bluuebunny/crossref_metadata_2025_split huggingface dataset:
The essential transcriptional regulator HDP1 drives expansion of the inner membrane complex during early sexual differentiation of malaria parasites
Authors: Morillo Riward Campelo , Tong Xinran , Xie Wei , Abel Steven , Orchard Lindsey M. , Daher Wassim , Patel Dinshaw J. , Llinás Manuel , Le Roch Karine G. , Kafsack Björn F.C. 
Published: October 2020

ABSTRACTTransmission of Plasmodium falciparum and other malaria parasites requires their differentiation from asexual blood stages into gametocytes, the non-replicative sexual stage necessary for transmission to the mosquito vector. This transition involves changes in gene expression and chromatin reorganization that result in the activation and silencing of stage-specific genes. However, the genomes of malaria parasites have been noted for their dearth of transcriptional and chromatin regulators and the molecular mediators of these changes remain largely unknown. We recently identified HomeoDomain Protein 1 (HDP1) as a DNA-binding protein that enhances the expression of key genes that are critical for early sexual differentiation. The discovery of a homeodomain-like DNA-binding protein marks a new class of transcriptional regulator in malaria parasites outside of the better-characterized ApiAP2 family. In this study, we show that HDP1 facilitates the necessary upregulation of inner membrane complex components during early gametocytogenesis that gives P. falciparum gametocytes they characteristic shape and is required for gametocyte maturation and parasite transmission.
Drosophilaclock cells use multiple mechanisms to transmit time-of-day signals in the brain
Authors: Barber Annika F. , Fong Shi Yi , Kolesnik Anna , Fetchko Michael , Sehgal Amita 
Published: October 2020

AbstractRegulation of circadian behavior and physiology by theDrosophilabrain clock requires communication from central clock neurons to downstream output regions, but the mechanism by which clock cells regulate downstream targets is not known. We show here that thepars intercerebralis(PI), previously identified as a target of the morning cells in the clock network, also receives input from evening cells. We determined that morning and evening clock neurons have time of day dependent connectivity to the PI, which is regulated by specific peptides as well as by fast neurotransmitters. Interestingly, PI cells that secrete the peptide DH44, and control rest:activity rhythms, are inhibited by clock inputs while insulin-producing cells are activated, indicating that the same clock cells can use different mechanisms to drive cycling in output neurons. Inputs of morning cells to theDILP2+ neurons are relevant for the circadian rhythm of feeding, reinforcing the role of the PI as a circadian relay that controls multiple behavioral outputs. Our findings provide mechanisms by which clock neurons signal to non-clock cells to drive rhythms of behavior.Significance StatementDespite our growing understanding of how the fly clock network maintains free-running rhythms of behavior and physiology, little is known about how information is communicated from the clock network to the rest of the brain to regulate behavior. We identify glutamate and acetylcholine as key neurotransmitters signaling from clock neurons to thepars interecerebralis(PI), a clock output region regulating circadian rhythms of sleep and metabolism. We report a novel link betweenDrosophilaevening clock neurons and the PI, and find that the effect of clock neurons on output neuron physiology varies, suggesting that the same clock cells use multiple mechanisms simultaneously to drive cycling in output neurons.
Embrace heterogeneity to improve reproducibility: A perspective from meta-analysis of variation in preclinical research
Authors: Usui Takuji , Macleod Malcolm R. , McCann Sarah K. , Senior Alistair M. , Nakagawa Shinichi 
Published: October 2020

AbstractThe reproducibility of research results has been a cause of increasing concern to the scientific community. The long-held belief that experimental standardization begets reproducibility has also been recently challenged, with the observation that the reduction of variability within studies can lead to idiosyncratic, lab-specific results that are irreproducible. An alternative approach is to, instead, deliberately introduce heterogeneity; known as “heterogenization” of experimental design. Here, we explore a novel perspective in the heterogenization program in a meta-analysis of variability in observed phenotypic outcomes in both control and experimental animal models of ischaemic stroke. First, by quantifying inter-individual variability across control groups we illustrate that the samount of heterogeneity in disease-state (infarct volume) differs according to methodological approach, for example, in disease-induction methods and disease models. We argue that such methods may improve reproducibility by creating diverse and representative distribution of baseline disease-state in the reference group, against which treatment efficacy is assessed. Second, we illustrate how meta-analysis can be used to simultaneously assess efficacy and stability (i.e., mean effect and among-individual variability). We identify treatments that have efficacy and are generalizable to the population level (i.e. low inter-individual variability), as well as those where there is high inter-individual variability in response; for these latter treatments translation to a clinical setting may require nuance. We argue that by embracing rather than seeking to minimise variability in phenotypic outcomes, we can motivate the shift towards heterogenization and improve both the reproducibility and generalizability of preclinical research.
Status and targets for rebuilding the three major fish stocks in Lake Victoria
Authors: Musinguzi Laban , Olokotum Mark , Natugonza Vianny 
Published: October 2020

AbstractWe determined fisheries management reference points for three major fish stocks in Lake Victoria (Nile tilapia, Nile perch and Dagaa) for Uganda and the whole lake. The aim was to ascertain stock status and define reasonable objectives and targets for rebuilding to sustainable levels. Dagaa was found to be healthy in Uganda and the whole lake but tending to overfished status. In Uganda, the stock status of Nile tilapia and Nile perch was recruitment impaired but tending more towards collapsed and overfished status respectively. In the whole lake, the stock status of Nile tilapia and Nile perch was collapsed and overfished respectively with the latter tending more towards recruitment impaired. Estimates of maximum sustainable yield (MSY) showed that catches could be increased under good management. Rebuilding the Nile tilapia and Nile perch stock biomasses to MSY level (Bmsy) could respectively increase the catches above the current level by 9.2% and 29.5% in Uganda and by 72.8% and 15.1% in the whole lake. The immediate objective for fisheries management should be to rebuild biomass for the Nile tilapia and Nile perch stocks to Bmsy. Elimination of illegal fishing practices has proved to be effective. In addition, management needs to keep catches at low levels until biomass for the stocks is ≥Bmsyfor at least three consecutive years.
Direct RNA-RNA interaction between Neat1 and RNA targets, as a mechanism for RNAs paraspeckle retention
Authors: Jacq Audrey , Becquet Denis , Guillen Séverine , Boyer Bénédicte , Bello-Goutierrez Maria-Montserrat , Franc Jean-Louis , François-Bellan Anne-Marie 
Published: October 2020

ABSTRACTParaspeckles are nuclear ribonucleic complex formed of a long non-coding RNA, nuclear-enriched abundant transcript one (Neat1) and associated RNA-binding proteins (RBP) whose cellular known functions are to sequester in the nucleus both proteins and RNAs. However, how RNAs are bound to paraspeckles is largely unknown. It is highly likely that binding of RNAs may occur via interactions with RBPs and accordingly, two structures present in the 3’UTR of some RNAs have been shown to allow their association to paraspeckles via protein binding. However, Neat1 could also be involved in the targeting of RNAs through direct RNA-RNA interactions. Using a RNA pull-down procedure adapted to select only RNAs engaged in direct RNA-RNA interactions and followed by RNA-seq we showed that in a rat pituitary cell line, GH4C1 cells, 1791 RNAs were associated with paraspeckles by direct interaction with Neat1. Neat1 was actually found able to bind more than 30% of the total transcripts targeted by the paraspeckles, we have identified in this cell line in a previous study. Furthermore, given the biological processes in which direct RNAs targets of Neat1 were involved as determined by gene ontology analysis, it was proposed that Neat1 played a major role in paraspeckle functions such as circadian rhythms, mRNA processing, RNA splicing and regulation of cell cycle. Finally, we provided evidence that direct RNA targets of Neat1 were preferentially bound to the 5’ end of Neat1 demonstrating that they are located in the shell region of paraspeckles.
Tracking cytosine depletion in SARS-CoV-2
Authors: Luo Ruibang , Wong Yat-Sing , Lam Tak-Wah 
Published: October 2020

AbstractMotivationDanchin et al. have pointed out that cytosine drives the evolution of SARS-CoV-2. A depletion of cytosine might lead to the attenuation of SARS-CoV-2.ResultsWe built a website to track the composition change of mono-, di-, and tri-nucleotide of SARS-CoV-2 over time. The website downloads new strains available from GISAID and updates its results daily. Our analysis suggests that the composition of cytosine in coronaviruses is related to their reported mortality. Using 137,315 SARS-CoV-2 strains collected in ten months, we observed cytosine depletion at a rate of about one cytosine loss per month from the whole genome.AvailabilityThe website is available athttp://www.bio8.cs.hku.hk/sarscov2/.Contactrbluo@cs.hku.hkSupplementary informationSupplementary data are available atBioinformaticsonline.
Which are the central aspects of infant sleep? The dynamic of sleep composites across infancy
Authors: Schoch Sarah F. , Huber Reto , Kohler Malcolm , Kurth Salome 
Published: October 2020

AbstractSleep is ubiquitous during infancy and important for the well-being of both infant and parent. Therefore, there is large interest to characterize infant sleep with reliable tools, for example by means of combining actigraphy with 24-h-diaries. However, it is critical to select the right variables to characterize sleep. With a principal component analysis, we identified 5 underlying sleep composites from 48 commonly used sleep variables:Sleep Night, Sleep Day, Sleep Activity, Sleep Timing and Sleep Variability.These composites accurately reflect the known changes of sleep throughout infancy asSleep Day(representing naps), Sleep Activity(representing sleep efficiency and consolidation) andSleep Variability(representing day-to-day stability) decrease across infancy, whileSleep Night(representing nighttime sleep) slightly increases andSleep Timingbecomes earlier with increasing age. Additionally, we uncover interesting dynamics between the sleep composites and demonstrate that infant sleep is not only highly variable between infants but also considerably dynamic within infants across time. Interestingly,Sleep Dayis associated with behavioral development and therefore a potential marker for maturation. We recommend the use of sleep composites or of those specific single variables, which are solid representatives of the sleep composites for more reliable research.
No impact of functional connectivity of the motor system on the resting motor threshold: A replication study
Authors: Engelhardt Melina , Komnenić Darko , Roth Fabia , Kawelke Leona , Finke Carsten , Picht Thomas 
Published: October 2020

AbstractThe physiological mechanisms of corticospinal excitability and factors influencing its measurement with transcranial magnetic stimulation are still poorly understood. A recent study reported an impact of functional connectivity between the primary motor cortex and dorsal premotor cortex on the resting motor threshold of the dominant hemisphere. We aimed to replicate these findings in a larger sample of 38 healthy right-handed subjects with data from both hemispheres. Resting-state functional connectivity was assessed between the primary motor cortex and five a-priori defined motor-relevant regions on each hemisphere as well as interhemispherically between both primary motor cortices. Following the procedure by the original authors, we included age, the cortical grey matter volume and coil to cortex distance as further predictors in the analysis. We report replication models for the dominant hemisphere as well as an extension to data from both hemispheres and support the results with Bayes factors. Functional connectivity between the primary motor cortex and dorsal premotor cortex did not explain variability in the resting motor threshold and we obtained moderate evidence for the absence of this effect. In contrast, coil to cortex distance could be confirmed as an important predictor with strong evidence. These findings contradict the previously proposed effect, thus questioning the notion of the dorsal premotor cortex playing a major role in modifying corticospinal excitability.
SETD2 regulates the methylation of translation elongation factor eEF1A1 in clear cell renal cell carcinoma
Authors: Hapke Robert , Venton Lindsay , Rose Kristie Lindsay , Sheng Quanhu , Reddy Anupama , Jones Angela , Rathmell W. Kimryn , Haake Scott 
Published: October 2020

AbstractSET domain-containing protein 2 (SETD2) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. To explore SETD2-dependent regulation of the kidney cancer proteome, we performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) andSETD2-knock out (KO) kidney cells. We observed decreased lysine methylation of the translation elongation factor eEF1A1.EEF1AKMT2andEEF1AKMT3are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function ofSETD2. Globally, we observe differential expression of hundreds of proteins in WT versusSETD2-KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression inSETD2-mutated tumors. Overall, these data suggest thatSETD2-mutated ccRCC, via loss of enzymetic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.
Invasion byFusobacterium nucleatumCauses Upregulation ofdll4andklf4Expression in Caco2 Cells
Authors: Cochrane Kyla , Robinson Avery V. , Powers Jacqueline , Brown Scott D. , Holt Robert A. , Allen-Vercoe Emma 
Published: October 2020

AbstractFusobacterium nucleatumis an emerging microbe of importance in the pathogenesis of colorectal cancer. Strains of this enigmatic bacterial species vary in their capacity to invade human epithelial cells, a virulence determinant which has important implications in disease. Here, we infected human colorectal epithelial (Caco-2) cellsin vitrowith a known, highly invasive strain ofF. nucleatumisolated from a Crohn’s Disease patient, as well as a further invasive isolate ofF. nucleatumderived from a colorectal cancer tumour. We used transcriptional profiling to determine the human genes upregulated during the invasion process compared to exposure to a non-invasiveE.colicontrol strain. Infection withF. nucleatumstrains resulted in the upregulation of several host genes, including two associated with tumorigenesis:dll4andklf4.
Set1-dependent H3K4 methylation becomes critical for DNA replication fork progression in response to changes in S phase dynamics inSaccharomyces cerevisiae
Authors: de La Roche Saint-André Christophe , Géli Vincent 
Published: October 2020

AbstractDNA replication is a highly regulated process that occurs in the context of chromatin structure and is sensitive to several histone post-translational modifications. InSaccharomyces cerevisiae, the histone methylase Set1 is responsible for the transcription-dependent deposition of H3K4 methylation (H3K4me) throughout the genome. Here we show that a combination of a hypomorphic replication mutation (orc5-1) with the absence of Set1 (set1Δ) compromises the progression through S phase, and this is associated with a large increase in DNA damage. The ensuing DNA damage checkpoint activation, in addition to that of the spindle assembly checkpoint, restricts the growth oforc5-1 set1Δ. Interestingly,orc5-1 set1Δis sensitive to the lack of RNase H activity while a reduction of histone levels is able to counterbalance the loss of Set1. We propose that the recently described Set1-dependent mitigation of transcription-replication conflicts becomes critical for growth when the replication forks accelerate due to decreased origin firing in theorc5-1background. Furthermore, we show that an increase of reactive oxygen species (ROS) levels, likely a consequence of the elevated DNA damage, is partly responsible for the lethality inorc5-1 set1Δ.Author summaryDNA replication, that ensures the duplication of the genetic material, starts at discrete sites, termed origins, before proceeding at replication forks whose progression is carefully controlled in order to avoid conflicts with the transcription of genes. In eukaryotes, DNA replication occurs in the context of chromatin, a structure in which DNA is wrapped around proteins, called histones, that are subjected to various chemical modifications. Among them, the methylation of the lysine 4 of histone H3 (H3K4) is carried out by Set1 inSaccharomyces cerevisiae, specifically at transcribed genes. We report that, when the replication fork accelerates in response to a reduction of active origins, the absence of Set1 leads to accumulation of DNA damage. Because H3K4 methylation was recently shown to slow down replication at transcribed genes, we propose that the Set1-dependent becomes crucial to limit the occurrence of conflicts between replication and transcription caused by replication fork acceleration. In agreement with this model, stabilization of transcription-dependent structures or reduction histone levels, to limit replication fork velocity, respectively exacerbates or moderates the effect of Set1 loss. Last, but not least, we show that the oxidative stress associated to DNA damage is partly responsible for cell lethality.
Darwin was right, in any given field, the spatial variability of earthworm communities in pastures isn’t driven by measurable soil properties
Authors: Hodson Mark E , Corstanje Ron , Jones David T , Witton Jo , Burton Victoria J , Sloan Tom , Eggleton Paul 
Published: October 2020

AbstractAbundance and distribution of earthworms in agricultural fields is frequently proposed as a measure of soil quality assuming that observed patterns of abundance are in response to improved or degraded environmental conditions. However, it is not clear that earthworm abundances can be directly related to their edaphic environment, as noted in Darwin’s final publication, perhaps limiting or restricting their value as indicators of ecological quality in any given field.We present results from a spatially explicit intensive survey of pastures within United Kingdom farms, looking for the main drivers of earthworm density at a range of scales. When describing spatial variability of earthworm abundance within any given field, the best predictor was earthworm abundance itself within 20 – 30 m of the sampling point; there were no consistent environmental correlates with earthworm numbers, suggesting that biological factors (e.g. colonisation rate, competition, predation, parasitism) drive or at least significantly modify earthworm distributions at this spatial level. However, at the national scale, earthworm abundance is well predicted by soil nitrate levels, density, temperature and moisture content, albeit not in a simple linear fashion. This suggests that although land can be managed at the farm scale to promote earthworm abundance and the resulting soil processes that deliver ecosystem services, within a field, earthworm distributions will remain patchy. The divergence in the interpretative value of earthworm abundance as an ecological indicator is a function of spatial scale, corresponding to species specific biological factors as well as a response to environmental pressures. Species abundance can effectively be used as ecological indicators, even if, at first, distributions seem random. However, care must be exercised, in the sampling design for the indicator species, if its abundance is to be used as a proxy for environmental quality at a particular scale (e.g. a management scale such as field scale).
Seipin traps triacylglycerols to facilitate their nanoscale clustering in the ER membrane
Authors: Prasanna Xavier , Salo Veijo T. , Li Shiqian , Ven Katharina , Vihinen Helena , Jokitalo Eija , Vattulainen Ilpo , Ikonen Elina 
Published: October 2020

AbstractSeipin is a disk-like oligomeric ER protein important for lipid droplet (LD) biogenesis and triacylglycerol (TAG) delivery to growing LDs. Here we show through biomolecular simulations bridged to experiments that seipin can trap TAGs in the ER bilayer via the luminal hydrophobic helices of the protomers delineating the inner opening of the seipin disk. This promotes the nanoscale sequestration of TAGs at a concentration that by itself is insufficient to induce TAG clustering in a lipid membrane. We identify Ser166 in the α3 helix as a favored TAG occupancy site and show that mutating it compromises the ability of seipin complexes to sequester TAGin silicoand to promote TAG transfer to LDs in cells. While seipin-S166D mutant colocalizes poorly with promethin, the association of nascent wild-type seipin complexes with promethin is promoted by TAGs. Together, these results suggest that seipin traps TAGs via its luminal hydrophobic helices, serving as a catalyst for seeding the TAG cluster from dissolved monomers inside the seipin ring, thereby generating a favorable promethin binding interface.
Atomic-level evolutionary information improves protein-protein interface scoring
Authors: Quignot Chloé , Granger Pierre , Chacón Pablo , Guerois Raphael , Andreani Jessica 
Published: October 2020

AbstractThe crucial role of protein interactions and the difficulty in characterising them experimentally strongly motivates the development of computational approaches for structural prediction. Even when protein-protein docking samples correct models, current scoring functions struggle to discriminate them from incorrect decoys. The previous incorporation of conservation and coevolution information has shown promise for improving protein-protein scoring. Here, we present a novel strategy to integrate atomic-level evolutionary information into different types of scoring functions to improve their docking discrimination.We applied this general strategy to our residue-level statistical potential from InterEvScore and to two atomic-level scores, SOAP-PP and Rosetta interface score (ISC). Including evolutionary information from as few as ten homologous sequences improves the top 10 success rates of these individual scores by respectively 6.5, 6 and 13.5 percentage points, on a large benchmark of 752 docking cases. The best individual homology-enriched score reaches a top 10 success rate of 34.4%. A consensus approach based on the complementarity between different homology-enriched scores further increases the top 10 success rate to 40%.All data used for benchmarking and scoring results, as well as pipelining scripts, are available athttp://biodev.cea.fr/interevol/interevdata/