bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTP regulates membrane-binding activity of the nucleoid occlusion protein Noc
Authors: Jalal Adam S. B. , Tran Ngat T. , Wu Ling J. , Ramakrishnan Karunakaran , Rejzek Martin , Gobbato Giulia , Stevenson Clare E. M. , Lawson David M. , Errington Jeff , Le Tung B. K. 
Published: February 2021

ABSTRACTATP and GTP-dependent molecular switches are extensively used to control functions of proteins in a wide range of biological processes. However, CTP switches are rarely reported. Here, we report that a nucleoid occlusion protein Noc is a CTPase enzyme whose membrane-binding activity is directly regulated by a CTP switch. InBacillus subtilis, Noc nucleates on 16-bpNBSsites before associating with neighboring non-specific DNA to form large membrane-associated nucleoprotein complexes to physically occlude assembly of the cell division machinery. Byin vitroreconstitution, we show that (i) CTP is required for Noc to form theNBS-dependent nucleoprotein complex, and (ii) CTP binding, but not hydrolysis, switches Noc to a membrane-active state. Overall, we suggest that CTP couples membrane-binding activity of Noc to nucleoprotein complex formation to ensure productive recruitment of DNA to the bacterial cell membrane for nucleoid occlusion activity.
Evidence for Multiple Teosinte Hybrid Zones in Central Mexico
Authors: Hufnagel David E. , Kananen Kathryn , Glaubitz Jeffrey C. , de Jesuś Sánchez-González José , Doebley John F. , Hufford Matthew B. 
Published: February 2021

1SummaryHybrid zones provide an excellent opportunity for studying population dynamics and whether hybrid genetic architectures are locally adaptive. The genus Zea contains many diverse wild taxa collectively called teosinte.Zea maysssp.parviglumis, the lowland progenitor of maize (Zea maysssp.mays), and its highland relativeZea maysssp.mexicanalive parapatrically and, while putative hybrids have been identified in regions of range overlap, these have never been deeply explored.Here we use a broadly sampled SNP data set to identify and confirm 112 hybrids betweenZea maysssp.parviglumisandZea maysssp.mexicana, mostly clustered in three genetically and geographically distinct hybrid groups in Central Mexico.These hybrid groups inhabit intermediate environments relative to parental taxa. We demonstrate that these individuals are true hybrids and not products of isolation by distance or ancestral to parviglumis and mexicana. This work expands on previous studies, clearly identifying hybrid zones inZea, genetically characterizing hybrid groups, and showing what appear to be unique genetic architectures of hybridization in distinct hybrid groups.With the potential for local adaptation, variable hybrid zone dynamics, and differential architectures of hybridization, we present these teosinte hybrids and parental taxa as a promising model system for studying hybridization and hybrid zones.
Destabilization of the holo-DNA Polδ by loss of Pol32 confers conditional lethality that can be suppressed by stabilizing Pol31-Pol3 interaction
Authors: Shimada Kenji , Tsai-Pflugfelder Monika , Motlagh Niloofar Davoodi Vijeh , Delgoshaie Neda , Fuchs Jeannette , Gasser Susan M. 
Published: February 2021

AbstractDNA Polymerase δ plays an essential role in genome replication and in the preservation of genome integrity. InS. cerevisiae, Polδ consists of three subunits: Pol3 (the catalytic subunit), Pol31 and Pol32. We have constructedpol31mutants by alanine substitution at conserved amino acids, and identified three alleles that do not confer any disadvantage on their own, but which suppress the cold-, HU- and MMS-hypersensitivity of yeast strains lacking Pol32. We have shown that Pol31 and Pol32 are both involved in translesion synthesis, error-free bypass synthesis, and in preservation of replication fork stability under conditions of HU arrest. We identified a solvent exposed loop in Pol31 defined by two alanine substitutions at T415 and W417. Whereas pol31-T4l5A compromises polymerase stability at stalled forks,pol31-W417A is able to suppress many, but not all, of the phenotypes arising frompol32Δ. ChIP analyses showed that the absence of Pol32 destabilizes Pole and Polα at stalled replication forks, but does not interfere with checkpoint kinase activation. We show that the Pol31-W417A-mediated suppression of replicationstress sensitivity inpol32Δ stems from enhanced interaction between Pol3 and Pol31, which stabilizes a functional Polδ.
Crystal structure of a bacterial CNNM magnesium transporter
Authors: Chen Yu Seby , Kozlov Guennadi , Armitano Joshua , Moeller Brandon E. , Fakih Rayan , Rohaim Ahmed , Roux Benoit , Burke John E. , Gehring Kalle 
Published: February 2021

AbstractCBS-pair domain divalent metal cation transport mediators (CNNMs) are a broadly conserved family of integral membrane proteins with close to 90,000 protein sequences known. CNNM proteins are associated with Mg2+transport but it is not known if they mediate transport themselves or regulate other transporters. Here, we determined the crystal structure of an archaeal CNNM protein with Mg2+-ATP bound. The structure reveals a novel transmembrane fold for the DUF21 domain, the largest family of domains of unknown function. The protein has a negatively charged cavity that penetrates halfway through the membrane suggesting it functions as a cation transporter. The cytosolic portion of the protein is comprised of highly charged four-helix bundle and a CBS-pair domain. HDX-MS experiments, molecular dynamics, and additional crystal structures show that the cytosolic domains undergo large conformational changes upon nucleotide binding suggesting a mechanism of regulation shared between human and bacterial orthologs. The molecular characterization of CNNM proteins has profound implications for understanding their biological functions in human diseases, including cancer, and in animals, bacteria and plants.
Polygenic prediction of type 2 diabetes in continental Africa
Authors: Chikowore Tinashe , Ekoru Kenneth , Vujkovic Marijana , Gill Dipender , Pirie Fraser , Young Elizabeth , Sandhu Manjinder S , McCarthy Mark , Rotimi Charles , Adeyemo Adebowale , Motala Ayesha , Fatumo Segun 
Published: February 2021

AbstractObjectivePolygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa, and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans.Research Design and MethodsUsing the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls).ResultsThe African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10thdecile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10-6) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile.ConclusionsAfrican American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.
The same ultra-rapid parallel brain dynamics underpin the production and perception of speech
Authors: Fairs Amie , Michelas Amandine , Dufour Sophie , Strijkers Kristof 
Published: February 2021

AbstractThe temporal dynamics by which linguistic information becomes available is one of the key properties to understand how language is organised in the brain. An unresolved debate between different brain language models is whether words, the building blocks of language, are activated in a sequential or parallel manner. In this study we approached this issue from a novel perspective by directly comparing the time course of word component activation in speech production versus perception. In an overt object naming task and a passive listening task we analysed with mixed linear models at the single-trial level the event-related brain potentials elicited by the same lexico-semantic and phonological word knowledge in the two language modalities. Results revealed that both word components manifested simultaneously as early as 75 ms after stimulus onset in production and perception; differences between the language modalities only became apparent after 300 ms of processing. The data provide evidence for ultra-rapid parallel dynamics of language processing and are interpreted within a neural assembly framework where words recruit the same integrated cell assemblies across production and perception. These word assemblies ignite early on in parallel and only later on reverberate in a behaviour-specific manner.
Longitudinal analysis of the faecal microbiome in pigs fedCyberlindnera jadiniiyeast as a protein source during the weanling period followed by a rapeseed- and faba bean-based grower-finisher diet
Authors: Iakhno S. , Delogu F. , Umu Ö.C.O. , Kjos N.P. , Håkenåsen I.M. , Mydland L.T. , Øverland M. , Sørum H. 
Published: February 2021

AbstractThe porcine gut microbiome is closely connected to diet and is central to animal health and growth. The gut microbiota composition in relation toCyberlindnera jadiniiyeast as a protein source in a weanling diet was studied previously. Also, there is a mounting body of knowledge regarding the porcine gut microbiome composition in response to the use of rapeseed (Brassica napussubsp.napus) meal, and faba beans (Vicia faba) as protein sources during the growing/finishing period. However, there is limited data on how the porcine gut microbiome respond to a combination ofC. jadiniiyeast in the weanling phase and rapeseed meal and faba beans in the growing/finishing phase. This work investigated how the porcine faecal microbiome was changing in response to a novel yeast diet with a high inclusion of yeast proteins (40% of crude protein) in a weanling diet followed by a diet based on rapeseed meal and faba beans during the growing/finishing period. The feacal microbiomes of the weanling pigs fed yeast were more diverse with higher relative abundance ofFirmicutesoverBacteroidetescompared with those of soybean meal-based diet fed weanlings. Reduced numbers ofPrevotellain the yeast fed faecal microbiomes remained a microbiome characteristic up until two weeks after the yeast diet was changed to the rapeseed/faba bean growing finishing diet. A number of differentially abundant bacterial phylotypes along with distinct co-occurrence patterns observed during the growing/finishing period indicated the presence of a “carry-over” effect of the yeast weanling diet onto the faecal microbiomes of the grower/finisher pigs.
gbpAandchiAgenes are not uniformly distributed amongst diverseVibrio cholerae
Authors: Fennell Thea G. , Blackwell Grace A. , Thomson Nicholas R. , Dorman Matthew J. 
Published: February 2021

AbstractMembers of the bacterial genusVibrioutilise chitin both as a metabolic substrate and a signal to activate natural competence.Vibrio choleraeis a bacterial enteric pathogen, sub-lineages of which can cause pandemic cholera. However, the chitin metabolic pathway inV. choleraehas been dissected using only a limited number of laboratory strains of this species. Here, we survey the complement of key chitin metabolism genes amongst 195 diverseV. cholerae.We show that the gene encoding GbpA, known to be an important colonisation and virulence factor in pandemic isolates, is not ubiquitous amongstV. cholerae.We also identify a putatively novel chitinase, and present experimental evidence in support of its functionality. Our data indicate that the chitin metabolic pathway within theV. choleraespecies is more complex than previously thought, and emphasise the importance of considering genes and functions in the context of a species in its entirety, rather than simply relying on traditional reference strains.Impact statementIt is thought that the ability to metabolise chitin is ubiquitous amongstVibriospp., and that this enables these species to survive in aqueous and estuarine environmental contexts. Although chitin metabolism pathways have been detailed in several members of this genus, little is known about how these processes vary within a singleVibriospecies. Here, we present the distribution of genes encoding key chitinase and chitin-binding proteins across diverseVibrio cholerae, and show that our canonical understanding of this pathway in this species is challenged when isolates from non-pandemicV. choleraelineages are considered alongside those linked to pandemics. Furthermore, we show that genes previously thought to be species core genes are not in fact ubiquitous, and we identify novel components of the chitin metabolic cascade in this species, and present functional validation for these observations.Data summaryThe authors confirm that all supporting data, code, and protocols have been provided within the article or through supplementary data files.No whole-genome sequencing data were generated in this study. Accession numbers for the publicly-available sequences used for these analyses are listed in Supplementary Table 1, Table 2, and the Methods.All other data which underpin the figures in this manuscript, including pangenome data matrices, modified and unmodified sequence alignments and phylogenetic trees, original images of gels and immunoblots, raw fluorescence data, amplicon sequencing reads, and the R code used to generate Figure 7, are available in Figshare:https://dx.doi.org/10.6084/m9.figshare.13169189(Note for peer-review: Figshare DOI is inactive but will be activated upon publication, please use temporary URLhttps://figshare.com/s/7795a2d80c13f694f8fafor review).
White-box Deep Neural Network Prediction of Genome-Wide Transcriptome Signatures
Authors: Magnusson Rasmus , Tegnér Jesper N. , Gustafsson Mika 
Published: February 2021

AbstractPrediction algorithms for protein or gene structures, including transcription factor binding from sequence information, have been transformative in understanding gene regulation. Here we ask whether human transcriptomic profiles can be predicted solely from the expression of transcription factors (TFs). To this end, we explore whether a neural network (NN) could predict the transcriptome from TFs. Using at least one hidden layer, we find that the expression of 1,600 TFs can explain >95% of variance in 25,000 genes. Using the light-up technique to inspect the trained NN, we find an overrepresentation of known TF-gene regulations. Furthermore, the learned prediction network has a hierarchical organization. A smaller set of around 125 core TFs could explain close to 80% of the variance. Interestingly, reducing the number of TFs below 500 induces a rapid decline in prediction performance. Next, we evaluated the prediction model using transcriptional data from 22 human diseases. The TFs were sufficient to predict the target genes’ dysregulation (rho=0.61, P < 10−216). By inspecting the model, key causative TFs could be extracted for subsequent validation using disease-associated genetic variants. In conclusion, we demonstrate the construction of an interpretable neural network predictor. Analysis of the predictors revealed key TFs that were inducing transcriptional changes during disease.
Cooperative virulence can emerge via horizontal gene transfer but is stabilized by transmission
Authors: Bakkeren Erik , Gül Ersin , Huisman Jana S. , Steiger Yves , Rocker Andrea , Hardt Wolf-Dietrich , Diard Médéric 
Published: February 2021

AbstractIntestinal inflammation fuelsSalmonellaTyphimurium (S.Tm) transmission despite a fitness cost associated with the expression of virulence. Cheater mutants can emerge that profit from inflammation without enduring this cost. Intestinal virulence inS.Tm is therefore a cooperative trait, and its evolution a conundrum. Horizontal gene transfer (HGT) of cooperative alleles may facilitate the emergence of cooperative virulence, despite its instability. To test this hypothesis, we clonedhilD, coding for a master regulator of virulence, into a conjugative plasmid that is highly transferrable during intestinal colonization. We demonstrate that virulence can emerge byhilDtransfer between avirulent strainsin vivo. However, this was indeed unstable andhilDmutant cheaters arose within a few days. The timing of cheater emergence depended on the cost. We further show that stabilization of cooperative virulence inS.Tm is dependent on transmission dynamics, strengthened by population bottlenecks, leading cheaters to extinction and allowing cooperators to thrive.
Hyper-connectivity between the left motor cortex and prefrontal cortex is associated with the severity of dysfunction of the descending pain modulatory system in fibromyalgia
Authors: de Oliveira Franco Álvaro , Fernandes Camila , Vicunha Paul , Bandeira Janete , Aratanha Maria Adelia , da Silva Torres Iraci Lucena , Fregni Felipe , Caumo Wolnei 
Published: February 2021

AbstractThe impaired cortical function likely plays a critical role in chronic pain maintenance and fibromyalgia symptoms. Functional connectivity (FC), as assessed by functional near-infrared spectroscopy (fNIRS), is a promising approach that evaluates cortical activation through hemodynamic response estimation. This study compared the FC of bilateral motor and prefrontal cortices between responders and nonresponders to the conditioned pain modulation test (CPM-test) induced by hand immersion in cold water (0–1°C). We included 37 women with fibromyalgia according to the American College of Rheumatology diagnoses criteria (n = 23 responders to CPM-test and n = 14 nonresponders). After the adjustment for multiple comparisons, we found that nonresponders relative to responders showed higher FC between the left motor cortex (LMC) with the left prefrontal cortex (LPFC) and right prefrontal cortex (RPFC). The psychiatric diagnoses were also positively associated with a higher FC in LMC–LPFC and LMC–RPFC. These results indicate that the increased connectivity between the left motor and bilateral prefrontal cortex might be a neural marker of DPMS dysfunction and an intermediate in the interplay between fibromyalgia and psychiatric disorders.
Motor planning under uncertainty
Authors: Alhussein Laith , Smith Maurice A. 
Published: February 2021

ABSTRACTActions often require the selection of a specific goal amongst a range of possibilities, like when a softball player must precisely position her glove to field a fast-approaching ground ball. Previous studies have suggested that during goal uncertainty, the brain prepares for all potential goals in parallel and averages the corresponding motor plans to command an intermediate movement that is progressively refined as additional information becomes available. Although intermediate movements are widely observed, they could instead reflect a neural decision about the single best action choice at each point in time given the remaining uncertainty. Here we systematically dissociate these possibilities using novel experimental manipulations, and find that when confronted with uncertainty, humans generate a single motor plan that optimizes task performance, rather than averaging potential motor plans. In addition to accurate predictions of population-averaged changes in motor output, a novel computational model based on this performance-optimization theory accounted for a remarkable 80-90% of the variance for individual differences between participants. Our findings resolve a long-standing question about how the brain selects an action to execute during goal uncertainty, providing fundamental insight into motor planning in the nervous system.
Re-investigation of classic T cell subsets and identification of novel cell subpopulations by single-cell RNA sequencing
Authors: Wang Xuefei , Shen Xiangru , Chen Shan , Liu Hongyi , Hong Ni , Chen Xi , Jin Wenfei 
Published: February 2021

AbstractClassic T cell subsets are defined by a small set of cell surface markers, while single cell RNA sequencing (scRNA-seq) clusters cells using genome-wide gene expression profiles. The relationship between scRNA-seq Clustered-Populations (scCPops) and cell surface marker-defined classic T cell subsets remain unclear. Here, we interrogated 6 bead-enriched T cell subsets with 62,235 single cell transcriptomes and re-grouped them into 9 scCPops. Bead-enriched CD4 Naïve and CD8 Naïve were mainly clustered into their scCPop counterparts, while cells from the other T cell subsets were assigned to multiple scCPops including mucosal-associated invariant T cells and natural killer T cells. The multiple T cell subsets that form a single scCPop exhibited similar expression pattern, but not vice versa, indicating scCPops are much homogeneous cell populations with similar cell states. Interestingly, we discovered and named IFNhiT, a new T cell subpopulation that highly expressed Interferon Signaling Associated Genes (ISAGs). We further enriched IFNhiT by FACS sorting of BST2 for scRNA-seq analyses. IFNhiT cluster disappeared on tSNE plot after removing ISAGs, while IFNhiT cluster showed up by tSNE analyses of ISAGs alone, indicating ISAGs are the major contributor of IFNhiT cluster. BST2+ T cells and BST2− T cells showing different efficiencies of T cell activation indicates high level of ISAGs may contribute to quick immune responses.
Plasma Aβ ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
Authors: O’Connor Antoinette , Pannee Josef , Poole Teresa , Arber Charles , Portelius Erik , Swift Imogen , Heslegrave Amanda J , Abel Emily , Willumsen Nanet , Rice Helen , Weston Philip SJ , Ryan Natalie S , Polke James M , Nicholas Jennifer M , Frost Chris , Mead Simon , Wray Selina , Chávez-Gutiérrez Lucía , Blennow Kaj , Zetterberg Henrik , Fox Nick C 
Published: February 2021

AbstractIn-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutationsin-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios betweenPresenilin1 (PSEN1)andAmyloid Precursor Protein (APP)carriers. We examined the relationship between plasma andin-vitromodels of Aβ processing and, amongPSEN1carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28PSEN1and 11APP).Age- and sex-adjusted models showed marked differences in plasma Aβ betweenAPPandPSEN1: higher Aβ42:38 inPSEN1versusAPP(p<0.001) and non-carriers (p<0.001); higher Aβ38:40 inAPPversusPSEN1(p<0.001) and non-carriers (p<0.001), while Aβ42:40 was higher inAPPandPSEN1compared to non-carriers (both p<0.001). Aβ profiles were reasonably consistent in plasma and cell lines. WithinPSEN1, sex-adjusted models demonstrated negative associations between (i)Aβ42:40 (ii)Aβ42:38 and parental AAO.In-vivodifferences in Aβ processing betweenAPPandPSEN1provide insights into ADAD pathophysiology which can inform therapy development.