bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide analysis of long noncoding RNAs affecting floral bud dormancy in pears in response to cold stress
Authors: Li Liang , Liu Jinhang , Liang Qin , Zhang Yanhui , Kang Kaiquan , Wang Wenting , Feng Yu , Wu Shaohua , Yang Chao , Li Yongyu
Published: October 2020

The versatile role of long noncoding RNAs (lncRNAs) in plant growth and development has been established, but a systematic identification and analysis of lncRNAs in the pear has not been reported. Bud dormancy is a crucial and complicated protective mechanism for plants in winter. The roles of lncRNAs in the dormancy process remain largely unclear. In this study, we induced pear floral buds to enter into different dormant statuses by simulating four different chilling accumulation conditions. Then, a time series of RNA-seq analysis was performed and we identified 7594 lncRNAs in Pyrus pyrifolia (Burm. F.) Nakai that have not been identified. The sequence and expression of the lncRNAs were confirmed by PCR analysis. In total, 6253 lncRNAs were predicted to target protein-coding genes including 692 cis-regulated pairs (596 lncRNAs) and 13,158 trans-regulated pairs (6181 lncRNAs). Gene Ontology analysis revealed that most of lncRNAs' target genes were involved in catalytic activity, metabolic processes and cellular processes. In the trend analysis, 124 long-term cold response lncRNAs and 80 short-term cold response lncRNAs were predicted. Regarding the lncRNA-miRNA regulatory networks, 59 lncRNAs were identified as potential precursors for miRNA members of 20 families, 586 lncRNAs were targets of 261 pear miRNAs and 53 lncRNAs were endogenous target mimics for 26 miRNAs. In addition, three cold response lncRNAs, two miRNAs and their target genes were selected for expression confirmed. The trend of their expression was consistent with the predicted relationships among them and suggested possible roles of lncRNAs in ABA metabolic pathway. Our findings not only suggest the potential roles of lncRNAs in regulating the dormancy of pear floral buds but also provide new insights into the lncRNA-miRNA-mRNA regulatory network in plants.
Revision of the higher taxonomy of Neotropical freshwater crabs of the family Pseudothelphusidae, based on multigene and morphological analyses
Authors: Álvarez Fernando , Ojeda Juan Carlos , Souza-Carvalho Edvanda , Villalobos José Luis , Magalhães Célio , Wehrtmann Ingo S , Mantelatto Fernando L
Published: October 2020

A new classification for the freshwater crabs of the Americas, the superfamily Pseudothelphusoidea¸ is presented based on a multigene phylogeny complemented by morphological analyses. We propose that the superfamily Pseudothelphusoidea be composed of two families, the Epiloboceridae and the Pseudothelphusidae, with the subsequent reorganization of the latter into eight subfamilies, of which five (Hypolobocerinae, Kingsleyinae, Potamocarcininae, Pseudothelphusinae, Strengerianinae) represent previously recognized tribes. We erect three new subfamilies: Guinotiinae, Ptychophallinae and Raddausinae, to reflect relationships that have become clear with the new analyses. The new classification scheme has a high level of congruence with the geographical distribution of species and genera. A divergence time estimate suggests that the Pseudothelphusoidea originated in the late Cretaceous around 68 Mya. Subsequent divergence events can be correlated with emergent landmasses throughout the range of the superfamily. There is high concordance among several elements of our proposal: (1) the main morphological types of male gonopods correspond to well defined clades obtained with molecular analyses; (2) the geographic distribution of the subfamilies has a structured pattern; and (3) the estimated times of divergence of each group can be associated to the geological history of each region. The combination of these elements results in a robust new classification scheme.
Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors
Authors: Boby Melissa L. , Fearon Daren , Ferla Matteo , Filep Mihajlo , Koekemoer Lizbé , Robinson Matthew C. ,   The COVID Moonshot Consortium, Chodera John D. , Lee Alpha A , London Nir , von Delft Annette , von Delft Frank
Published: October 2020

We report the results of theCOVID Moonshot, a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a non-covalent, non-peptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>840 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.
Ribosome-linked mRNA-rRNA chimeras reveal active novel virus host associations
Authors: Ignacio-Espinoza J. Cesar , Laperriere Sarah M. , Yeh Yi-Chun , Weissman Jake , Hou Shengwei , Long Andrew M. , Fuhrman Jed A.
Published: October 2020

Viruses of prokaryotes greatly outnumber their hosts1and impact microbial processes across scales, including community assembly, evolution, and metabolism1. Metagenomic discovery of novel viruses has greatly expanded viral sequence databases, but only rarely can viral sequences be linked to specific hosts. Here, we adapt proximity ligation methods to ligate ribosomal RNA to transcripts, including viral ones, during translation. We sequenced the resulting chimeras, directly linking marine viral gene expression to specific hosts by transcript association with rRNA sequences. With a sample from the San Pedro Ocean Time-series (SPOT), we found viral-host links to Cyanobacteria, SAR11, SAR116, SAR86, OM75, and Rhodobacteracae hosts, some being the first viruses reported for these groups. We used the SPOT viral and cellular DNA database to track abundances of multiple virus-host pairs monthly over 5 years, e.g. withRoseovariusphages tracking the host. Because the vast majority of proximity ligations should occur between an organism’s ribosomes and its own transcripts, we validated our method by looking for self- vs non-self mRNA-rRNA chimeras, by read recruitment to marine single amplified genomes; verifiable non-self chimeras, suggesting off-target linkages, were very rare, indicating host-virus hits were very unlikely to occur by mistake. This approach in practice could link any transcript and its associated processes to specific microorganisms.
Archaeogenomic Distinctiveness of the Isthmo-Colombian Area
Authors: Capodiferro Marco Rosario , Aram Bethany , Raveane Alessandro , Migliore Nicola Rambaldi , Colombo Giulia , Ongaro Linda , Rivera Javier , Mendizábal Tomás , Hernández-Mora Iosvany , Tribaldos Maribel , Perego Ugo Alessandro , Li Hongjie , Scheib Christiana Lyn , Modi Alessandra , Gòmez-Carballa Alberto , Grugni Viola , Lombardo Gianluca , Hellenthal Garrett , Pascale Juan Miguel , Bertolini Francesco , Grieco Gaetano , Cereda Cristina , Lari Martina , Caramelli David , Pagani Luca , Metspalu Mait , Friedrich Ronny , Knipper Corina , Olivieri Anna , Salas Antonio , Cooke Richard , Montinaro Francesco , Motta Jorge , Torroni Antonio , Martín Juan Guillermo , Semino Ornella , Malhi Ripan Singh , Achilli Alessandro
Published: October 2020

The recently enriched genomic history of Indigenous groups in the Americas is still meagre concerning continental Central America. Here, we report ten pre-Hispanic (plus two early colonial) genomes and 84 genome-wide profiles from seven groups presently living in Panama. Our analyses reveal that pre-Hispanic demographic changes and isolation events contributed to create the extensive genetic structure currently seen in the area, which is also characterized by a distinctive Isthmo-Colombian Indigenous component. This component drives these populations on a specific variability axis and derives from the local admixture of different ancestries of northern North American origin(s). Two of these ancestries were differentially associated to Pleistocene Indigenous groups that also moved into South America leaving heterogenous footprints. An additional Pleistocene ancestry was brought by UPopI, a still unsampled population that remained restricted to the Isthmian area, expanded locally during the early Holocene, and left genomic traces up to the present.
The prophase oocyte nucleus is a homeostatic G-actin buffer
Authors: Scheffler Kathleen , Giannini Federica , Mogessie Binyam
Published: October 2020

Formation of healthy mammalian eggs from oocytes requires specialised F-actin structures. F-actin disruption produces aneuploid eggs, which are a leading cause of human embryo deaths, genetic disorders, and infertility. We found that oocytes regulate F-actin organisation and function by promptly transferring excess monomeric G-actin from the cytoplasm to the nucleus. Inside healthy oocyte nuclei, transferred monomers form dynamic F-actin structures, a conserved feature that significantly declines with maternal age. Monomer transfer must be controlled tightly. Blocked nuclear import of G-actin triggers assembly of a dense cytoplasmic F-actin network, while excess G-actin in the nucleus dramatically stabilises nuclear F-actin. Imbalances in either direction predispose oocytes to aneuploidy. The large oocyte nucleus is thus a homeostatic G-actin buffer that is used to maintain cytoplasmic F-actin form and function.

One Sentence Summary

Mammalian oocyte nuclei buffer cytosolic G-actin
Flower Power: Floral reversion as a viable alternative to nodal micropropagation inCannabis sativa
Authors: Monthony A.S. , Bagheri S. , Zheng Y. , Jones A.M.P.
Published: October 2020

The legalization ofCannabis sativaL. for recreational and medical purposes has been gaining global momentum, leading to a rise in interest inCannabistissue culture as growers look for large-scale solutions to germplasm storage and clean plant propagation. Mother plants used in commercial propagation are susceptible to insect pests and disease and require considerable space. While micropropagation can produce disease free starting material in less space, current publishedin vitromicropropagation methods are not robust and few report high multiplication rates. Further, these micropropagation methods rely on photoperiod-sensitive plants which can be maintained in a perpetual vegetative state. Current methods are not adaptable to long-term tissue culture of day-neutral cultivars, which cannot be maintained in perpetual vegetative growth. In this study, we chose to develop a micropropagation system which usesC. sativainflorescences as starting materials. This study used two cannabis cultivars, two plant growth regulators (PGR; 6-benzylaminopurine and meta-topolin) at different concentrations, and two different numbers of florets. Here we show that floral reversion occurs from meristematic tissue inC. sativaflorets and that it can be used to enhance multiplication rates compared to existingin vitromethods. Floret number was shown to have a significant impact on percent reversion, with pairs of florets reverting more frequently and producing healthier explants than single florets, while cultivar and PGR had no significant effect on percent reversion. Compared with our previously published nodal culture studies, the current floral reversion method produced up to eight times more explants per tissue culture cycle. Floral reversion provides a foundation for effective inflorescence-based micropropagation systems inC. sativa.
Global regulatory transitions at core promoters demarcate the mammalian germline cycle
Authors: Cvetesic Nevena , Borkowska Malgorzata , Hatanaka Yuki , Yu Changwei , Vincent Stéphane D. , Müller Ferenc , Tora László , Leitch Harry G. , Hajkova Petra , Lenhard Boris
Published: October 2020

Core promoters integrate regulatory inputs of genes1–3. Global dynamics of promoter usage can reveal systemic changes in how genomic sequence is interpreted by the cell4Here we report the first analysis of promoter dynamics and code switching in the mammalian germ line, characterising the full cycle of transitions from embryonic stem cells through germline, oogenesis, and zygotic genome activation. Using Super Low Input Carrier-CAGE5,6(SLIC-CAGE) we show that mouse germline development starts with the somatic promoter code, followed by a prominent switch to the maternal code during follicular oogenesis. The sequence features underlying the shift from somatic to maternal code are conserved across vertebrates, despite large differences in promoter nucleotide compositions. In addition, we show that, prior to this major shift, the promoters of gonadal germ cells diverge from the canonical somatic transcription initiation. This divergence is distinct from the promoter code used later by developing oocytes and reveals genome-wide promoter remodelling associated with alternative nucleosome positioning during early female and male germline development. Collectively, our findings establish promoter-level regulatory transitions as a central, conserved feature of the vertebrate life cycle.
Single-PanIN-seq Unveils that ARID1A Deficiency Promotes Pancreatic Tumorigenesis by Attenuating KRAS Induced Senescence
Authors: Liu Shou , Cao Wenjian , Niu Yichi , Luo Jiayi , Zhao Yanhua , Hu Zhiying , Zong Chenghang
Published: October 2020

ARID1A is one of the most frequently mutated epigenetic regulators in a wide spectrum of cancers. Recent studies have shown that ARID1A deficiency induces global changes in the epigenetic landscape of enhancers and promoters. These broad and complex effects make it challenging to identify the driving mechanisms of ARID1A deficiency in promoting cancer progression. Here we identified the anti-senescence effect of ARID1A deficiency in the progression of pancreatic intraepithelial neoplasia (PanIN) by profiling the transcriptome of individual PanINs in the mouse model. Interestingly, we found that ARID1A deficiency upregulates the expression of Aldehyde dehydrogenase ALDH1A1, which plays an essential role in attenuating the senescence induced by oncogenic KRAS. Despite that ALDH proteins have been commonly used as cancer stem cell markers, their effect in promoting attenuation of senescence is not known before. Therefore, ALDH proteins could be considered a potential adjuvant drug target in treating pancreatic cancer.
Fitting penalized regressions on very large genetic data using snpnet and bigstatsr
Authors: Privé Florian , Vilhjálmsson Bjarni J. , Aschard Hugues
Published: October 2020

Both R packages snpnet and bigstatsr allow for fitting penalized regressions on individual-level genetic data as large as the UK Biobank. Here we benchmark bigstatsr against snpnet for fitting penalized regressions on large genetic data. We find bigstatsr to be an order of magnitude faster than snpnet when applied to the UK Biobank data (from 4.5x to 35x). We also discuss the similarities and differences between the two packages, provide theoretical insights, and make recommendations on how to fit penalized regressions in the context of genetic data.
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

Background

The 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.

Results

We 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.

Conclusions

The 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

Based 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

Hind-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.

SIGNIFICANCE

Mouse 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

The 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.

SIGNIFICANCE

We 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

Microbial 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

The 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

RASopathies 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

T-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

The 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

The 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

Antibiotic 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

Children’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

While 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.
A dynamic relationship between crude oil price and Indian equity market: an empirical study with special reference to Indian benchmark index Sensex
Authors: Yadav Nikhil , Tandon Priyanka , Tripathi Ravindra , Shastri Rajesh Kumar
Published: October 2020

Purpose

The purpose of the study is to investigate the long-run and short-run dynamic relationship between crude oil prices and the movement of Sensex for the period of 2000–2018.

Design/methodology/approach

The study uses the augmented Dickey–Fuller test for the presence of unit root, Johansen cointegration test for estimating the cointegration among the variables. Further, in the case of no cointegration found, the study employed the vector autoregression (VAR) model to estimate the long-run relationship and the Granger causality/Wald test for short-run relationship. The study also conducted tests for the prerequisites of the model: serial correlation, heteroskedasticity and normality of data.

Findings

The study found that both the variables, crude oil prices and Sensex are integrated of order 1, that is,I(1), and there is no cointegration between them. Further, the results proliferated from the VAR model unfold the marked effect of previous month crude oil prices (lag 1) on the movement of Indian stock market represented by Sensex considered as the benchmark index. Furthermore, VAR–Granger causality/block exogeneity Wald tests results indicated that there is a causal relationship between the crude oil prices and Sensex under the VAR environment. The model does not have any serial correlation and heteroskedasticity indicating toward the unbiased and robust estimates.

Research limitations/implications

The study is conducted till the year 2018, and data for the present period (post-2018) is excluded due to ongoing trade issues between the USA and oil-exporting countries such as Iran. The current COVID-19 outbreak has also put serious issues. Due to limited time and availability of standardized data, researchers have considered Sensex as equity index only, but for more generalized research outcome few other equity indexes could have been taken for study.

Originality/value

The study is completely original in nature and is an extensive study of the relationship between the crude oil price and Indian stock market with reference to causality between the variables.
Countering effects of technostress on productivity: moderating role of proactive personality
Authors: Tiwari Vivek
Published: October 2020

Purpose

Too much reliance on information technology has given rise to technostress, which may impact the productivity of an individual. In case this is true, does it impact everyone equally, and if not, then what is behind this difference and how does this work? The purpose of the present research is to explore the role of proactive personality as a moderator to the relationship of individual productivity of an employee and the technostress. The study utilizes moderation technique to study and analyze the relationships.

Design/methodology/approach

The present work is an attempt to investigate the moderating role of proactive personality to the relationship between technostress and productivity by utilizing the concepts from person–environment fit model. Moderation analysis has been performed with the help of hierarchical multiple regression on the primary data collected via survey methods with the help of structure instruments.

Findings

A survey was conducted from 233 employees working at different levels in different organizations belonging to north-western parts of the country. After analyzing the randomly collected primary data, it was found that technostress impacts productivity negatively. It was also further established that relationship between technostress and individual productivity gets moderated by proactive personality.

Research limitations/implications

Strategies concerning implementation and designing of a training program should be designed by being mindful of the individual personalities going to be trained.

Practical implications

From organizational point of view, a training program (made to introduce and implement some new technology in the organization) should be tailored by keeping individuals' personalities and their specific needs in mind.

Originality/value

This work is an important addition to the existing literature concerning technostress. Such work would help in understanding the difference that a human factor may have on the bearings of technostress on productivity and other such crucial outcomes, which has not been studied earlier in the present context.
Limiting role of resource dependence: an examination of director interlocks, board meetings and family ownership
Authors: Sukumara Panicker Vidya , Upadhyayula Rajesh Srinivas
Published: October 2020

Purpose

This paper attempts to examine the activity and involvement of board of directors in internationalization activities of firms in emerging markets, by evaluating the resource provisioning roles of interlocks provided by board of directors, and the frequency of board meetings. We demonstrate that the effectiveness of board involvement is contingent upon the levels of family ownership in firms since family ownership could impact the firm’s ability to utilize the presence of different types of board members.

Design/methodology/approach

The authors test our hypotheses on a sample of listed Indian companies, extracted from the Prowess database published by the Centre for Monitoring Indian Economy (CMIE), a database of the financial performance of Indian companies. On a panel of 3,133 firm years of 605 unique Indian firms with foreign investments, over a time period of 2006–2017, the authors apply different estimation techniques.

Findings

The results demonstrate that both board meeting frequency and director interlocks are instrumental in supporting internationalization activities in emerging market firms. However, family ownership moderates the role of insider and independent interlocks on internationalization investments in different ways; the authors find that interlocks provided by independent directors support internationalization activities in family firms, whereas those provided by insider directors do not. Further, the study also finds that board meetings are less effective in internationalization of family firms.

Practical implications

The authors conclude that family firms aiming at international diversification require to develop more connected and networked independent directors to enable internationalization in firms. While independent director interlocks enhance the international investments, it is also useful to know that board meetings are ineffective in utilizing the resources in family firms. This points to the possibility that family firms should device mechanisms to integrate family meetings with board meetings so that they can utilize the within-family processes to aid in their internationalization decisions.

Originality/value

The study contributes to resource dependence theory by understanding its limiting role in family firms. Theoretically, it helps delineate the limiting resource provision role of the insider directors vis-à-vis independent directors. The authors argue that the resource provision role of insider director interlocks does not effectively help in internationalization in comparison to independent director interlocks in family-dominated firms. Consequently, the study shows the limiting role of resource provision and utilization by family-owned firms in comparison to non-family-owned firms.
A political history of Chinese historiography on “foreign education”
Authors: Chen Luxi , Su Yiqing
Published: October 2020

Purpose

This paper examines China's historiography on foreign education since 1900, with an emphasis on the period since 1949. The understanding of “foreign education” in China during this period shifted rapidly from the Western-centered approach that had been introduced from Japanese during the late Qing dynasty and the Republic of China to the Soviet-centered approach that followed the founding of New China to a restoration of Western-centered approaches after the “opening” of the late 1970s and 1980s. The paper asks: how has the study of foreign educational history changed over time in the People's Republic of China, how has the broader discipline of history of education changed, and how have successive generations of historians of education conceived of their intellectual and political roles?

Design/methodology/approach

Grounded in archival documents and the published works of influential historians of education, this study notes the ways in which political regime change affected the construction and application of academic knowledge.

Findings

This study identifies four stages in the Chinese historiography on foreign education: a formative stage (from 1900 until the late 1940s); a difficult post-revolutionary recovery, followed by growth and then suppression (from 1949 until the mid-1970s); a period of achievement combined with an academic crisis (from 1978 until the early 2000s); and finally, a recent transition marked by theoretical innovation and global integration (from the 2000s until the present).

Originality/value

This study finds that a narrow focus on “practical utility” or service to politics and policy has perturbed historians of foreign education in China and stunted their field's development. A look back at early periods in the historiography offers a warning about the potential dangers of extreme ideological/political utilitarianism. These dangers existed not only in the history of foreign education but also in the history of education research more broadly. A close examination of these dangers can help twenty-first-century historians of education in China balance the practical, political and professional dimensions of their research. To grasp the meaning of foreign education, historical research needs to be politically independent.