bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiome of the Black Sea water column analyzed by genome centric metagenomics
Authors: Cabello-Yeves Pedro J. , Callieri Cristiana , Picazo Antonio , Mehrshad Maliheh , Haro-Moreno Jose M. , Roda-Garcia Juan J. , Dzhembekova Nina , Slabakova Violeta , Slabakova Nataliya , Moncheva Snejana , Rodriguez-Valera Francisco 
Published: October 2020

AbstractBackgroundThe Black Sea is the largest brackish water body in the world, although it is connected to the Mediterranean Sea and presents an upper water layer similar to some regions of the former albeit with lower salinity and (mostly) temperature. In spite of its well-known hydrology and physico chemistry, this enormous water mass remains poorly studied at the microbial genomics level.ResultsWe have sampled its different water masses and analyzed the microbiome by classic and genome-resolved metagenomics generating a large number of metagenome-assembled genomes (MAGs) from them. The oxic zone presents many similarities to the global ocean while the euxinic water mass has similarities to other similar aquatic environments of marine or freshwater (meromictic monimolimnion strata) origin. The MAG collection represents very well the different types of metabolisms expected in this kind of environments and includes Cyanobacteria (Synechococcus), photoheterotrophs (largely with marine relatives), facultative/microaerophilic microbes again largely marine, chemolithotrophs (N and S oxidizers) and a large number of anaerobes, mostly sulfate reducers but also a few methanogens and a large number of “dark matter” streamlined genomes of largely unpredictable ecology.ConclusionsThe Black Sea presents a mixture of similarities to other water bodies. The photic zone has many microbes in common with that of the Mediterranean with the relevant exception of the absence of Prochlorococcus. The chemocline already presents very different characteristics with many examples of chemolithotrophic metabolism (Thioglobus) and facultatively anaerobic microbes. Finally the euxinic anaerobic zone presents, as expected, features in common with the bottom of meromictic lakes with a massive dominance of sulfate reduction as energy generating metabolism and a small but detectable methanogenesis.We are adding critical information about this unique and important ecosystem and its microbiome.
Therapeutic doses of paracetamol with co-administration of cysteine and mannitol during early development result in long term behavioral changes in laboratory rats
Authors: Suda Navneet , Hernandez Jasmine Cendejas , Poulton John , Jones John P , Konsoula Zacharoula , Smith Caroline , Parker William 
Published: October 2020

AbstractBased on several lines of evidence, numerous investigators have suggested that paracetamol exposure during early development can induce neurological disorders. We had previously postulated that paracetamol exposure early in life, if combined with antioxidants that prevent accumulation of NAPQI, the toxic metabolite of paracetamol, might be innocuous. In this study, we administered paracetamol at or below the currently recommended therapeutic dose to male laboratory rat pups aged 4-10 days. The antioxidants cysteine and mannitol were included to prevent accumulation of NAPQI. In addition, animals were exposed to a cassette of common stress factors: an inflammatory diet, psychological stress, antibiotics, and mock infections using killed bacteria. At age 37-49 days, observation during introduction to a novel conspecific revealed increased rearing behavior, an asocial behavior, in animals treated with paracetamol plus antioxidants, regardless of their exposure to oxidative stress factors (2-way ANOVA; P < 0.0001). This observation would suggest that the initial hypothesis is incorrect, and that oxidative stress mediators do not entirely eliminate the effects of paracetamol on neurodevelopment. This study provides additional cause for caution when considering the use of paracetamol in the pediatric population, and provides evidence that the effects of paracetamol on neurodevelopment need to be considered both in the presence and in the absence of oxidative stress.
Signature molecular changes in the skeletal muscle of hindlimb unloaded mice
Authors: Azeem M. , Qaisar R. , Karim A. , Ranade A. , Elmoselhi A. 
Published: October 2020

ABSTRACTHind-limb unloaded (HU) mouse is a well-recognized model of muscle atrophy; however the molecular changes in the skeletal muscle during unloading are poorly characterized. We have used Fourier transform infrared (FTIR) and Raman spectroscopy to evaluate the structure and behavior of signature molecules involved in regulating muscle structural and functional health. The FTIR and the Raman spectroscopic analysis of gastrocnemius muscles was compared between 16-18 weeks old HU c57Bl/6J mice and ground-based controls. The molecular components of the samples were identified by using the FTIR spectra from the control and the unloaded samples. The Raman spectra showed that the signals for asparagine and glutamine were reduced in HU mice, possibly indicating increased catabolism. The peaks for hydroxyproline and proline were split, pointing towards molecular breakdown and reduced tendon repair. We also report a consistently increased intensity in > 1300 cm−1range in the Raman spectra along with a shift towards higher frequencies in the HU mice, indicating activation of sarcoplasmic reticulum (SR) stress during HU.SIGNIFICANCEMouse model of hindlimb unloading recapitulates many features of disuse muscle atrophy due to spaceflight and prolonged bed rest. However, a thorough understanding of molecular changes underlying muscle detriment in disuse partly remains elusive. We have applied the spectroscopic and density functional techniques conjointly to characterize the molecular changes in the skeletal muscle of hindlimb unloaded mice. A number of conformational changes and the breakdown of the molecular bonds in the skeletal muscle are observed, which can potentially dictate loss of muscle mass and strength during mechanical unloading. Our reporting of the signature spectral changes in the unloaded skeletal muscle can be a useful step towards the therapeutic interventions targeting specific molecules.
Moleculewise semi-grand canonical ensembles
Authors: Girard M. , Bereau T. 
Published: October 2020

ABSTRACTThe plasma membrane is the interface between cells and exterior media. While its existence has been known for a long time, organization of its constituent lipids remain a challenge. Recently, we have proposed that lipid populations may be controlled by chemical potentials of different lipid species, resulting in semi-grand canonical thermodynamic ensembles. However, the currently available molecular dynamics software packages do not allow for molecule-based chemical potentials. Here, we propose a variation on existing algorithms that allow defining chemical potentials for molecules. Additionally, we allow coupling with collective variables and show that it can be used to dynamically create asymmetric membranes. We release an implementation of the algorithm for the HOOMD-Blue molecular dynamics engine.SIGNIFICANCEWe demonstrate an algorithm that allows for simulations of molecules in the semi-grand canonical ensemble. It also allows coupling the chemical potential values to collective variable and create asymmetric membranes.
Engineering precursor pools for increasing production of odd-chain fatty acids inYarrowia lipolytica
Authors: Park Young-Kyoung , Bordes Florence , Letisse Fabien , Nicaud Jean-Marc 
Published: October 2020

AbstractMicrobial production of lipids is one of the promising alternatives to fossil fuels with increasing environmental and energy concern. Odd-chain fatty acids (OCFA), a type of unusual lipids, are recently gaining a lot of interest as target compounds in microbial production due to their diverse applications in the medical, pharmaceutical, and chemical industries. In this study, we aimed to enhance the pool of precursors with three-carbon chain (propionyl-CoA) and five-carbon chain (β-ketovaleryl-CoA) for the production of OCFAs inYarrowia lipolytica. We evaluated different propionate-activating enzymes and the overexpression of propionyl-CoA transferase gene fromRalstonia eutrophaincreased the accumulation of OCFAs by 3.8 times over control strain, indicating propionate activation is the limiting step of OCFAs synthesis. It was shown that acetate supplement was necessary to restore growth and to produce a higher OCFA contents in total lipids, suggesting the balance of the precursors between acetyl-CoA and propionyl-CoA is crucial for OCFA accumulation. To improve β-ketovaleryl-CoA pools for further increase of OCFA production, we co-expressed thebktBencoding β-ketothiolase in the producing strain, and the OCFA production was increased by 33 % compared to control. Combining strain engineering and the optimization of the C/N ratio promoted the OCFA production up to 1.87 g/L representing 62% of total lipids, the highest recombinant OCFAs titer reported in yeast, up to date. This study provides a strong basis for the microbial production of OCFAs and its derivatives having high potentials in a wide range of applications.
TheGhsrQ343Xallele favors the storage of fat by acting on nutrient partitioning
Authors: Marion Candice , Zizzari Philippe , Denis Raphael G.P. , Hassouna Rim , Chebani Yacine , Le Pen Gwenaëlle , Noble Florence , Luquet Serge , Pantel Jacques 
Published: October 2020

AbstractThe Growth Hormone Secretagogue Receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor endowed of a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signalingin vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343Xmutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparingGhsrM/Mrats to wild-type littermate rats 1) as freely behaving animals using an automated system to monitor simultaneously energy intake and expenditure, respiratory exchanges and voluntary activity and 2) in feeding and locomotor paradigms. Herein,GhsrM/Mrats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved.Ad libitumfedGhsrM/Mrats consumed and conditioned for sucrose similarly to littermate control rats. In calorie-restricted conditions,GhsrM/Mrats retained food anticipatory activity and maintained better their body weight and glycemia. Finally, prior to fat accumulationGhsrM/Mrats showed shifted fuel preference towards carbohydrates utilization without alterations of energy intake, energy expenditure or physical activity. Overall, the present study provides proof of concept that shifted GHSR signaling can operate a specific alteration in nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.
Drosophila RASopathy Models Identify Disease Subtype Differences and Biomarkers of Drug Efficacy
Authors: Das Tirtha K. , Gatto Jared , Mirmira Rupa , Hourizadeh Ethan , Kaufman Dalia , Gelb Bruce D. , Cagan Ross 
Published: October 2020

AbstractRASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the RAS/MAPK pathway. In aggregate, they are among the more common Mendelian disorders. They share overlapping pathologies that include structural birth and developmental defects that affect the heart, craniofacial and skeletal, lymphatic, and nervous systems. Variants in different genes—including those encoding KRAS, NRAS, BRAF, RAF1, and SHP2—are associated with overlapping but distinct phenotypes. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human disease isoform associated with a form of RASopathy. Similar to their human counterparts, each Drosophila line has common aspects but also important phenotypic distinctions including signaling pathways as well as response to therapeutics. For some lines, these differences represent activation of pathways outside the core RAS signaling pathway including the Hippo and SAPK/JNK signaling networks. We identified two classes of clinically relevant drugs, statins and histone deacetylase inhibitors, that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved poorly effective against,e.g., SHP2-expressing lines encoded byPTPN11. Our study provides a whole animal platform for comparison of a large number of RASopathy-associated variants. Among these variants we have identified differences in tissue phenotypes, in activation signaling pathways in biomarkers of disease progression and drug efficacy, and suggest drug classes that can be tolerated over long treatment periods for consideration in broad RASopathy trials.
NFAT Transcription Factors are Essential and Redundant Actors for Leukemia Initiating Potential in T-cell Acute Lymphoblastic Leukemia
Authors: Catherinet Claire , Passaro Diana , Gachet Stéphanie , Medyouf Hind , Reynaud Anne , Lasgi Charlène , Ghysdael Jacques , Quang Christine Tran 
Published: October 2020

ABSTRACTT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with few available targeted therapies. We previously reported that the phosphatase calcineurin (Cn) is required for LIC (leukemia Initiating Capacity) potential of T-ALL pointing to Cn as an interesting therapeutic target. Calcineurin inhibitors have however unwanted side effect. NFAT transcription factors play crucial roles downstream of calcineurin during thymocyte development, T cell differentiation, activation and anergy. Here we elucidate NFAT functional relevance in T-ALL. Using murine T-ALL models in whichNfatgenes can be inactivated either singly or in combination, we show that NFATs are required for T-ALL LIC potential and essential to survival, proliferation and migration of T-ALL cells. We also demonstrate thatNfatgenes are functionally redundant in T-ALL and identified a node of genes commonly deregulated upon Cn or NFAT inactivation, which may serve as future candidate targets for T-ALL.
Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools
Authors: Hepowit Nathaniel L. , Macedo Jessica K. A. , Young Lyndsay E. A. , Liu Ke , Sun Ramon C. , MacGurn Jason A. , Dickson Robert C. 
Published: October 2020

AbstractThe increasing prevalence of age-related diseases and resulting healthcare insecurity and emotional burden require novel treatment approaches. Several promising strategies seek to limit nutrients and promote healthy aging. Unfortunately, the human desire to consume food means this strategy is not practical for most people but pharmacological approaches might be a viable alternative. We previously showed that myriocin, which impairs sphingolipid synthesis, increases lifespan inSaccharomyces cerevisiaeby modulating signaling pathways including the target of rapamycin complex 1 (TORC1). Since TORC1 senses cellular amino acids, we analyses amino acid pools and identified 17 that are lowered by myriocin treatment. Studying the methionine transporter, Mup1, we found that newly synthesized Mup1 traffics to the plasma membrane and is stable for several hours but is inactive in drug-treated cells. Activity can be restored by adding phytosphingosine to culture medium thereby bypassing drug inhibition, thus confirming a sphingolipid requirement for Mup1 activity. Importantly, genetic analysis of myriocin-induced longevity revealed a requirement for the Gtr1/2 (mammalian Rags) and Vps34-Pib2 amino acid sensing pathways upstream of TORC1, consistent with a mechanism of action involving decreased amino acid availability. These studies demonstrate the feasibility of pharmacologically inducing a state resembling amino acid restriction to promote healthy aging.
Rspo2 inhibits TCF3 phosphorylation to antagonize Wnt signaling during vertebrate anteroposterior axis specification
Authors: Reis Alice H. , Sokol Sergei Y. 
Published: October 2020

SummaryThe Wnt pathway activates target genes by controlling the β-catenin-T-cell factor (TCF) transcriptional complex during embryonic development and cancer. This pathway can be potentiated by R-spondins, a family of proteins that bind RNF43/ZNRF3 E3 ubiquitin ligases and LGR4/5 receptors to prevent Frizzled degradation. Here we demonstrate that, duringXenopusanteroposterior axis specification, Rspo2 functions as a Wnt antagonist, both morphologically and at the level of gene targets and pathway mediators. Unexpectedly, the binding to RNF43/ZNRF3 and LGR4/5 was not required for the Wnt inhibitory activity. Moreover, Rspo2 did not influence Dishevelled phosphorylation in response to Wnt ligands, suggesting that Frizzled activity is not affected. Further analysis indicated that the Wnt antagonism is due to the inhibitory effect of Rspo2 on TCF3/TCF7L1 phosphorylation that normally leads to target gene activation. Consistent with this mechanism, Rspo2 anteriorizing activity has been rescued in TCF3-depleted embryos. These observations suggest that Rspo2 is a context-specific regulator of TCF3 phosphorylation and Wnt signaling.
Development of antibacterial compounds that block evolutionary pathways to resistance
Authors: Zhang Yanmin , Chowdhury Sourav , Rodrigues João V. , Shakhnovich Eugene. 
Published: October 2020

AbstractAntibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants ofE. colidihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC5050-75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP inin vitroevolution. Whole genome sequencing of CD15-3 resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which block evolutionary escape routes in pathogens.
Neuroplasticity associated with changes in conversational turn-taking following a family-based intervention
Authors: Romeo Rachel R. , Leonard Julia A. , Grotzinger Hannah M. , Robinson Sydney T. , Takada Megumi E. , Mackey Allyson P. , Scherer Ethan , Rowe Meredith L. , West Martin R. , Gabrieli John D. E. 
Published: October 2020

AbstractChildren’s early language environments are associated with linguistic, cognitive, and academic development, as well as concurrent brain structure and function. This study investigated neurodevelopmental mechanisms linking language input to development by measuring neuroplasticity associated with an intervention designed to enhance language environments of families primarily from lower socioeconomic backgrounds. Families of 52 4-to-6 year-old children were randomly assigned to a 9-week, interactive, family-based intervention or no-contact control group. Children completed pre- and post-assessments of verbal and nonverbal cognition (n=52), structural magnetic resonance imaging (n=45), and home auditory recordings of language exposure (n=39). Families who completed the intervention exhibited greater increases in adult-child conversational turns, and changes in turn-taking mediated intervention effects on language and executive functioning measures. Collapsing across groups, turn-taking changes were also positively correlated with cortical thickening in left inferior frontal and supramarginal gyri, the latter of which mediated relationships between changes in turn-taking and children’s language development. This is the first study of longitudinal neuroplasticity in response to changes in children’s language environments, and findings suggest that conversational turns support language development through cortical growth in language and social processing regions. This has implications for early interventions to enhance children’s language environments to support neurocognitive development.
Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells
Authors: Sumida Tomokazu S. , Dulberg Shai , Schupp Jonas , Stillwell Helen A. , Axisa Pierre-Paul , Comi Michela , Lincoln Matthew , Unterman Avraham , Kaminski Naftali , Madi Asaf , Kuchroo Vijay K. , Hafler David A. 
Published: October 2020

AbstractWhile inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection1,2. Here we show that IFN-I regulates co-inhibitory receptors expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed both canonical and non-canonical IFN-I transcriptional regulators, and identified unique regulators that control expression of co-inhibitory receptors. To provide directin vivoevidence for the role of IFN-I on co-inhibitory receptors, we then performed single cell RNA-sequencing in subjects infected with SARS-CoV-2, where viral load was strongly associated with T cell IFN-I signatures. We found that the dynamic IFN-I responsein vitroclosely mirrored T cell features with acute IFN-I linked viral infection, with highLAG3and decreasedTIGITexpression. Finally, our gene regulatory network identifiedSP140as a key regulator for differentialLAG3andTIGITexpression. The construction of co-inhibitory regulatory networks induced by IFN-I with identification of unique transcription factors controlling their expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity.