bluuebunny/crossref_metadata_2025_split huggingface dataset:
The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression
Authors: Kedmi Adi , Sloutskin Anna , Epstein Natalie , Gasri-Plotnitsky Lital , Ickowicz Debby , Shoval Irit , Doniger Tirza , Darmon Eliezer , Ideses Diana , Porat Ziv , Yaron Orly , Juven-Gershon Tamar 
Published: March 2020

AbstractTRF2 (TATA-box-binding protein-related factor 2) is an evolutionarily conserved general transcription factor that is essential for embryonic development ofDrosophila melanogaster, C. elegans, zebrafish andXenopus. Nevertheless, the cellular processes that are regulated by TRF2 are largely underexplored.Here, usingDrosophilaSchneider cells as a model, we discovered that TRF2 regulates cell cycle progression. Using flow cytometry, high-throughput microscopy and advanced imaging-flow cytometry, we demonstrate that TRF2 knockdown regulates cell cycle progression and exerts distinct effects on G1 and specific mitotic phases. RNA-seq analysis revealed that TRF2 regulates the expression ofCyclin Eand the mitotic cyclins,Cyclin A, Cyclin BandCyclin B3, but notCyclin DorCyclin C. To identify proteins that could account for the observed regulation of these cyclin genes, we searched for TRF2-interacting proteins. Interestingly, mass spectrometry analysis of TRF2-containing complexes identified GFZF, a nuclear glutathione S-transferase implicated in cell cycle regulation, and Motif 1 binding protein (M1BP). Furthermore, available ChIP-exo data revealed that TRF2, GFZF and M1BP co-occupy the promoters of TRF2-regulated genes. Using RNAi to knockdown the expression of either M1BP, GFZF, TRF2 or their combinations, we demonstrate that although GFZF and M1BP interact with TRF2, it is TRF2, rather than GFZF or M1BP, that is the main factor regulating the expression ofCyclin Eand the mitotic cyclins. Taken together, our findings uncover a critical and unanticipated role of a general transcription factor as a key regulator of cell cycle.
A naturaltimelesspolymorphism allowing circadian clock synchronization in ‘white nights’
Authors: Lamaze Angelique , Chen Chenghao , Leleux Solene , Xu Min , George Rebekah , Stanewsky Ralf 
Published: March 2020

AbstractDaily temporal organisation of behavioural and physiological functions offers a fitness advantage for most animals. Optimized temporal niches are determined by an interplay between external environmental rhythms and internal circadian clocks. While daily light:dark cycles serve as a robust time cue (Zeitgeber) to synchronise circadian clocks, it is not clear how animals experiencing only weak environmental cues deal with this problem. Like humans, flies of the genus Drosophila originate in sub-Saharan Africa and spread North in Europe up to the polar circle where they experience extremely long days in the summer or even constant light (LL). LL is known to disrupt clock function, due to constant activation of the deep brain photoreceptor CRYPTOCHROME (CRY), which induces constant degradation of the clock protein TIMELESS (TIM). Temperature cycles are able to overcome these arrhythmia inducing effects of LL, reinstating clock protein oscillations and rhythmic behaviour. We show here that for this to occur a recently evolved natural allele (ls-tim) of thetimelessgene is required, whereby the presence of this allele within the central clock neurons is sufficient. Thels-timallele encodes a longer, less-light sensitive form of TIM (L-TIM) in addition to the shorter (S-TIM) form, the only form encoded by the ancients-timallele. Only after blocking light-input by removing functional CRY,s-timflies are able to synchronise molecular and behavioural rhythms to temperature cycles in LL. Additional removal of light input from the visual system results in a phase advance of molecular and behavioural rhythms, showing that the visual system contributes to temperature synchronization in LL. We show thatls-tim, but nots-timflies can synchronise their behavioural activity to semi-natural LL and temperature cycle conditions reflecting long Northern Europe summer days, the season when Drosophila populations massively expand. Our observations suggest that this functional gain associated withls-timis driving the Northern spread of this allele by directional selection.
Morphological peculiarities of DNA-protein complexes in dormantEscherichia colicells, subjected to prolonged starvation Condensation of DNA in dormant cells ofEscherichia coli
Authors: Loiko Natalia , Danilova Yana , Moiseenko Andrey , Kovalenko Vladislav , Tereshkina Ksenia , El-Registan Galina I. , Sokolova Olga S. , Krupyanskii Yurii F. 
Published: March 2020

AbstractOne of the adaptive strategies for the constantly changing conditions of the environment utilized in bacterial cells involves the condensation of DNA in complex with the DNA-binding protein, Dps. With the use of electron microscopy and electron tomography, we observed several morphologically different types of DNA condensation in dormantEscherichia colicells, namely:nanocrystalline, liquid crystalline, and thefolded nucleosome-like. We confirmed the presence of both Dps and DNA in all of the ordered structures using EDX analysis. The comparison of EDX spectra obtained for the three different ordered structures revealed that innanocrystallineformation the majority of Dps protein is tightly bound to nucleoid DNA. We demonstrated that the population of the dormant cell is structurally heterogeneous, which allows cells to respond flexibly to environmental changes. It increases the ability of the whole bacterial population to survive under extreme stress conditions.
Drivers of change and ecosystem status in a temperate lake over the last Post-Glacial period from 14.5 kyr
Authors: Tõnno I , Freiberg R , Talas L , Kisand A , Belle S , Stivrins N , Alliksaar T , Heinsalu A , Veski S , Kisand V 
Published: March 2020

AbstractUnderstanding the long-term dynamics of ecological communities on the centuries-to-millennia scale is important for explaining present-day biodiversity patterns. Placing these patterns in a historical context could yield reliable tools for predicting possible future scenarios. Paleoarchives of macro+ and micro-fossil remains, and most importantly biomarkers such as fossil pigments and ancient DNA present in various sedimentary deposits, allow long term changes in ecological communities to be analysed. We use recent compilations of data including fossil pigments, metabarcoding of sedimentary ancient DNA and microfossils together with data analysis to understand the impact of gradualversusabrupt climate changes on a lake`s ecosystem status over the last 14.5 kyr. We give examples of hypotheses that need long-term data, which can be addressed using well-established paleoproxy variables. These variables describe the climate, together with vegetation change and the appearance of anthropogenic forcing, either as a gradual change or an abrupt event. We were able to detect abrupt changes in the lake ecosystem during the stable period of the Holocene Thermal Maximum and we highlight the increased frequency and degree of perturbation in lakes due to non-immediate human activity over a larger region. Both observations demonstrate an impaired relationship between a gradual external driver and ecosystem response and apply to future scenarios of climate warming and increased human impact in north-eastern Europe.
Disarrangement of Endoplasmic reticulum-mitochondria communication impairs Ca2+homeostasis in FRDA
Authors: Rodríguez Laura R. , Calap-Quintana Pablo , Lapeña-Luzón Tamara , Pallardó Federico V. , Schneuwly Stephan , Navarro Juan A. , Gonzalez-Cabo Pilar 
Published: March 2020

AbstractFriedreich ataxia (FRDA) is a neurodegenerative disorder characterized by neuromuscular and neurological manifestations. It is caused by mutations in gene FXN, which results in loss of the mitochondrial protein frataxin. Endoplasmic Reticulum-mitochondria associated membranes (MAMs) are inter-organelle structures involved in the regulation of essential cellular processes, including lipid metabolism and calcium signaling. In the present study, we have analyzed in both, unicellular and multicellular models of FRDA, an analysis of calcium management and of integrity of MAMs. We observed that function of MAMs is compromised in our cellular model of FRDA, which was improved upon treatment with antioxidants. In agreement, promoting mitochondrial calcium uptake was sufficient to restore several defects caused by frataxin deficiency in Drosophila Melanogaster. Remarkably, our findings describe for the first time frataxin as a member of the protein network of MAMs, where interacts with two of the main proteins implicated in endoplasmic reticulum-mitochondria communication. These results suggest a new role of frataxin, indicate that FRDA goes beyond mitochondrial defects and highlight MAMs as novel therapeutic candidates to improve patient’s conditions.
Understanding functional consequences of type 2 diabetes risk loci using the universal data integration and visualization R package CONQUER
Authors: Bouland Gerard A , Beulens Joline WJ , Nap Joey , van der Slik Arno R , Zaldumbide Arnaud , Hart Leen M’t , Slieker Roderick C 
Published: March 2020

ABSTRACTBackgroundNumerous large genome-wide association studies (GWASs) have been performed to understand the genetic factors of numerous traits, including type 2 diabetes. Many identified risk loci are located in non-coding and intergenic regions, which complicates the understanding how genes and their downstream pathways are influenced. An integrative data approach is required to understand the mechanism and consequences of identified risk loci.ResultsHere, we developed the R-package CONQUER. Data for SNPs of interest (build GRCh38/hg38) were acquired from static- and dynamic repositories, such as, GTExPortal, Epigenomics Project, 4D genome database and genome browsers such as ENSEMBL. CONQUER modularizes SNPs based on the underlying co-expression data and associates them with biological pathways in specific tissues. CONQUER was used to analyze 403 previously identified type 2 diabetes risk loci. In all tissues, the majority of SNPs (mean = 13.50, SD = 11.70) were linked to metabolism. A tissue-shared effect was found for four type 2 diabetes-associated SNPs (rs601945, rs1061810, rs13737, rs4932265) that were associated with differential expression ofHLA-DQA2, HSD17B12, MAN2C1andAP3S2respectively. Seven SNPs were identified that influenced the expression of seven ribosomal proteins in multiple tissues. Finally, one SNP (rs601945) was found to influence multipleHLAgenes in all twelve tissues investigated.ConclusionWe present an universal R-package that aggregates and visualizes data in order to better understand functional consequences of GWAS loci. Using CONQUER, we showed that type 2 diabetes risk loci have many tissue-shared effects on multiple pathways including metabolism, the ribosome and HLA pathway.
SynaptoPAC, an Optogenetic Tool for Induction of Presynaptic Plasticity
Authors: Oldani Silvia , Moreno-Velasquez Laura , Stumpf Alexander , Rosenmund Christian , Schmitz Dietmar , Rost Benjamin R. 
Published: March 2020

AbstractOptogenetic manipulations have transformed neuroscience in recent years. While sophisticated tools now exist for controlling the firing patterns of neurons, it remains challenging to optogenetically define the plasticity state of individual synapses. A variety of synapses in the mammalian brain express presynaptic long-term potentiation (LTP) upon elevation of presynaptic cyclic adenosine monophosphate (cAMP), but the molecular expression mechanisms as well as the impact of presynaptic LTP on network activity and behavior are not fully understood. In order to establish optogenetic control of presynaptic cAMP levels and thereby presynaptic potentiation, we developed synaptoPAC, a presynaptically targeted version of the photoactivated adenylyl cyclase bPAC. In cultures of hippocampal granule cells, activation of synaptoPAC with blue light increases action potential-evoked transmission, an effect not seen in hippocampal cultures of non-granule cells. In acute brain slices, synaptoPAC activation immediately triggers a strong presynaptic potentiation at mossy fiber terminals in CA3, but not at Schaffer collateral synapse in CA1. Following light-triggered potentiation, mossy fiber transmission decreases within 20 minutes, but remains enhanced still after 30 min. Optogenetic potentiation alters the short-term plasticity dynamics of release, reminiscent of presynaptic LTP. SynaptoPAC is the first optogenetic tool that allows acute light-controlled potentiation of transmitter release at specific synapses of the brain, and will enable to investigate the role of presynaptic potentiation in network function and the animal’s behavior in an unprecedented manner.Significance StatementSynaptoPAC is a novel optogenetic tool that allows increasing synaptic transmission by light-controlled induction of presynaptic plasticity.
Transcriptome analysis uncovers a link between copper metabolism, and both fungal fitness and antifungal sensitivity in the opportunistic yeast Candida albicans
Authors: Khemiri Inès , Tebbji Faiza , Sellam Adnane 
Published: March 2020

AbstractCopper homeostasis is an important determinant for virulence of many human pathogenic fungi such as the highly prevalent yeast Candida albicans. However, beyond the copper transporter Ctr1, little is known regarding other genes and biological processes that are affected by copper. To gain insight into the cellular processes that are modulated by copper abundance in C. albicans, we monitored the global gene expression dynamic under both copper depletion and excess using RNA-seq. Beyond copper metabolism, other different transcriptional programs related to fungal fitness such as stress responses, antifungal sensitivity, host invasion and commensalism were modulated in response to copper variations. We have also investigated the transcriptome of the mutant of the copper utilization regulator, mac1, and identified potential direct targets of this transcription factor under copper starvation. We also showed that Mac1 was required for the invasion and adhesion to host cells and antifungal tolerance. This study provides a framework for future studies to examine the link between copper metabolism and essential functions that modulate fungal virulence and fitness inside the host.
Hypoxic gene expression in chronic hepatitis B infected patients is not observed in state-of-artin vitroand mouse infection models
Authors: Liu PJ , Harris JM , Marchi E , D’Arienzo V , Michler T , Wing PAC , Magri A , Ortega-Prieto AM , van de Klundert M , Wettengel J , Durantel D , Dorner M , Klenerman P. , Protzer U , Giotis S , McKeating JA 
Published: March 2020

ABSTRACTHepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-artin vitroandin vivoHBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBVde novoinfection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression.
Engineered chemotaxis core signaling units indicate a constrained kinase-off state
Authors: Muok Alise R. , Chua Teck Khiang , Srivastava Madhur , Yang Wen , Maschmann Zach , Borbat Petr P. , Chong Jenna , Zhang Sheng , Freed Jack H. , Briegel Ariane , Crane Brian R. 
Published: March 2020

AbstractBacterial chemoreceptors, the CheA histidine kinase, and the coupling protein CheW comprise transmembrane molecular arrays with remarkable sensing properties. An unanswered question concerns how receptors turn off CheA kinase activity. Chemoreceptor cytoplasmic regions engineered to assume a trimer-of-receptor-dimers configuration form well-defined complexes with CheA and CheW and promote a kinase-off state. These mimics of core signaling units were assembled to homogeneity and investigated by site-directed spin-labeling with pulse-dipolar ESR spectroscopy (PDS), small-angle x-ray scattering, targeted protein cross-linking, and cryo-electron microscopy. The kinase-off state is especially stable, has relatively low domain mobility and associates the histidine substrate domain P1 and docking domain P2 with the kinase core. Distances measured between spin-labeled ADP molecules bound to the P4 kinase domain provide evidence for a “dipped conformation” that has been previously proposed from molecular dynamics simulations. Taken together, the data provide an experimentally restrained model for the inhibited state of the core-signaling unit and suggest that chemoreceptors indirectly sequester the kinase and substrate domains to limit histidine autophosphorylation.
Apoptosis, G1 phase stall and premature differentiation account for low chimeric competence of Human and rhesus monkey naïve pluripotent stem cells
Authors: Aksoy Irène , Rognard Cloé , Moulin Anaïs , Marcy Guillaume , Masfaraud Etienne , Wianny Florence , Cortay Véronique , Bellemin-Ménard Angèle , Doerflinger Nathalie , Dirheimer Manon , Mayère Chloé , Bourillot Pierre-Yves , Lynch Cian , Raineteau Olivier , Joly Thierry , Dehay Colette , Serrano Manuel , Afanassieff Marielle , Savatier Pierre 
Published: March 2020

SummaryAfter reprogramming to naïve pluripotency, human pluripotent stem cells (PSCs) still exhibit very low ability to make interspecies chimeras. Whether this is because they are inherently devoid of the attributes of chimeric competency or because naïve PSCs cannot colonize embryos from distant species remains to be elucidated. Here, we have used different types of mouse, human and rhesus monkey naïve PSCs and analyzed their ability to colonize rabbit and cynomolgus monkey embryos. Mouse embryonic stem cells (ESCs) remained mitotically active and efficiently colonized host embryos. In contrast, primate naïve PSCs colonized host embryos with much lower efficiency. Unlike mouse ESCs, they slowed DNA replication after dissociation and, after injection into host embryos, they stalled in the G1 phase and differentiated prematurely, regardless of host species. We conclude that human and non-human primate naïve PSCs do not efficiently make chimeras because they are inherently unfit to remain mitotically active during colonization.
WNK1 regulates uterine homeostasis and its ability to support pregnancy
Authors: Chi Ru-pin Alicia , Wang Tianyuan , Huang Chou-Long , Wu San-pin , Young Steven , Lydon John , DeMayo Francesco 
Published: March 2020

AbstractWNK1 is an atypical kinase protein ubiquitously expressed in humans and mice. A mutation in its encoding gene causes hypertension in humans which is associated with abnormal ion homeostasis. Our earlier findings demonstrated that WNK1 is critical forin vitrodecidualization in human endometrial stromal cells – pointing towards an unrecognized role of WNK1 in female reproduction. Here, we employed a mouse model with conditional WNK1 ablation from the female reproductive tract to define itsin vivorole in uterine biology. Loss of WNK1 altered uterine morphology, causing endometrial epithelial hyperplasia, adenomyosis and a delay in embryo implantation, ultimately resulting in compromised fertility. Combining transcriptomic, proteomic and interactomic analyses revealed a novel regulatory pathway whereby WNK1 represses AKT phosphorylation through the phosphatase PP2A in endometrial cells from both humans and mice. We show that WNK1 interacts with PPP2R1A, an isoform of the PP2A scaffold subunit. This interaction stabilizes the PP2A complex, which then dephosphorylates AKT. Therefore, loss of WNK1 reduced PP2A activity, causing AKT hypersignaling. Using FOXO1 as a readout of AKT activity, we demonstrate that there was escalated FOXO1 phosphorylation and nuclear exclusion, leading to a disruption in the regulation of genes that are crucial for embryo implantation.
Transiently structured head domains control intermediate filament assembly
Authors: Zhou Xiaoming , Lin Yi , Liszczak Glen , Sysoev Vasily , Sutherland Lillian , Mori Eiichiro , Murray Dylan , Kato Masato , Tycko Robert , McKnight Steven L. 
Published: March 2020

SummaryLow complexity (LC) head domains 92 and 108 residues in length are, respectfully, required for assembly of neurofilament light (NFL) and desmin intermediate filaments (IFs). As studied in isolation, these IF head domains interconvert between states of conformational disorder and labile, β-strand-enriched polymers. Solid state nuclear magnetic resonance (ss-NMR) spectroscopic studies of NFL and desmin head domain polymers reveal spectral patterns consistent with structural order. A combination of intein chemistry and segmental isotope labeling allowed preparation of fully assembled NFL and desmin IFs that could also be studied by ss-NMR. Assembled IFs revealed spectra overlapping with those observed for β-strand-enriched polymers formed from the isolated NFL and desmin head domains. Phosphorylation and disease causing mutations reciprocally alter NFL and desmin head domain self-association, yet commonly impede IF assembly. These observations show how facultative structural assembly of LC domains via labile, β-strand-enriched self-interactions may broadly influence cell morphology.