bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cannabidiol (CBD) repurposing as antibacterial: promising therapy of CBD plus polymyxin B against superbugs
Authors: Abichabki Nathália , Zacharias Luísa V. , Moreira Natália C. , Bellissimo-Rodrigues Fernando , Moreira Fernanda L. , Benzi Jhohann R. L. , Ogasawara Tânia M. C. , Ferreira Joseane C. , Pereira Leonardo R. L. , Braga Gilberto Ú. L. , Ribeiro Camila M. , Pavan Fernando R. , Zuardi Antonio W. , Hallak Jaime E. C. , Crippa José A. S. , Lanchote Vera L. , Cantón Rafael , Darini Ana Lúcia C. , Andrade Leonardo N. 
Published: April 2021

AbstractMultidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria are a major worldwide public health problem. In the last decades, resistance to last-resort antibiotics such as polymyxin B (PB) have been increasingly observed among these superbugs, compromising the effectiveness of antimicrobial therapy. The present study aimed (i) to assess the ultrapure Cannabidiol (CBD) antibacterial activity against a broad diversity of Gram-negative (GN) and Gram-positive (GP) bacteria (44 different species, 95 strains), comprising standard strains and clinical isolates, and (ii) to investigate the antibacterial activity of the combination CBD + PB against GN bacteria, including chromosomal- and plasmid-acquired PB-resistant and intrinsically PB-resistant GNB. We evaluated CBDin vitroantibacterial activity using the standard broth microdilution method, and the antibacterial activity of the combination CBD + PB was screened using the standard broth microdilution and confirmed by checkerboard assay. CBD exhibited antibacterial activity against different GP bacterial species, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae,Neisseria meningitidis, andMoraxella catarrhalis), andMycobacterium tuberculosis. The combination CBD + PB exhibited antibacterial activity against PB-resistant GNB (e.g.,Klebsiella pneumoniae) as well as additive and/or synergistic effect against LOS-expressing GND. The antibacterial activity of the combination CBD + PB againstPseudomonas aeruginosaand plasmid-mediated colistin-resistant (MCR-1)E. colistrains could be only demonstrated in the presence of phenylalanine-arginine-β-naphthylamide (PAβN). In conclusion, our results show promising translational potential of the combination CBD + PB against MDR and XDR GNB, including PB-resistantK. pneumoniae, highlighting its potential as a rescue treatment for life-threatening infections caused by these superbugs.One Sentence SummaryPromising combination of cannabidiol (CBD) + polymyxin B (PB) against superbugs (e.g., PB-resistant Gram-negative bacilli): Repurposing CBD
Mechanism of riboregulation of p62 protein oligomerisation by vault RNA1-1 in selective autophagy
Authors: Büscher Magdalena , Horos Rastislav , Haubrich Kevin , Dobrev Nikolay , Baudin Florence , Hennig Janosch , Hentze Matthias W. 
Published: April 2021

ABSTRACTMacroautophagy ensures the clearance of intracellular substrates ranging from single ubiquitinated proteins to large proteotoxic aggregates and defective organelles. The selective autophagy receptor p62 binds these targets and recruits them to double-membrane vesicles, which fuse with lysosomes to degrade their content. We recently uncovered that p62 function is riboregulated by the small non-coding vault RNA1-1. Here, we present detailed insight into the underlying mechanism. We show that the PB1 domain and adjacent linker region of p62 (aa 1-122) are necessary and sufficient for specific vault RNA1-1 binding, and identify lysine 7 and arginine 21 as key hinges for p62 riboregulation. Chemical structure probing of vault RNA1-1 further reveals a central flexible loop within the RNA that mediates the specific p62 interaction. Our data define molecular determinants that govern mammalian autophagy via the p62-vault RNA1-1 riboregulatory pair.
Beneficial substrate partitioning boosts non-aqueous catalysis in de novo enzyme-alginate beads
Authors: Stenner Richard , Adrian Bunzel H. , Mulholland Adrian J. , Ross Anderson J. L. 
Published: April 2021

ABSTRACTSynthetic reactions often require solvents incompatible with biocatalysts. Here, we encapsulate ade novoheme-containing enzyme, C45, in calcium-alginate hydrogel beads to facilitate heterogeneous biocatalysis in neat organic solvents. Post-encapsulation, C45 retains activity even when the beads are suspended in organic solvents. In particular, the carbene transferase activity of C45 is enhanced when reactions are performed in aprotic, non-polar solvents such as hexane and toluene. Activity-solvent dependencies reveal that this activity boost is likely due to beneficial partitioning of the substrate into the beads from the organic phase. Furthermore, encapsulation facilitates enzyme recovery and recycling after the reaction. Such encapsulation opens up novel opportunities for biocatalysis in organic solvent systems, combining desired solvent properties of organic chemistry with enzymatic selectivity and proficiency.
Renalase is a novel tissue and serological biomarker in pancreatic ductal adenocarcinoma
Authors: Gao Yasheen , Wang Melinda , Guo Xiaojia , Hu Joanna , Chen Tian-min , Finn Sade’ M.B. , Lacy Jill , Kunstman John W. , Cha Charles H. , Bellin Melena D. , Robert Marie E. , Desir Gary V. , Gorelick Fred S. 
Published: April 2021

AbstractDysregulated expression of the secretory protein renalase (RNLS) can promote pancreatic ductal adenocarcinoma (PDAC) growth in animal models. We characterized RNLS expression in premalignant and malignant PDAC tissue and investigated whether plasma RNLS levels corresponded to clinical PDAC characteristics. RNLS immunohistochemistry was used to determine the presence and distribution of RNLS in normal pancreas, chronic pancreatitis, PDAC precursor lesions, and PDAC tissues. Associations between pretreatment plasma RNLS and PDAC clinical status were assessed in patients with varied clinical stages of PDAC and included tumor characteristics, surgical resection in locally advanced/borderline resectable PDAC, and overall survival. Data were retrospectively obtained and correlated using non-parametric analysis. Mild to no RNLS was detected by histochemistry in the normal pancreas in the absence of abdominal trauma. In chronic pancreatitis, RNLS immunoreactivity localized to peri-acinar spindle-shaped cells in some samples. It was also widely present in PDAC precursor lesions and PDAC tissue. Among 240 patients with PDAC, elevated plasma RNLS levels were associated with worse tumor characteristics, including greater angiolymphatic invasion (80.0% vs. 58.1%, p = 0.012) and greater node positive disease (76.5% vs. 56.5%, p = 0.024). Overall survival was worse in patients with high plasma RNLS levels with median follow-up of 27.70 months vs. 65.03 months (p < 0.001). RNLS levels also predicted whether patients with locally advanced/borderline resectable (LA/BR) PDAC underwent resection (AUC 0.674; 95%CI 0.42-0.82, p = 0.04). Overall tissue RNLS was increased in both premalignant and malignant PDAC tissues compared to normal pancreas. Elevated plasma RNLS levels were associated with advanced tumor characteristics, decreased overall survival, and reduced resectability in patients with LA/BR PDAC. These studies show that RNLS levels are increased in premalignant pancreatic tissues and that its levels in plasma correspond to the clinical behavior of PDAC.
Cold-triggered induction of ROS- and raffinose-related metabolism in freezing-sensitive taproot tissue of sugar beet
Authors: Keller Isabel , Müdsam Christina , Rodrigues Cristina Martins , Kischka Dominik , Zierer Wolfgang , Sonnewald Uwe , Harms Karsten , Czarnecki Olaf , Fiedler-Wiechers Karin , Koch Wolfgang , Neuhaus H. Ekkehard , Ludewig Frank , Pommerrenig Benjamin 
Published: April 2021

AbstractSugar beet (Beta vulgaris subsp. vulgaris) is the exclusive source of sugar in the form of sucrose in temperate climate zones. There, sugar beet is grown as an annual crop from spring to autumn because of the damaging effect of freezing temperatures to taproot tissue. Natural and breeded varieties display variance in the degree of tolerance to freezing temperatures and genotypes with elevated tolerance to freezing have been isolated. Here we compare initial responses to frost between genotypes with either low and high winter survival rates. The selected genotypes differed in the severity of frost injury. We combined transcriptomic and metabolite analyses of leaf- and taproot tissues from such genotypes to elucidate mechanisms of the early freezing response and to dissect genotype- and tissue-dependent responses. Freezing temperatures induced drastic downregulation of photosynthesis-related genes in leaves but upregulation of genes related to minor carbohydrate metabolism, particularly of genes involved in raffinose metabolism in both, leaf and taproot tissue. In agreement with this, it has been revealed that raffinose and the corresponding intermediates, inositol and galactinol, increased markedly in these tissues. We found that genotypes with improved tolerance to freezing, showed higher accumulation of raffinose in a defined interior region within the upper part of the taproot, the pith, representing the tissue most susceptible to freeze damages. This accumulation was accompanied by specific upregulation of raffinose synthesizing enzymes in taproots, suggesting a protective role for raffinose and its precursors for freezing damage in sugar beet.
In vivo genome-wide CRISPR screens identify SOCS1 as a major intrinsic checkpoint of CD4+Th1 cell response
Authors: Del Galy Aurélien Sutra , Menegatti Silvia , Fuentealba Jaime , Perrin Laetitia , Lucibello Francesca , Helft Julie , Darbois Aurélie , Saitakis Michael , Tosello Jimena , Rookhuizen Derek , Deloger Marc , Gestraud Pierre , Socié Gérard , Amigorena Sebastian , Lantz Olivier , Menger Laurie 
Published: April 2021

SummaryThe expansion of antigen experienced CD4+T cells is limited by intrinsic factors. Usingin vivogenome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals and blocking multiple signaling pathways to abrogate CD4+Th1 cell response. In CD8+T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.
Cortical tracking of a background speaker modulates the comprehension of a foreground speech signal
Authors: Keshavarzi Mahmoud , Varano Enrico , Reichenbach Tobias 
Published: April 2021

AbstractUnderstanding speech in background noise is a difficult task. The tracking of speech rhythms such as the rate of syllables and words by cortical activity has emerged as a key neural mechanism for speech-in-noise comprehension. In particular, recent investigations have used transcranial alternating current stimulation (tACS) with the envelope of a speech signal to influence the cortical speech tracking, demonstrating that this type of stimulation modulates comprehension and therefore evidencing a functional role of the cortical tracking in speech processing. Cortical activity has been found to track the rhythms of a background speaker as well, but the functional significance of this neural response remains unclear. Here we employ a speech-comprehension task with a target speaker in the presence of a distractor voice to show that tACS with the speech envelope of the target voice as well as tACS with the envelope of the distractor speaker both modulate the comprehension of the target speech.Because the envelope of the distractor speech does not carry information about the target speech stream, the modulation of speech comprehension through tACS with this envelope evidences that the cortical tracking of the background speaker affects the comprehension of the foreground speech signal. The phase dependency of the resulting modulation of speech comprehension is, however, opposite to that obtained from tACS with the envelope of the target speech signal. This suggests that the cortical tracking of the ignored speech stream and that of the attended speech stream may compete for neural resources.Significance StatementLoud environments such as busy pubs or restaurants can make conversation difficult. However, they also allow us to eavesdrop into other conversations that occur in the background. In particular, we often notice when somebody else mentions our name, even if we have not been listening to that person. However, the neural mechanisms by which background speech is processed remain poorly understood. Here we employ transcranial alternating current stimulation, a technique through which neural activity in the cerebral cortex can be influenced, to show that cortical responses to rhythms in the distractor speech modulate the comprehension of the target speaker. Our results evidence that the cortical tracking of background speech rhythms plays a functional role in speech processing.
Critical evaluation of kinetic schemes for coagulation
Authors: Ranc Alexandre , Bru Salome , Mendez Simon , Giansily-Blaizot Muriel , Nicoud Franck , Méndez Rojano Rodrigo 
Published: April 2021

AbstractComputational models of the coagulation cascade are used for a wide range of applications in bio-medical engineering such as drug and bio-medical device developments. However, a lack of robustness of numerical models has been highlighted when studying clinically relevant scenarios. In order to develop more robust models, numerical simulations need to be confronted with realistic situations relevant to clinical practice. In this work, two well-established numerical representations of the coagulation cascade initiated by the intrinsic and extrinsic systems, respectively, were compared with thrombin generation assays considering realistic pathological conditions. Proper modifications were needed to align thein vitroandin silicodata, namely; adapting initial conditions to the thrombin assay system, omitting reactions irrelevant to our case study, and improving the fitting of some reaction rates. The modified models were able to capture the experimental trends of thrombin generation for a range of concentrations of factors XII, XI, and VIII for cases in which the coagulation cascade is triggered through the extrinsic and intrinsic systems. Our work emphasizes that when existing coagulation cascade models are extrapolated to experimental settings for which they were not calibrated, careful adjustments must be made. We show that the two coagulation models used in this work can predict physiological conditions, but when studying pathological conditions, proper modifications are needed to improve the numerical results.
The Kinship Matrix: Inferring the Kinship Structure of a Population from its Demography
Authors: Coste Christophe F. D. , Bienvenu François , Ronget Victor , Ramirez-Loza Juan-Pablo , Cubaynes Sarah , Pavard Samuel 
Published: April 2021

AbstractThe familial structure of a population and the relatedness of its individuals are determined by its demography. There is, however, no general method to infer kinship directly from the life-cycle of a structured population. Yet this question is central to fields such as ecology, evolution and conservation, especially in contexts where there is a strong interdependence between familial structure and population dynamics. Here, we give a general formula to compute, from any matrix population model, the expected number of arbitrary kin (sisters, nieces, cousins, etc) of a focal individualego, structured by the class ofegoand of its kin. Central to our approach are classic but little-used tools known as genealogical matrices. Our method can be used to obtain both individual-based and population-wide metrics of kinship, as we illustrate. It also makes it possible to analyze the sensitivity of the kinship structure to the traits implemented in the model.
Developmental changes in story-evoked responses in the neocortex and hippocampus
Authors: Cohen Samantha S. , Tottenham Nim , Baldassano Christopher 
Published: April 2021

AbstractHow does the representation of naturalistic life events change with age? Here we analyzed fMRI data from 414 children and adolescents (5 - 19 years) as they watched a narrative movie. In addition to changes in the degree of inter-subject correlation (ISC) with age in sensory and medial parietal regions, we used a novel measure (between-group ISC) to reveal age-related shifts in the responses across the majority of the neocortex. Over the course of development, brain responses became more discretized into stable and coherent events and shifted earlier in time to anticipate upcoming perceived event transitions, measured behaviorally in an age-matched sample. However, hippocampal responses to event boundaries actually decreased with age, suggesting a shifting division of labor between episodic encoding processes and schematic event representations between the ages of 5 and 19.
A counter-enzyme complex regulatesglutamate metabolism inBacillus subtilis
Authors: Jayaraman Vijay , Lee D. John , Elad Nadav , Vimer Shay , Sharon Michal , Fraser James S. , Tawfik Dan S. 
Published: April 2021

SummaryMulti-enzyme assemblies composed of metabolic enzymes catalyzing sequential reactions are being increasingly studied. Here, we report the discovery of a 1.6 megadalton multi-enzyme complex fromBacillus subtiliscomposed of two enzymes catalyzing opposite rather than sequential reactions (“counter-enzymes”): glutamate synthase (GltAB), and glutamate dehydrogenase (GudB), that make and break glutamate, respectively.In vivoandin vitrostudies show that the primary role of complex formation is to inhibit GudB’s activity as this enzyme is constitutively expressed including in glutamate-limiting conditions. Using cryo-electron microscopy, we elucidated the structure of the complex and the basis of GudB’s inhibition. Finally, we show that this complex that exhibits unusual oscillatory progress curves is a necessity for planktonic growth in glutamate-limiting conditions, but is also essential for biofilm growth in glutamate-rich media, suggesting a regulatory role at fluctuating glutamate concentrations.
The Hippo pathway regulates density-dependent proliferation of iPSC-derived cardiac myocytes
Authors: Neininger Abigail C. , Dai Xiaozhaun , Liu Qi , Burnette Dylan T. 
Published: April 2021

ABSTRACTInducing cardiac myocytes to proliferate is considered a potential therapy to target heart disease, however, modulating cardiac myocyte proliferation has proven to be a technical challenge. The Hippo pathway is a kinase signaling cascade that regulates cell proliferation during the growth of the heart. Inhibition of the Hippo pathway increases the activation of the transcription factors YAP/TAZ, which translocate to the nucleus and upregulate transcription of pro-proliferative genes. The Hippo pathway regulates the proliferation of cancer cells, pluripotent stem cells, and epithelial cells through a cell-cell contact-dependent manner, however it is unclear if cell density-dependent cell proliferation is a consistent feature in cardiac myocytes. Here, we used culturedhuman iPSC-derivedcardiacmyocytes (hiCMs) as a model system to investigate this concept. hiCMs have a comparable transcriptome to the immature cardiac myocytes that proliferate during heart developmentin vivo. Our data indicate that a dense syncytium of hiCMs can regain cell cycle activity and YAP expression and activity when plated sparsely or when density is reduced through wounding. We found that combining two small molecules, XMU-MP-1 and S1P, increased YAP activity and further enhanced proliferation of low-density hiCMs. Importantly, these compounds had no effect on hiCMs within a dense syncytium. These data add to a growing body of literature that link the Hippo pathway regulation with cardiac myocyte proliferation and demonstrate that regulation is restricted to cells with reduced contact inhibition.
Biphasic roles of hedgehog signaling in the production and self-renewal of outer radial glia in the ferret cerebral cortex
Authors: Hou Shirui , Ho Wan-Ling , Wang Lei , Kuo Bryan , Park Jun Young , Han Young-Goo 
Published: April 2021

AbstractThe neocortex, the center for higher brain function, emerged in mammals and expanded in the course of evolution. The expansion of outer radial glia (oRGs) and intermediate progenitor cells (IPCs) plays key roles in the expansion and consequential folding of the neocortex. Therefore, understanding the mechanisms of oRG and IPC expansion is important for understanding neocortical development and evolution. By using mice and human cerebral organoids, we previously revealed that hedgehog (HH) signaling expands oRGs and IPCs. Nevertheless, it remained to be determined whether HH signaling expanded oRGs and IPCsin vivoin gyrencephalic species, in which oRGs and IPCs are naturally expanded. Here, we show that HH signaling is necessary and sufficient to expand oRGs and IPCs in ferrets, a gyrencephalic species, through conserved cellular mechanisms. HH signaling increases oRG-producing division modes of ventricular radial glia (vRGs), oRG self-renewal, and IPC proliferation. Notably, HH signaling affects vRG division modes only in an early restricted phase before superficial-layer neuron production peaks. Beyond this restricted phase, HH signaling promotes oRG self-renewal. Thus, HH signaling expands oRGs and IPCs in two distinct but continuous phases during cortical development.
DDX21 is a p38-MAPK sensitive nucleolar protein necessary for mouse preimplantation embryo development and cell-fate specification
Authors: Bora Pablo , Gahurova Lenka , Hauserova Andrea , Stiborova Martina , Collier Rebecca , Potěšil David , Zdráhal Zbyněk , Bruce Alexander W. 
Published: April 2021

AbstractSuccessful navigation of the mouse preimplantation stages of development, during which three distinct blastocyst lineages are derived, represents a prerequisite for continued development. We previously identified a role for p38-mitogen-activated kinases (p38-MAPK) regulating blastocyst inner cell mass (ICM) cell-fate, specifically primitive endoderm (PrE) differentiation, that is intimately linked to rRNA precursor processing, polysome formation and protein translation regulation. Here, we develop this work by assaying the role of DEAD-box RNA helicase 21 (Ddx21), a known regulator of rRNA processing, in the context of p38-MAPK regulation of preimplantation mouse embryo development. We show nuclearDdx21protein is robustly expressed from the 16-cell stage, becoming exclusively nucleolar during blastocyst maturation; a localisation dependent on active p38-MAPK. Efficient siRNA mediated clonalDdx21knockdown within developing embryos is associated with profound cell autonomous and non-autonomous proliferation defects and reduced blastocyst volume, by the equivalent peri-implantation blastocyst stage. Moreover, ICM residingDdx21knockdown clones express the EPI marker NANOG but rarely express the PrE differentiation marker GATA4. These data contribute extra significance to emerging importance of lineage specific translation regulation, as identified for p38-MAPK, during mouse preimplantation development.