimer-conjugated dexamethasone treatments resulted in: 1) decreased toxicity, 2) selective targeting of reactive microglia and, 3) “super-accelerated” retinal regeneration kinetics. These data support the use of dendrimer-based drug formulations for modulating microglia reactivity in degenerative disease contexts, especially as therapeutic strategies for promoting regenerative responses to neuronal cell loss.
Computational Model for Biological Neural Network for Localisation of Sound in the Vertical Plane
Authors: De Anandita , Cox Daniel 
Published: August 2020

AbstractWe build a computational rate model for a biological neural network found in mammals that is thought to be important in the localisation of the sound in the vertical plane. We find the response of neurons in the brain stem that participate in the localisation neural circuit to pure tones, broad band noise and notched noise and compare them to experimentally obtained response of these neurons. Our model is able to reproduce the sensitivity of these neurons in the brain stem to spectral properties of sounds that are important in localisation. This is the first rate based population model that elucidates all the response properties of the neurons in the vertical localisation pathway to our knowledge.
Musculoskeletal Model Personalization Affects Metabolic Cost Estimates for Walking
Authors: Arones Marleny , Shourijeh Mohammad , Patten Carolynn , Fregly Benjamin J. 
Published: August 2020

AbstractAssessment of metabolic energy cost as a metric for human performance has expanded across various fields within the scientific, clinical, and engineering communities. As an alternative to measuring metabolic cost experimentally, musculoskeletal models incorporating metabolic cost models have been developed. However, to utilize these models for practical applications, the accuracy of their metabolic cost predictions requires improvement. Previous studies have reported the benefits of using personalized musculoskeletal models for various applications, yet no study has evaluated how model personalization affects metabolic cost estimation. This study investigated the effect of musculoskeletal model personalization on estimates of metabolic cost of transport (CoT) during post-stroke walking using three commonly used metabolic cost models. We analyzed data previously collected from two male stroke survivors with right-sided hemiparesis. The three metabolic cost models were implemented within three musculoskeletal modeling approaches involving different levels of personalization. The first approach used a scaled generic OpenSim model and found muscle activations via static optimization (SOGen). The second approach used a personalized EMG-driven musculoskeletal model with personalized functional axes but found muscle activations via static optimization (SOCal). The third approach used the same personalized EMG-driven model but calculated muscle activations directly from EMG data (EMGCal). For each approach, the muscle activation estimates were used to calculate each subject’s cost of transport (CoT) at different gait speeds using three metabolic cost models (Umberger 2003, Umberger 2010, and Bhargava 2004). The calculated CoT values were compared with published CoT trends as a function of stance time, double support time, step positions, walking speed, and severity of motor impairment (i.e., Fugl-Meyer score). Overall, U10-SOCal, U10-EMGCal, U03-SOCal, and U03-EMGCal were able to produce slopes between CoT and the different measures of walking asymmetry that were statistically similar to those found in the literature. Although model personalization seemed to improve CoT estimates, further tuning of parameters associated with the different metabolic cost models in future studies may allow for realistic CoT predictions. An improvement in CoT predictions may allow researchers to predict human performance, surgical, and rehabilitation outcomes reliably using computational simulations.
QTL mapping in an interspecific sorghum population uncovers candidate regulators of salinity tolerance
Authors: Hostetler Ashley N. , Govindarajulu Rajanikanth , Hawkins Jennifer S. 
Published: August 2020

AbstractSalt stress impedes plant growth and disrupts normal metabolic processes, resulting in decreased biomass and increased leaf senescence. Therefore, the ability of a plant to maintain biomass when exposed to salinity stress is critical for the production of salt tolerant crops. To identify the genetic basis of salt tolerance in an agronomically important grain crop, we used a recombinant inbred line (RIL) population derived from an interspecific cross between domesticatedSorghum bicolor(inbred Tx7000) and a wild relative,Sorghum propinquum. A high-density genetic map was generated from 177 F3:5RILs and covered the 10Sorghumchromosomes with 1991 markers. The genetic map was used to identify 19 total QTL related to plant growth and overall health in optimal and saline conditions. Of these 19 QTL detected, 10 were specific to the salt stress response. The salt-responsive QTL contained numerous genes that have been previously shown to play a role in ionic tolerance, tissue tolerance, and osmotic tolerance, including many aquaporins.
A combined pipeline for quantitative analysis of human brain cytoarchitecture
Authors: Costantini Irene , Mazzamuto Giacomo , Roffilli Matteo , Laurino Annunziatina , Castelli Filippo Maria , Neri Mattia , Lughi Giovanni , Simonetto Andrea , Lazzeri Erica , Pesce Luca , Destrieux Christophe , Silvestri Ludovico , Conti Valerio , Guerrini Renzo , Pavone Francesco S. 
Published: August 2020

AbstractThe 3D analysis of the human brain architecture at cellular resolution is still a big challenge. In this work, we propose a pipeline that solves the problem of performing neuronal mapping in large human brain samples at micrometer resolution. First, we introduce the SWITCH/TDE protocol: a robust methodology to clear and label human brain tissue. Then, we implement the 2.5D method based on a Convolutional Neural Network, to automatically detect and segment all neurons. Our method proved to be highly versatile and was applied successfully on specimens from different areas of the cortex originating from different subjects (young, adult and elderly, both healthy and pathological). We quantitatively evaluate the density and, more importantly, the mean volume of the thousands of neurons identified within the specimens. In conclusion, our pipeline makes it possible to study the structural organization of the brain and expands the histopathological studies to the third dimension.
Morphologically constrained modeling of spinous inhibition in the somato-sensory cortex
Authors: Gemin Olivier , Serna Pablo , Assendorp Nora , Fossati Matteo , Rostaing Philippe , Triller Antoine , Charrier Cécile 
Published: August 2020

ABSTRACTPyramidal neurons are covered by thousands of dendritic spines receiving excitatory synaptic inputs. The ultrastructure of dendritic spines shapes signal compartmentalization but ultrastructural diversity is rarely taken into account in computational models of synaptic integration. Here, we developed a 3D correlative light-electron microscopy (3D-CLEM) approach allowing the analysis of specific populations of synapses in genetically defined neuronal types in intact brain circuits. We used it to reconstruct segments of basal dendrites of layer 2/3 pyramidal neurons of adult mouse somatosensory cortex and quantify spine ultrastructural diversity. We found that 10% of spines were dually-innervated and 38% of inhibitory synapses localized to spines. Using our morphometric data to constrain a model of synaptic signal compartmentalization, we assessed the impact of spinous versus dendritic shaft inhibition. Our results indicate that spinous inhibition is locally more efficient than shaft inhibition and that it can decouple voltage and calcium signaling, potentially impacting synaptic plasticity.
Sequestration to lipid droplets promotes histone availability by preventing turnover of excess histones
Authors: Stephenson Roxan A. , Thomalla Jonathon M. , Chen Lili , Kolkhof Petra , Beller Mathias , Welte Michael A. 
Published: August 2020

AbstractBecause dearth and overabundance of histones result in cellular defects, histone synthesis and demand are typically tightly coupled. InDrosophilaembryos, histones H2B/H2A/H2Av accumulate on lipid droplets (LDs), cytoplasmic fat storage organelles. Without this binding, maternally provided H2B/H2A/H2Av are absent; however, the molecular basis of how LDs ensure histone storage is unclear. Using quantitative imaging, we uncover when during oogenesis these histones accumulate, and which step of accumulation is LD-dependent. LDs originate in nurse cells and are transported to the oocyte. Although H2Av accumulates on LDs in nurse cells, the majority of the final H2Av pool is synthesized in oocytes. LDs promote intercellular transport of the histone-anchor Jabba and thus its presence in the ooplasm. Jabba prevents ooplasmic H2Av from degradation, safeguarding the H2Av stockpile. Our findings provide insight into the mechanism for establishing histone stores duringDrosophilaoogenesis and shed light on the function of LDs as protein-sequestration sites.
Peptide Antidotes to SARS-CoV-2 (COVID-19)
Authors: Watson Andre , Ferreira Leonardo , Hwang Peter , Xu Jinbo , Stroud Robert 
Published: August 2020

ABSTRACTThe design of an immunogenic scaffold that serves a role in treating a pathogen, and can be rapidly and predictively modeled, has remained an elusive feat.Here, we demonstrate that SARS-BLOCK™ synthetic peptide scaffolds act as antidotes to SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells. Critically, SARS-BLOCK™ peptides are able to potently and competitively inhibit SARS-CoV-2 S1 spike protein receptor binding domain (RBD) binding to ACE2, the main cellular entry pathway for SARS-CoV-2, while also binding to neutralizing antibodies against SARS-CoV-2. In order to create this potential therapeutic antidote-vaccine, we designed, simulated, synthesized, modeled epitopes, predicted peptide folding, and characterized behavior of a novel set of synthetic peptides. The biomimetic technology is modeled off the receptor binding motif of the SARS-CoV-2 coronavirus, and modified to provide enhanced stability and folding versus the truncated wildtype sequence. These novel peptides attain single-micromolar binding affinities for ACE2 and a neutralizing antibody against the SARS-CoV-2 receptor binding domain (RBD), and demonstrate significant reduction of infection in nanomolar doses. We also demonstrate that soluble ACE2 abrogates binding of RBD to neutralizing antibodies, which we posit is an essential immune-evasive mechanism of the virus. SARS-BLOCK™ is designed to “uncloak” the viral ACE2 coating mechanism, while also binding to neutralizing antibodies with the intention of stimulating a specific neutralizing antibody response. Our peptide scaffolds demonstrate promise for future studies evaluating specificity and sensitivity of immune responses to our antidote-vaccine. In summary, SARS-BLOCK™ peptides are a promising COVID-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.
Landscape genetics and species delimitation in the Andean palm rocket frog,Rheobatesspp
Authors: Genty Gabrielle , Guarnizo Carlos E. , Ramírez Juan P. , Barrientos Lucas , Crawford Andrew J. 
Published: August 2020

AbstractThe complex topography of the species-rich northern Andes creates heterogeneous environmental landscapes that are hypothesized to have promoted population fragmentation and diversification by vicariance, gradients and/or the adaptation of species. Previous phylogenetic work on the Palm Rocket Frog (Anura: Aromobatidae:Rheobatesspp.), endemic to mid-elevation forests of Colombia, suggested valleys were important in promoting divergence between lineages. In this study, we use a spatially, multi-locus population genetic approach of two mitochondrial and four nuclear genes from 25 samples representing the complete geographic range of the genus to delimit species and test for landscape effects on genetic divergence withinRheobates. We tested three landscape genetic models: isolation by distance, isolation by resistance, and isolation by environment. Bayesian species delimitation (BPP) and a Poisson Tree Process (PTP) model both recovered five highly divergent genetic lineages withinRheobates, rather than the three inferred in a previous study. We found that an isolation by environment provided the only variable significantly correlated with genetic distances for both mitochondrial and nuclear genes, suggesting that local adaptation may have a role driving the genetic divergence within this genus of frogs. Thus, genetic divergence inRheobatesmay be driven by the local environments where these frogs live, even more so that by the environmental characteristics of the intervening regions among populations (i.e., geographic barriers).
High-resolution mapping ofRym14Hb, a wild relative resistance gene to barley yellow mosaic disease
Authors: Pidon Hélène , Wendler Neele , Habekuβ Antje , Maasberg Anja , Ruge-Wehling Brigitte , Perovic Dragan , Ordon Frank , Stein Nils 
Published: August 2020

AbstractBarley yellow mosaic disease is caused by Barley yellow mosaic virus and Barley mild mosaic virus, and leads to severe yield losses in barley (Hordeum vulgare) in Central Europe and East-Asia. Several resistance loci are used in barley breeding. However, cases of resistance-breaking viral strains are known, raising concerns about the durability of those genes.Rym14Hbis a dominant major resistance gene on chromosome 6HS, originating from barley’s secondary genepool wild relativeHordeum bulbosum. As such, the resistance mechanism may represent a case of non-host resistance, which could enhance its durability. A susceptible barley variety and a resistantH. bulbosumintrogression line were crossed to produce a large F2mapping population (n=7,500), to compensate for a ten-fold reduction in recombination rate compared to intraspecific barley crosses. After high-throughput genotyping, theRym14Hblocus was assigned to a 2Mbp telomeric interval on chromosome 6HS. The co-segregating markers developed in this study can be used for marker-assisted introgression of this locus into barley elite germplasm with a minimum of linkage drag.
matchms - processing and similarity evaluation of mass spectrometry data
Authors: Huber Florian , Verhoeven Stefan , Meijer Christiaan , Spreeuw Hanno , Castilla Efraín Manuel Villanueva , Geng Cunliang , van der Hooft Justin J. J. , Rogers Simon , Belloum Adam , Diblen Faruk , Spaaks Jurriaan H. 
Published: August 2020

SummaryMass spectrometry data is at the heart of numerable applications in the biomedical and life sciences. With growing use of high throughput techniques researchers need to analyse larger and more complex datasets. In particular through joint effort in the research community, fragmentation mass spectrometry datasets are growing in size and number. Platforms such as MassBank (Horai et al. 2010), GNPS (Wang et al. 2016) or MetaboLights (Haug et al. 2020) serve as an open-access hub for sharing of raw, processed, or annotated fragmentation mass spectrometry data (MS/MS). Without suitable tools, however, exploitation of such datasets remains overly challenging. In particular, large collected datasets contain data aquired using different instruments and measurement conditions, and can further contain a significant fraction of inconsistent, wrongly labeled, or incorrect metadata (annotations).
Opposing functions of the plantTOPLESSgene family during SNC1-mediated autoimmunity
Authors: Garner Christopher M. , Spears Benjamin J. , Su Jianbin , Cseke Leland , Smith Samantha N. , Rogan Conner J. , Gassmann Walter 
Published: August 2020

AbstractRegulation of the plant immune system is important for controlling the specificity and amplitude of responses to pathogens and in preventing growth-inhibiting autoimmunity that leads to reductions in plant fitness. In previous work, we reported that SRFR1, a negative regulator of effector-triggered immunity, interacts with SNC1 and EDS1. WhenSRFR1is non-functional in the Arabidopsis accession Col-0,SNC1levels increase, causing a cascade of events that lead to autoimmunity phenotypes. Previous work showed that some members of the transcriptional co-repressor family TOPLESS interact with SNC1 to repress negative regulators of immunity. Therefore, to explore potential connections betweenSRFR1andTOPLESSfamily members, we took a genetic approach that examined the effect of eachTOPLESSmember in thesrfr1mutant background. The data indicated that an additive genetic interaction exists betweenSRFR1and two members of theTOPLESSfamily,TPR2andTPR3, as demonstrated by increased stunting and elevatedPR2expression insrfr1 tpr2andsrfr1 tpr2 tpr3mutants. Furthermore, thetpr2mutation intensifies autoimmunity in the auto-activesnc1-1mutant, indicating a novel role of theseTOPLESSfamily members in negatively regulatingSNC1-dependent phenotypes. This negative regulation can also be reversed by overexpressingTPR2in thesrfr1 tpr2background. Thus, this work uncovers diverse functions of individual members of the TOPLESS family in Arabidopsis and provides evidence for the additive effect of transcriptional and post-transcriptional regulation ofSNC1.Author SummaryThe immune system is a double-edged sword that affords organisms with protection against infectious diseases but can also lead to negative effects if not properly controlled. Plants only possess an innate antimicrobial immune system that relies on rapid upregulation of defenses once immune receptors detect the presence of microbes. Plant immune receptors known as resistance proteins play a key role in rapidly triggering defenses if pathogens breach other defenses. A common model of unregulated immunity in the reference Arabidopsis variety Columbia-0 involves a resistance gene calledSNC1. When the SNC1 protein accumulates to unnaturally high levels or possesses auto-activating mutations, the visible manifestations of immune overactivity include stunted growth and low biomass and seedset. Consequently, expression of this gene and accumulation of the encoded protein are tightly regulated on multiple levels. Despite careful study the mechanisms ofSNC1gene regulation are not fully understood. Here we present data on members of the well-known TOPLESS family of transcriptional repressors. While previously characterized members were shown to function in indirect activation of defenses, TPR2 and TPR3 are shown here to function in preventing high defense activity. This study therefore contributes to the understanding of complex regulatory processes in plant immunity.