bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Comparison of fMRI and Behavioral Models for Predicting Inter-Temporal Choices
Authors: Knorr Felix G. , Neukam Philipp T. , Fröhner Juliane H. , Mohr Holger , Smolka Michael N. , Marxen Michael 
Published: December 2019

AbstractIn an inter-temporal choice (IteCh) task, subjects are offered a smaller amount of money immediately or a larger amount at a later time point. Here, we are using trial-by-trial fMRI data from 363 recording sessions and machine learning in an attempt to build a classifier that would ideally outperform established behavioral model given that it has access to brain activity specific to a single trial. Such methods could allow for future investigations of state-like factors that influence IteCh choices.To investigate this, coefficients of a GLM with one regressor per trial were used as features for a support vector machine (SVM) in combination with a searchlight approach for feature selection and cross-validation. We then compare the results to the performance of four different behavioral models.We found that the behavioral models reached mean accuracies of 90% and above, while the fMRI model only reached 54.84% at the best location in the brain with a spatial distribution similar to the well-known value-tracking network. This low, though significant, accuracy is in line with simulations showing that classifying based on signals with realistic correlations with subjective value produces comparable, low accuracies. These results emphasize the limitations of fMRI recordings from single events to predict human choices, especially when compared to conventional behavioral models. Better performance may be obtained with paradigms that allow the construction of miniblocks to improve the available signal-to-noise ratio.
Diaci v3.0: Chromosome-level assembly,de novotranscriptome and manual annotation ofDiaphorina citri,insect vector of Huanglongbing
Authors: Shippy Teresa D. , Hosmani Prashant S. , Flores-Gonzalez Mirella , Mann Marina , Miller Sherry , Weirauch Matthew T. , Vosburg Chad , Massimino Crissy , Tank Will , de Oliveira Lucas , Chen Chang , Hoyt Stephanie , Adams Rebekah , Adkins Samuel , Bailey Samuel T. , Chen Xiaoting , Davis Nina , DeLaFlor Yesmarie , Espino Michelle , Gervais Kylie , Grace Rebecca , Harper Douglas , Hasan Denisse L. , Hoang Maria , Holcomb Rachel , Jernigan Margaryta R. , Kemp Melissa , Kennedy Bailey , Kercher Kyle , Klaessan Stefan , Kruse Angela , Licata Sophia , Lu Andrea , Masse Ron , Mathew Anuja , Michels Sarah , Michels Elizabeth , Neiman Alan , Norman Seantel , Norus Jordan , Ortiz Yasmin , Panitz Naftali , Paris Thomson , Perentesis Kitty M. R. , Perry Michael , Reynolds Max , Sena Madison M. , Tamayo Blessy , Thate Amanda , Vandervoort Sara , Ventura Jessica , Weis Nicholas , Wise Tanner , Shatters Robert G. , Heck Michelle , Benoit Joshua B. , Hunter Wayne B. , Mueller Lukas A. , Brown Susan J. , D’Elia Tom , Saha Surya 
Published: December 2019

AbstractBackgroundDiaphorina citriis a vector of “CandidatusLiberibacter asiaticus” (CLas), the gram-negative bacterial pathogen associated with citrus greening disease. Control measures rely on pesticides with negative impacts on the environment, natural ecosystems and human and animal health. In contrast, gene-targeting methods have the potential to specifically target the vector species and/or reduce pathogen transmission.ResultsTo improve the genomic resources needed for targeted pest control, we assembled aD. citrigenome based on PacBio long reads followed by proximity ligation-based scaffolding. The 474 Mb genome has 13 chromosomal-length scaffolds. 1,036 genes were manually curated as part of a community annotation project, composed primarily of undergraduate students. We also computationally identified a total of 1,015 putative transcription factors (TFs) and were able to infer motifs for 337 TFs (33 %). In addition, we produced a genome-independent transcriptome and genomes forD. citriendosymbionts.ConclusionsManual annotation provided more accurate gene models for use by researchers and also provided an excellent training opportunity for students from multiple institutions. All resources are available onCitrusGreening.organd NCBI. The chromosomal-lengthD. citrigenome assembly serves as a blueprint for the development of collaborative genomics projects for other medically and agriculturally significant insect vectors.
EcDBS1R6: A new broad-spectrum cationic antibacterial peptide derived from a signal peptide sequence
Authors: Porto William F. , Irazazabal Luz N. , Humblot Vincent , Haney Evan F. , Ribeiro Suzana M. , Hancock Robert E. W. , Ladram Ali , Franco Octavio L. 
Published: December 2019

ABSTRACTBacterial infections represent a major worldwide health problem, with an special highlight on Gram-negative bacteria, which were assigned by the World Health Organization (WHO) as the most critical priority for development of novel antimicrobial compounds. Antimicrobial peptides (AMPs) have been considered as potential alternative agents for treating these infections. Here we demonstrated the broad-spectrum activity of EcDBS1R6, a peptide derived from a signal peptide sequence ofEscherichia colithat we previously turned into an AMP by making changes predicted through the Joker algorithm. Signal peptides are known to naturally interact with membranes; however, the modifications introduced by Joker made this peptide capable of killing bacteria. Membrane damage of the bacterial cells was observed by measuring membrane integrity using fluorescent probes and through scanning electron microscopy imaging. Structural analysis revealed that the C-terminus was unable to fold into an α-helix, indicating that the EcDBS1R6 antibacterial activity core was located at the N-terminus, corresponding to the signal peptide portion of the parent peptide. Therefore, the strategy of transforming signal peptides into AMPs seems to be promising and could be used for producing novel antimicrobial agents.
O-GlcNAcylation of small heat shock proteins enhances their anti-amyloid chaperone activity
Authors: Balana Aaron T. , Levine Paul M. , Mukherjee Somnath , Pedowitz Nichole J. , Moon Stuart P. , Takahashi Terry T. , Becker Christian F. W. , Pratt Matthew R. 
Published: December 2019

AbstractA major role for the intracellular posttranslational modification O-GlcNAc appears to be the inhibition of protein aggregation. Most of the previous studies in this area have focused on O-GlcNAcylation of the amyloid-forming proteins themselves. Here, we use synthetic protein chemistry to discover that O-GlcNAc also activates the anti-amyloid activity of certain small heat shock proteins (sHSPs), a potentially more important modification event that can act broadly and substoichiometrically. More specifically, we find that O-GlcNAcylation increases the ability of sHSPs to block the amyloid formation of both α-synuclein and Aβ. Mechanistically, we show that O-GlcNAc near the sHSP IXI-domain prevents its ability to intramolecularly compete with substrate binding. Our results have important implications for neurodegenerative diseases associated with amyloid formation and potentially other areas of sHSP biology.
Sex differences in traumatic stress reactivity of rats with a history of alcohol drinking
Authors: Albrechet-Souza Lucas , Schratz Connor L. , Gilpin Nicholas W. 
Published: December 2019

AbstractBackgroundAlcohol misuse and post-traumatic stress disorder (PTSD) are highly comorbid and treatment outcomes are worse in individuals with both conditions. Although more men report experiencing traumatic events than women, the lifetime prevalence of PTSD is twice as high in females. Despite these data trends in humans, preclinical studies of traumatic stress reactivity have been performed almost exclusively in male animals.MethodsThis study was designed to examine sex differences in traumatic stress reactivity in alcohol-naïve rats and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks. Rats were exposed to predator odor (bobcat urine) and tested for avoidance of the odor-paired context 24 hours later; unstressed Controls were never exposed to odor. Two days after stress, we measured physiological arousal using the acoustic startle response (ASR) test. We also measured anxiety-like behavior using the elevated plus-maze (EPM) and circulating corticosterone levels before and immediately after odor exposure.ResultsMale and female rats exposed to predator odor displayed blunted weight gain 24 hours post-stress, but only a subset of stressed animals exhibited avoidance behavior. Chronic intermittent alcohol drinking increased the proportion of Avoiders in males and predator odor exposure increased ASR in these animals. Predator odor stress reduced ASR in females relative to unstressed females and stressed males, regardless of alcohol drinking history. Bobcat urine exposure did not promote persistent anxiety-like behavior, but alcohol-experienced males exhibited reduced activity in the EPM in comparison to alcohol-experienced females.Furthermore, predator odor increased circulating corticosterone levels in females relative to males and baseline.ConclusionsWe report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, chronic moderate alcohol drinking increased traumatic stress reactivity in males but not females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior.
RNA-Seq Analysis Illuminates the Early Stages ofPlasmodiumLiver Infection
Authors: Toro-Moreno Maria , Sylvester Kayla , Srivastava Tamanna , Posfai Dora , Derbyshire Emily R. 
Published: December 2019

ABSTRACTThe apicomplexan parasitesPlasmodiumspp. are the causative agents of malaria, a disease that poses a significant global health burden.Plasmodiumspp. initiate infection of the human host by transforming and replicating within hepatocytes. This liver stage (LS) is poorly understood when compared to otherPlasmodiumlife stages, which has hindered our ability to target these parasites for disease prevention. We conducted an extensive RNA-seq analysis throughout thePlasmodium bergheiLS, covering as early as 2 hours post infection (hpi) and extending to 48 hpi. Our data revealed that hundreds of genes are differentially expressed at 2 hpi, and that multiple genes shown to be important for later infection are upregulated as early as 12 hpi. Using hierarchical clustering along with co-expression analysis, we identified clusters functionally enriched for important liver-stage processes such as interactions with the host cell and redox homeostasis. Furthermore, some of these clusters were highly correlated to the expression of ApiAP2 transcription factors, while showing enrichment of mostly uncharacterized DNA binding motifs. This finding presents potential LS targets for these transcription factors, while also hinting at alternative uncharacterized DNA binding motifs and transcription factors during this stage. Our work presents a window into the previously undescribed transcriptome ofPlasmodiumupon host hepatocyte infection to enable a comprehensive view of the parasite’s LS. These findings also provide a blueprint for future studies that extend hypotheses concerning LS gene function inP. bergheito human-infectivePlasmodiumparasites.IMPORTANCEThe LS ofPlasmodiuminfection is an asymptomatic yet necessary stage for producing blood-infective parasites, the causative agents of malaria. Blocking the liver stage of the life cycle can prevent clinical malaria, but relatively less is known about the parasite’s biology at this stage. Using the rodent modelP. berghei, we investigated whole-transcriptome changes occurring as early as 2 hpi of hepatocytes. The transcriptional profiles of early time points (2, 4, 12, and 18 hpi) have not been accessible before due to the technical challenges associated with liver-stage infections. Our data now provides insights into these early parasite fluxes that may facilitate establishment of infection, transformation and replication in the liver.
Identification of Microorganisms by Liquid Chromatography-Mass Spectrometry (LC-MS1) and in silico Peptide Mass Data
Authors: Lasch Peter , Schneider Andy , Blumenscheit Christian , Doellinger Joerg 
Published: December 2019

1.ABSTRACTOver the past decade, modern methods of mass spectrometry (MS) have emerged that allow reliable, fast and cost-effective identification of pathogenic microorganisms. While MALDI-TOF MS has already revolutionized the way microorganisms are identified, recent years have witnessed also substantial progress in the development of liquid chromatography (LC)-MS based proteomics for microbiological applications. For example, LC-tandem mass spectrometry (LC-MS2) has been proposed for microbial characterization by means of multiple discriminative peptides that enable identification at the species, or sometimes at the strain level. However, such investigations can be very time-consuming, especially if the experimental LC-MS2 data are tested against sequence databases covering a broad panel of different microbiological taxa.In this proof of concept study, we present an alternative bottom-up proteomics method for microbial identification. The proposed approach involves efficient extraction of proteins from cultivated microbial cells, digestion by trypsin and LC-MS measurements. MS1 data are then extracted and systematically tested against an in silico library of peptide mass data compiled in house. The library has been computed from the UniProt Knowledgebase Swiss-Prot and TrEMBL databases and comprises more than 12,000 strain-specific in silico profiles, each containing tens of thousands of peptide mass entries. Identification analysis involves computation of score values derived from spectral distances between experimental and in silico peptide mass data and compilation of score ranking lists. The taxonomic positions of the microbial samples are then determined by using the best-matching database entries. The suggested method is computationally efficient – less than two minutes per sample - and has been successfully tested by a set of 19 different microbial pathogens. The approach is rapid, accurate and automatable and holds great potential for future microbiological applications.
Shotgun metagenomics and metabolomics reveal glyphosate alters the gut microbiome of Sprague-Dawley rats by inhibiting the shikimate pathway
Authors: Mesnage Robin , Teixeira Maxime , Mandrioli Daniele , Falcioni Laura , Ducarmon Quinten Raymond , Zwittink Romy Daniëlle , Amiel Caroline , Panoff Jean-Michel , Belpoggi Fiorella , Antoniou Michael N 
Published: December 2019

AbstractThere is intense debate as to whether glyphosate can interfere with aromatic amino acid biosynthesis in microorganisms inhabiting the gastrointestinal tract, which could potentially lead to negative health outcomes. We have addressed this major gap in glyphosate toxicology by using a multi-omics strategy combining shotgun metagenomics and metabolomics. We tested whether glyphosate (0.5, 50, 175 mg/kg bw/day), or its representative EU commercial herbicide formulation MON 52276 at the same glyphosate equivalent doses, has an effect on the rat gut microbiome in a 90-day subchronic toxicity test. Clinical biochemistry measurements in blood and histopathological evaluations showed that MON 52276 but not glyphosate was associated with statistically significant increase in hepatic steatosis and necrosis. Similar lesions were also present in the liver of glyphosate-treated groups but not in the control group. Caecum metabolomics revealed that glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase in the shikimate pathway as evidenced by an accumulation of shikimic acid and 3-dehydroshikimic acid. Levels of caecal microbiome dipeptides involved in the regulation of redox balance (γ-glutamylglutamine, cysteinylglycine, valylglycine) had their levels significantly increased. Shotgun metagenomics showed that glyphosate affected caecum microbial community structure and increased levels of Eggerthella spp. and Homeothermacea spp.. MON 52276, but not glyphosate, increased the relative abundance of Shinella zoogleoides. Since Shinella spp. are known to degrade alkaloids, its increased abundance may explain the decrease in solanidine levels measured with MON 52776 but not glyphosate. Other glyphosate formulations may have different effects since Roundup® GT Plus inhibited bacterial growth in vitro at concentrations at which MON 52276 did not present any visible effect. Our study highlights the power of a multiomics approach to investigate effects of pesticides on the gut microbiome. This revealed the first biomarker of glyphosate effects on rat gut microbiome. Although more studies will be needed to ascertain if there are health implications arising from glyphosate inhibition of the shikimate pathway in the gut microbiome, our findings can be used in environmental epidemiological studies to understand if glyphosate can have biological effects in human populations.Graphical Abstract
GIV•Kindlin interaction is required for Kindlin-Mediated Integrin Recognition and Activation
Authors: Rohena Cristina , Kalogriopoulos Nicholas , Rajapakse Navin , Roy Suchismita , Lopez-Sanchez Inmaculada , Ablack Jailal , Sahoo Debashis , Ghosh Pradipta 
Published: December 2019

ABSTRACTCells perceive and respond to the extracellular matrix (ECM)viaintegrin receptors; their dysregulation has been implicated in inflammation and cancer metastasis. Here we show that a guanine nucleotide exchange modulator of trimeric-GTPase Gαi, GIV (a.k.aGirdin), directly binds the integrin adaptor Kindlin-2. A non-canonical short linear motif within GIV’s C-terminus binds Kindlin-2-FERM3 domain at a site that is distinct from the binding site for the canonical NPxY motif on the -integrin tail. Binding of GIV to Kindlin-2 allosterically enhances Kindlin-2’s affinity for β1-integrin. Consequently, integrin activation and clustering are maximized, which augments cell adhesion, spreading and invasion. Findings elucidate how the GIV•Kindlin-2 complex has a two-fold impact: it allosterically synergizes integrin activation and enables β1-integrins to indirectly access and modulate trimeric GTPasesviathe complex. Furthermore, Cox proportional-hazard models on tumor transcriptomics provide trans-scale evidence of synergistic interactions between GIV•Kindlin-2•β1-integrin on time to progression to metastasis.The eTOC blurbIntegrins mediate cell adhesion to the extracellular matrix; their dysregulation fuels inflammation, cancer cell invasion and metastasis. Authors show how two pro-metastatic scaffold proteins, Kindlin and GIV/Girdin bind and cooperatively enhance their allosteric coupling to integrins, and their subsequent activation. Findings reveal novel interfaces in integrin signaling for pharmacologic manipulation.HIGHLIGHTSGIV and Kindlin(K2), two integrin adaptors that promote metastasis, bind each otherBinding of GIV or integrin to K2 allosterically enhances GIV•K2•integrin complexesBinding is required for the maximal recruitment of GIV and K2 to active integrinsBinding facilitates integrin clustering, activation, tumor cell adhesion, invasion.
InhibitingMycobacterium tuberculosisCoaBC by targeting a new allosteric site
Authors: Mendes Vitor , Green Simon R. , Evans Joanna C. , Hess Jeannine , Blaszczyk Michal , Spry Christina , Bryant Owain , Cory-Wright James , Chan Daniel S-H. , Torres Pedro H.M. , Wang Zhe , O’Neill Sandra , Damerow Sebastian , Post John , Bayliss Tracy , Lynch Sasha L. , Coyne Anthony G. , Ray Peter C. , Abell Chris , Rhee Kyu Y. , Boshoff Helena I. M. , Barry Clifton E. , Mizrahi Valerie , Wyatt Paul G. , Blundell Tom L. 
Published: December 2019

AbstractCoenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens includingMycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, includingM. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal inM. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organismMycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent inhibitors ofM. tuberculosisCoaB, which we show to bind to a novel cryptic allosteric site within CoaB.
A novel mouse model of cholangiocarcinoma uncovers a role for a SOX17-Tensin 4 pathway in tumor progression
Authors: Di-Luoffo Mickaël , Pirenne Sophie , Saandi Thoueiba , Loriot Axelle , Gérard Claude , Dauguet Nicolas , Lamoline Florence , Konobrocka Katarzyna , De Greef Vitaline , Komuta Mina , Jacquemin Patrick , Lemaigre Frédéric P. 
Published: December 2019

AbstractBackground & AimsAlthough earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) is necessary to improve therapy, there is still limited information available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression towards invasive tumor using experimental models that faithfully recapitulate human tumorigenesis.MethodsWe generated a new mouse model which combines cholangiocyte-specific expression ofKrasG12Dwith 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines.ResultsMice expressingKrasG12Din cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs) and eventually iCCAs. The histology of mouse and human IPNBs were highly similar, and mouse iCCAs displayed histological characteristics of human mucin-producing large duct type iCCA. Signaling pathways activated in human iCCA were activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We provide evidence that a gene cascade which comprisesKRASG12D, SRY-related HMG box transcription factor 17 (SOX17) and Tensin 4 (TNS4), and which is activated by epidermal growth factor, promotes tumor progression.ConclusionsWe developed a novel mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade promoting tumor progression.