bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling
Authors: Paige Candler , Barba-Escobedo Priscilla A. , Mecklenburg Jennifer , Patil Mayur , Goffin Vincent , Grattan David , Dussor Gregory , Akopian Armen N. , Price Theodore J. 
Published: April 2020

AbstractMany clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2hypersensitivity was more persistent in females. This difference in PGE2response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.
bak1-5mutation uncouples tryptophan-dependent and independent postinvasive immune pathways triggered in Arabidopsis by multiple fungal pathogens
Authors: Kosaka Ayumi , Pastorczyk Marta , Piślewska-Bednarek Mariola , Nishiuchi Takumi , Suemoto Haruka , Ishikawa Atsushi , Frerigmann Henning , Kaido Masanori , Mise Kazuyuki , Bednarek Paweł , Takano Yoshitaka 
Published: April 2020

ABSTRACTRobust nonhost resistance ofArabidopsis thalianaagainst the nonadapted hemibiotrophic fungusColletotrichum tropicalerequires PEN2-dependent preinvasive and CYP71A12/CYP71A13-dependent postinvasive resistance, which both rely on tryptophan (Trp) metabolism. Here we report that CYP71A12 and CYP71A13 are critical for Arabidopsis’ postinvasive resistance toward both the necrotrophicAlternaria brassicicolaand the adapted hemibiotrophicC. higginsianumfungi. Metabolite analyses suggest that the production of indole-3-carboxylic acid derivatives (ICAs) and camalexin is induced upon pathogen invasion, while phenotypic comparison ofcyp79B2 cyp79B3andpen2 cyp71A12 cyp71A13plants indicates that the contribution of ICAs to postinvasive resistance is dose-dependent. We also found that the disruption of intact pattern recognition receptor complex caused bybak1–5mutation significantly reduced postinvasive resistance againstC. tropicaleandA. brassicicola, indicating that pattern recognition commonly contributes to this second defense-layer against pathogens with distinct infection strategies. However, thebak1–5mutation had no detectable effects on Trp-metabolite accumulation triggered by pathogen invasion. Together with this, further comparative gene expression analyses suggested that pathogen invasion in Arabidopsis activates (i)bak1–5insensitive Trp-metabolism that leads to antimicrobial secondary metabolites, and (ii) abak1–5sensitive immune pathway that activates the expression of antimicrobial proteins.
Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner
Authors: Wang Wei , Silva Luciane M. , Wang Henry H. , Kavanaugh Matthew A. , Pottorf Tana S. , Allard Bailey A. , Jacobs Damon T. , Dong Rouchen , Cornelius Joseph T. , Chaturvedi Aakriti , Pritchard Michele T. , Sharma Madhulika , Slawson Chad , Wallace Darren P. , Calvet James P. , Tran Pamela V. 
Published: April 2020

AbstractPrimary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multi-protein complexes. Deletion of different IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult Autosomal Dominant (AD) PKD mouse models, while deletion of an IFT-A adaptor,Tulp3, attenuates PKD severity in adult mice only. These studies indicate that dysfunction of specific cilia components has potential therapeutic value. To broaden our understanding of cilia dysfunction and its therapeutic potential, here we investigate the impact of global deletion of an IFT-A gene,Thm1, in juvenile and adult ADPKD mouse models. Both juvenile and adult models exhibited increased kidney weight:body weight (KW/BW) ratios, renal cysts, inflammation, lengthened renal cilia, and increased levels of the nutrient sensor, O-linked β-N-acetylglucosamine (O-GlcNAc).Thm1deletion in juvenile ADPKD mice reduced KW/BW ratios and cortical collecting duct cystogenesis, but increased proximal tubular and glomerular dilations and did not reduce inflammation, cilia lengths, and O-GlcNAc signaling. In contrast,Thm1deletion in adult ADPKD mice markedly attenuated renal cystogenesis, inflammation, cilia lengths, and O-GlcNAc. Thus, unlike IFT-B genes, the role ofThm1deletion in ADPKD mouse models is development-specific. Unlike an IFT-A adaptor gene, deletingThm1in juvenile ADPKD mice is partially ameliorative. Our studies suggest that different microenvironmental factors found in distinct nephron segments and between developing and mature kidneys modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a novel feature and critical regulator of certain key ADPKD pathological processes.
A fully open-source framework for deep learning protein real-valued distances
Authors: Adhikari Badri 
Published: April 2020

AbstractAs deep learning algorithms drive the progress in protein structure prediction, a lot remains to be studied at this emerging crossway of deep learning and protein structure prediction. Recent findings show that inter-residue distance prediction, a more granular version of the well-known contact prediction problem, is a key to predict accurate models. We believe that deep learning methods that predict these distances are still at infancy. To advance these methods and develop other novel methods, we need a small and representative dataset packaged for fast development and testing. In this work, we introduce Protein Distance Net (PDNET), a dataset derived from the widely used DeepCov dataset and consists of 3456 representative protein chains for training and validation. It is packaged with all the scripts that were used to curate the dataset, generate the input features and distance maps, and scripts with deep learning models to train, validate and test. Deep learning models can also be trained and tested in a web browser using free platforms such as Google Colab. We discuss how this dataset can be used to predict contacts, distance intervals, and real-valued distances (in Å) by designing regression models. All scripts, training data, deep learning code for training, validation, and testing, and Python notebooks are available athttps://github.com/ba-lab/pdnet/.
Experimental multi-species microbial (co)evolution results in local maladaptation
Authors: Castledine Meaghan , Padfield Daniel , Buckling Angus 
Published: April 2020

AbstractInterspecific coevolutionary interactions can result in rapid biotic adaptation, but most studies have focused only on species pairs. Here, we (co)evolved five microbial species in replicate polycultures and monocultures and quantified local adaptation. Specifically, growth rate assays were used to determine adaptations of each species’ populations to (1) the presence of the other four species in general and (2) sympatric vs allopatric communities. We found no evidence for general biotic adaptation: ancestral, polyculture- and monoculture-evolved populations did not have significantly different growth rates when measured within communities. However, 4/5 species’ growth rates were significantly lower within the community they evolved in. This “local maladaptation” suggests that species evolved increased competitive interactions to sympatric species’ populations. This increased competition did not affect community stability or productivity. Our results suggest that (co)evolution within communities can increase competitive interactions that are specific to (co)evolved community members.
Quality control of low-frequency variants in SARS-CoV-2 genomes
Authors: Rayko Mikhail , Komissarov Aleksey 
Published: April 2020

AbstractDuring the current outbreak of COVID-19, research labs around the globe submit sequences of the local SARS-CoV-2 genomes to the GISAID database to provide a comprehensive analysis of the variability and spread of the virus during the outbreak. We explored the variations in the submitted genomes and found a significant number of variants that can be seen only in one submission (singletons). While it is not completely clear whether these variants are erroneous or not, these variants show lower transition/transversion ratio. These singleton variants may influence the estimations of the viral mutation rate and tree topology. We suggest that genomes with multiple singletons even marked as high-covered should be considered with caution. We also provide a simple script for checking variant frequency against the database before submission.
Emergence of multiple variants of SARS-CoV-2 with signature structural changes
Authors: Bhowmik Debaleena , Pal Sourav , Lahiri Abhishake , Talukdar Arindam , Paul Sandip 
Published: April 2020

AbstractThis study explores the divergence pattern of SARS-CoV-2 using whole genome sequences of the isolates from various COVID-19 affected countries. The phylogenomic analysis indicates the presence of at least four distinct groups of the SARS-CoV-2 genomes. The emergent groups have been found to be associated with signature structural changes in specific proteins. Also, this study reveals the differential levels of divergence patterns for the protein coding regions. Moreover, we have predicted the impact of structural changes on a couple of important viral proteins via structural modelling techniques. This study further advocates for more viral genetic studies with associated clinical outcomes and hosts’ response for better understanding of SARS-CoV-2 pathogenesis enabling better mitigation of this pandemic situation.
Effect of tryptophan depletion on conditioned threat memory expression: role of intolerance of uncertainty
Authors: Kanen Jonathan W , Arntz Frederique E , Yellowlees Robyn , Christmas David M , Price Annabel , Apergis-Schoute Annemieke M , Sahakian Barbara J , Cardinal Rudolf N , Robbins Trevor W 
Published: April 2020

AbstractBackgroundResponding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occurs in many psychiatric disorders including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and schizophrenia, where emotional responses can persist pathologically. Whilst there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does pharmacological lowering of serotonin affect the retention of conditioned threat memory?MethodsForty-seven healthy participants underwent threat conditioning on Day 1 followed by an extinction session. Emotional responding was assessed by the skin conductance response (SCR). On Day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind placebo-controlled randomized between-groups design. We then tested for the return of conditioned threat memory spontaneous recovery). We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression.ResultsThe expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion.ConclusionsThese results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology.
Differential DNA methylation in theVinvpromoter region controls Cold Induced Sweetening in potato
Authors: Shumbe L. , Visse M. , Soares E. , Smit I. , Dupuis B. , Vanderschuren H. 
Published: April 2020

AbstractControl of potato sprouting is important to ensure constant supply of high-quality potato to the industry. Efficient control of sprouting can be achieved by chemical treatment or cold temperature. Recent bans on anti-sprouting molecules are prompting the use of cold storage in the potato value chain. Unfortunately, storage of potato at low temperatures is associated with cold induced sweetening (CIS) due to the induction of the vacuolar invertase gene under low temperatures. Because CIS is associated with the production of the potentially carcinogenic acrylamide in processed potatoes, concise knowledge on the regulatory mechanisms controlling the CIS-phenotype in potatoes is expected to help pave the way for the production of CIS-resistant potato varieties. Here, we dissect the promoters of the Vacuolar invertase (Vinv) genes from CIS-susceptible and CIS-resistant varieties to investigate their implication in CIS-phenotype determination. Using bisulfite sequencing and CRISPR-dCas9-DRM2-mediatedde novoDNA methylation, we show that the CIS-resistant phenotype of Verdi, is in part due to hypermethylation of itsVinvpromoter, more specifically in the 1.0-1.7kb region. Those findings open new perspectives to engineer CIS-resistant potatoes by genome and epigenome modifications.
A low-cost smart system for electrophoresis-based nucleic acids detection at the visible spectrum
Authors: Cunha Eduardo Nogueira , de Souza Maria Fernanda Bezerra , Lanza Daniel Carlos Ferreira , Lima João Paulo Matos Santos 
Published: April 2020

ABSTRACTNucleic acid detection by electrophoresis is still a quick and accessible technique for many diagnosis methods, primarily at research laboratories or at the point of care units. Standard protocols detect DNA/RNA molecules through specific bound chemical dyes using a UV-transilluminator or UV-photo documentation system. However, the acquisition costs and availability of these devices, mainly the ones with photography and internet connection capabilities, can be prohibitive, especially in developing countries public health units. Also, ultraviolet radiation is a common additional risk factor to professionals that use electrophoresis-based nucleic acid detection. With that in mind, this work describes the development of a low-cost DNA/RNA detection smart system capable of obtaining qualitative and semi-quantitative data from gel analysis. The proposed device explores the visible light absorption range of commonly used DNA/RNA dyes using readily available parts, and simple manufacturing processes, such as light-emitting diodes (LEDs) and 3D impression. By applying IoT techniques, our system covers a wide range of color spectrum in order to detect bands from various commercially used dyes, using Bluetooth communication and a smartphone for hardware control, image capturing, and sharing. The project also enables process scalability and has low manufacturing and maintenance costs. The use of LEDs at the visible spectrum can achieve very reproducible images, providing a high potential for rapid and point-of-care diagnostics as well as applications in several fields such as healthcare, agriculture, and aquaculture.
Contributions of the Heme Coordinating Ligands of thePseudomonas aeruginosaOuter Membrane Receptor HasR to Extracellular Heme Sensing and Transport
Authors: Dent Alecia T. , Wilks Angela 
Published: April 2020

ABSTRACTPseudomonas aeruginosaexhibits a high requirement for iron which it can acquire via several mechanisms including the acquisition and utilization of heme.P. aeruginosaencodes two heme uptake systems, thehemeassimilationsystem (Has) and thePseudomonashemeutilization (Phu) system. Extracellular heme is sensed via the Has system that encodes an extra cytoplasmic function (ECF) σ factor system. Previous studies have shown release of heme from the extracellular hemophore HasAp to the outer membrane receptor HasR is required for activation of the σ factor HasI. Herein, employing site-directed mutagenesis, allelic exchange, quantitative PCR analyses, immunoblotting and13C-heme uptake studies, we characterize the differential contributions of the outer membrane receptor HasR extracellular FRAP/PNPNL loop residue His-624 and the N-terminal plug residue His-221 to heme transport and signaling, respectively. Specifically, we show mutation of the N-terminal plug His-221 disrupts both signaling and transport. The data is consistent with a model where heme release from HasAp to the N-terminal plug of HasR is required to initiate signaling, whereas His624 is required for simultaneously closing off the heme transport channel from the extracellular medium and triggering heme transport. Furthermore, mutation of His-221 leads to dysregulation of both the Has and Phu uptake systems suggesting a possible functional link that is coordinated through the ECF σ factor system.
The Genetic Basis of phage susceptibility, cross-resistance and host-range in Salmonella
Authors: Adler Benjamin A. , Kazakov Alexey E. , Zhong Crystal , Liu Hualan , Kutter Elizabeth , Lui Lauren M. , Nielsen Torben N. , Carion Heloise , Deutschbauer Adam M. , Mutalik Vivek K. , Arkin Adam P. 
Published: April 2020

SummaryThough bacteriophages (phages) are known to play a crucial role in bacterial fitness and virulence, our knowledge about the genetic basis of their interaction, cross-resistance and host-range is sparse. Here, we employed genome-wide screens in Salmonella enterica serovar Typhimurium to discover host determinants involved in resistance to eleven diverse lytic phages including 4 new phages isolated from a therapeutic phage cocktail. We uncovered 301 diverse host factors essential in phage infection, many of which are shared between multiple phages demonstrating potential cross-resistance mechanisms. We validate many of these novel findings and uncover the intricate interplay between RpoS, the virulence-associated general stress response sigma factor and RpoN, the nitrogen starvation sigma factor in phage cross-resistance. Finally, the infectivity pattern of eleven phages across a panel of 23 genome sequenced Salmonella strains indicates that additional constraints and interactions beyond the host factors uncovered here define the phage host range.
Flap dynamics in pepsin-like aspartic proteases: a computational perspective using Plasmepsin-II and BACE-1 as model systems
Authors: Bhakat Soumendranath , Söderhjelm Pär 
Published: April 2020

AbstractThe flexibility of aβhairpin structure known as theflapplays a key role in catalytic activity and substrate intake in pepsin-like aspartic proteases. Most of these enzymes share structural and sequential similarity. In the apo form of the proteases, a conserved tyrosine residue in the flap region is in dynamic equilibrium between the normal and flipped states through rotation of theχ1andχ2angles. In this study, we have used apo Plm-II and BACE-1 as model systems. Independent MD simulations of Plm-II and BACE-1 remained stuck either in the normal or flipped state. Metadynamics simulations using side-chain torsion angles (χ1andχ2of tyrosine) as collective variables sampled the transition between the normal and flipped states. Qualitatively, the two states were predicted to be equally populated. The normal and flipped states were stabilised by H-bond interactions to a tryptophan residue and to the catalytic aspartate, respectively. Further, mutation of tyrosine to an amino-acid with smaller side-chain, such as alanine, reduced the flexibility of the flap and resulted in a flap collapse (flap loses flexibility and remains stuck in a particular state). This is in accordance with previous experimental studies, which showed that mutation to alanine resulted in loss of activity in pepsin-like aspartic proteases. Our results suggest that the rotation of the tyrosine side-chain is the key movement that governs flap dynamics and opening of the binding pocket in most pepsin-like aspartic proteases.
The collapse indicators of the dominant species outperform community-level critical slowing down indicators
Authors: Pálinkás Melinda , Hufnagel Levente 
Published: April 2020

AbstractWe studied similarities of collapses and concluded that dominant species have a universal effect on the pattern of collapses. We used open paleoecological and modern data to detect ‘early warning signals’ of collapses. We tested and ranked collapse indicators at the community level (abundance, species richness, constancy, dominance, Shannon’s H, standard deviation, variance, lag-1 autocorrelation of community abundance, lag-1 autocorrelation of Shannon’s H) and at the level of the dominant species (total changes of pre-collapse and collapse dominant species, lag-1 autocorrelation of pre-collapse and collapse dominant species) based on their performances. We distinguished between small-scale signals (sharp drops and peaks) and large-scale signals (trend changes). Small-scale signals and large-scale signals can be at the same time, however, small-scale signals can also precede large-scale signals. Small-scale signals indicate environmental events. Large-scale trend changes refer to the decline and eventually the collapse of the community. Our results show that the collapse indicators of the dominant species outperform community-level critical slowing down indicators, which suggests that the dominant species probably have an important role in community-level collapses triggered by environmental events. We also concluded that unusual environmental events might be the number one cause of collapses therefore small-scale signals should be involved in analyses.