bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological Impact of a Large Scale Genomic Inversion that Grossly Disrupts the Relative Positions of the Origin and Terminus Loci of the Streptococcus pyogenes Chromosome
Authors: Savic Dragutin J. , Nguyen Scott V. , McCullor Kimberly , McShan W. Michael 
Published: January 2019

ABSTRACTA large-scale genomic inversion encompassing 0.79 Mb of the 1.816 Mb-longStreptococcus pyogenesserotype M49 strain NZ131 chromosome spontaneously occurs in a minor subpopulation of cells, and in this report genetic selection was used to obtain a stable lineage with this chromosomal rearrangement. This inversion, which drastically displaces theorisite, changes the relative length of the replication arms so that one replichore is approximately 0.41 Mb while the other is about 1.40 Mb in length. Genomic reversion to the original chromosome constellation is not observed in PCR-monitored analyses after 180 generations of growth in rich medium. As compared to the parental strain, the inversion surprisingly demonstrates a nearly identical growth pattern in exponential phase. Similarly, when cultured separately in rich medium during prolong stationary phase or in an experimental acute infection animal model (Galleria mellonella), the survival rate of both the parental strain and the invertant is equivalent. However, when co-incubated together, both in vitro and in vivo, the survival of the invertant declines relative to the parental strain. The accompanying aspect of the study suggests that inversions taking place nearbyoriC, always happen to secure the linkage oforiC to DNA sequences responsible for chromosome partition. The biological relevance of large scale inversions is also discussed.IMPORTANCEBased on our previous work, we created to our knowledge the largest asymmetric inversion covering 43.5% of theS. pyogenesgenome. In spite of a drastic replacement of origin of replication and the unbalanced size of replichores (1.4 Mb vs 0.41 Mb), the invertant, when not challenged with its progenitor, showed impressive vitality for growthin vitroand pathogenesis assays. The mutant supports the existing idea that slightly deleterious mutations can provide the setting for secondary adaptive changes. Furthermore, comparative analysis of the mutant with previously published data strongly indicate that even large genomic rearrangements survive provided that the integrity of theoriC and the chromosome partition cluster is preserved.
The strikingflower-in-flowerphenotype ofArabidopsis thalianaNossen (No-0) is caused by a novelLEAFYallele
Authors: Mohrholz Anne , Sun Hequan , Glöckner Nina , Hummel Sabine , Kolukisaoglu Üner , Schneeberger Korbinian , Harter Klaus 
Published: January 2019

SummaryThe transition to reproduction is a crucial step in the life cycle of any organism. InArabidopsis thalianathe establishment of reproductive growth can be divided into two phases: In the first phase, cauline leaves with axillary meristems are formed and internode elongation begins. In the second phase, lateral meristems develop into flowers with defined organs. Floral shoots are usually determinate and suppress the development of lateral shoots. Here, we describe aDstransposon insertion mutant in the Nossen (No-0) accession with severe defects in floral development and flower morphology. The most striking aspect is the outgrowth of stems from the axillary bracts of the primary flower carrying terminal secondary flowers. Therefore, we named this mutantflower-in-flower(fif). However, the insertion of the transposon in the annotated gene is not responsible for thefifphenotype. By means of classical and genome sequencing-based mapping, the mutation responsible for thefifphenotype was found to be in theLEAFY(LFY) gene. The mutation, a G-to-A exchange in the second exon ofLFY, creates a novellfyallele and causes a cysteine-to-tyrosine exchange in the α1-helix of the LFY DNA-binding domain. Whereas subcellular localization and homomerization are not affected, the DNA-binding of LFYFIFis abolished. We propose that the amino acid exchange interferes with the cooperative binding of LFY to its target DNA. To generate the strongfifphenotype, LFYFIFmay act dominant-negatively by either forming non-binding LFY/LFYFIFheteromers or by titrating out the interaction partners, required for LFY function as transcription factor.Significant Statement:Thefifphenotype ofArabidopsis thalianaNo-0 is caused by a novel allele of theLEAFYgene
DeePaC: Predicting pathogenic potential of novel DNA with a universal framework for reverse-complement neural networks
Authors: Bartoszewicz Jakub M. , Seidel Anja , Rentzsch Robert , Renard Bernhard Y. 
Published: January 2019

AbstractMotivation:We expect novel pathogens to arise due to their fast-paced evolution, and new species to be discovered thanks to advances in DNA sequencing and metagenomics. What is more, recent developments in synthetic biology raise concerns that some strains of bacteria could be modified for malicious purposes. Traditional approaches to open-view pathogen detection depend on databases of known organisms, limiting their performance on unknown, unrecognized, and unmapped sequences. In contrast, machine learning methods can infer pathogenic phenotypes from single NGS reads even though the biological context is unavailable. However, modern neural architectures treat DNA as a simple character string and may predict conflicting labels for a given sequence and its reverse-complement. This undesirable property may impact model performance.Results:We present DeePaC, a Deep Learning Approach to Pathogenicity Classification. It includes a universal, extensible framework for neural architectures ensuring identical predictions for any given DNA sequence and its reverse-complement. We implement reverse-complement convolutional neural networks and LSTMs, which outperform the state-of-the-art methods based on both sequence homology and machine learning. Combining a reverse-complement architecture with integrating the predictions for both mates in a read pair results in cutting the error rate almost in half in comparison to the previous state-of-the-art.Availability:The code and the models are available at:https://gitlab.com/rki_bioinformatics/DeePaC
Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan
Authors: Zhang Lei , Dong Xiao , Lee Moonsook , Maslov Alexander Y. , Wang Tao , Vijg Jan 
Published: January 2019

Introductory paragraphThe accumulation of mutations in somatic cells have been implicated as a cause of ageing since the 1950s1,2. Yet, attempts to establish a causal relationship between somatic mutations and ageing have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide detailed, genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan, from newborns to centenarians, using a recently developed, highly accurate single-cell whole-genome sequencing method3. We found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, located at immunoglobulin genes associated with somatic hypermutation. B cell-specific mutation signatures were observed associated with development, ageing or somatic hypermutation (SHM). The SHM signature strongly correlated with the signature found in human chronic lymphocytic leukemia and malignant B-cell lymphomas4, indicating that even in B cells of healthy individuals the potential cancer-causing events are already present. We also identified multiple mutations in sequence features relevant to cellular function, i.e., transcribed genes and gene regulatory regions. Such mutations increased significantly during ageing, but only at approximately half the rate of the genome average, indicating selection against mutations that impact B cell function. This first full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.
DnaJB6 is a RanGTP-regulated protein involved in dynein-dependent microtubule organization during mitosis
Authors: M. Rosas-Salvans , Vernos Isabelle 
Published: January 2019

SummaryBipolar spindle organization is essential for the faithful segregation of chromosomes during cell division. This organization relies on the collective activities of motor proteins. The minus-end directed dynein motor complex generates spindle inward forces and plays a major role in spindle pole focusing. The dynactin complex regulates many dynein functions increasing its processivity and force production.Here we show that DnaJB6 is a novel RanGTP regulated protein. It interacts with dynactin p150Glued in a RanGTP-dependent manner specifically in M-phase and promotes spindle pole focusing and dynein force generation. Our data suggest a novel mechanism by which RanGTP regulates dynein activity during M-phase.Summary statementWe describe DnaJB6 as a novel RanGTP-regulated protein important for spindle assembly. Our data suggest that RanGTP regulates dynein-dependent inward spindle force generation and pole focusing through DnaJB6
The enigmatic role of fungal annexins: the case of Cryptococcus neoformans
Authors: Maryam Maria , Fu Man Shun , Alanio Alexandre , Camacho Emma , Goncalves Diego S. , Faneuff Eden E. , Grossman Nina T. , Casadevall Arturo , Coelho Carolina 
Published: January 2019

AbstractAnnexins are multifunctional proteins that bind to phospholipid membranes in a calcium-dependent manner. Annexins play a myriad of critical and well-characterized roles in mammals, ranging from membrane repair to vesicular secretion. The role of annexins in the kingdoms of bacteria, protozoa and fungi have been largely overlooked. The fact that there is no known homologue of annexins in the model organism may contribute to this gap in knowledge. However, annexins are found in most medically important fungal pathogens, with the notable exception of Candida albicans. In this study we evaluated the function of the one annexin gene in Cryptococcus neoformans, a causative agent of cryptococcosis. This gene CNAG_02415, is annotated in the C. neoformans genome as a target of calcineurin through its transcription factor Crz1, and we propose to update its name to cryptococcal annexin, AnnexinC1. C. neoformans strains deleted for AnnexinC1 revealed no difference in survival after exposure to various chemical stressor relative the wild type, as well as no major alteration in virulence or mating. The only alteration observed in strains deleted for AnnexinC1 was a small increase in the titan cells formation in vitro. The preservation of annexins in many different fungal species suggests an important function, and therefore the lack of a strong phenotype for annexin-deficient C. neoformans is suggestive of either redundant genes that can compensate for the absence of AnnexinC1 function or novel functions not revealed by standard assays of cell function and pathogenicity.ImportanceCryptococcus neoformans is the deadliest human fungal pathogen, causing almost 200,000 deaths each year. Treatment of this lethal infection is lengthy, and in some patients therapy is not curative and patients require lifelong therapy. Fundamental research in this yeast is needed so that we can understand mechanisms of infection and disease and ultimately devise better therapies. In this work we investigated a fungal representative of the annexin family of proteins, specifically in the context of virulence and mating. We find that the cryptococcal annexin does not seem to be involved in virulence or mating but affects generation of titan cells, enlarged yeast cells that are detected in the lungs of mammalian hosts. Our data provides new knowledge in an unexplored area of fungal biology.
A novel mesocosm set-up reveals strong methane emission reduction in submerged peat moss Sphagnum cuspidatum by tightly associated methanotrophs
Authors: Kox Martine A. R. , Smolders Alfons J. P. , Speth Daan R. , Lamers Leon P. M. , Op den Camp Huub J. M. , Jetten Mike S. M. , van Kessel Maartje A. H. J. 
Published: January 2019

AbstractWetlands present the largest natural sources of methane (CH4) and their potential CH4 emissions greatly vary due to the activity of CH4-oxidizing bacteria associated with wetland plant species. In this study, the association of CH4-oxidizing bacteria with submerged Sphagnum peat mosses was studied, followed by the development of a novel mesocosm set-up. This set-up enabled the precise control of CH4 input and allowed for monitoring the dissolved CH4 in a Sphagnum moss layer while mimicking natural conditions. Two mesocosm set-ups were used in parallel: one containing a Sphagnum moss layer in peat water, and a control only containing peat water. Moss-associated CH4 oxidizers in the field could reduce net CH4 emission up to 93%, and in the mesocosm set-up up to 31%. Furthermore, CH4 oxidation was only associated with Sphagnum, and did not occur in peat water. Especially methanotrophs containing a soluble methane monooxygenase enzyme were significantly enriched during the 32 day mesocosm incubations. Together these findings showed the new mesocosm setup is very suited to study CH4 cycling in submerged Sphagnum moss community under controlled conditions. Furthermore, the tight associated between Sphagnum peat mosses and methanotrophs can significantly reduce CH4 emissions in submerged peatlands.
Molecular Dynamics simulations of Alzheimer’s variants, R47H and R62H, in TREM2 provide evidence for structural alterations behind functional changes
Authors: Menzies Georgina E , Sims Rebecca , Williams Julie 
Published: January 2019

AbstractThere is strong evidence supporting the association between Alzheimer’s disease (AD) and protein-coding variants, R47H and R62H in TREM2. The TREM2 protein is an immune receptor found in brain microglia. A structural alteration could therefore have a large effect on the protein. Crystallised structures were used as a base for both WT and mutated proteins. These subjected to 300ns of molecular dynamic simulation (MD). Results suggest structural alterations in both mutated forms of TREM2. A large change was noted in the R47H simulation in the complementarity-determining region two (CDR2) binding loop, a proposed binding sites for ligands such as APOE, a smaller change was observed in the R62H model. These differing levels of structural impact could explain the in vitro observed differences in TREM2-ligand binding.Author SummaryA number of mutations have been found in the TREM2 protein in populations of people with Alzheimer’s and other dementias. Two of these mutations are similar in that the both cause the same coding change in the same domain of the protein. However, they both cause a very different result in terms of risk and in vitro observed changes. Why these two similar mutations are so different is largely unknown. Here we have used a in silico, simulation, approach to understanding the structural changes which occur in both of the mutations. Our results suggest that the mutation which carries a higher risk, but it less commonly observed, has a much larger impact on the protein structure than the mutation which is thought to be less damaging. This structural change is observed at a part of the protein which is thought to code for a binding loop and a change here could have a big impact on the proteins function. Further studies to investigate this binding loop could help not only a better understanding of TREM2’s role in the onset of dementia but also possibly provide a target for therapeutics.
Higher seroprevalence ofEntamoeba histolyticathan that of HIV-1 at a voluntary counselling and testing centre in Tokyo
Authors: Yanagawa Yasuaki , Nagashima Mami , Gatanaga Hiroyuki , Kikuchi Yoshimi , Oka Shinichi , Yokoyama Keiko , Shinkai Takayuki , Sadamasu Kenji , Watanabe Koji 
Published: January 2019

AbstractBackgroundAmebiasis, which is caused byEntamoeba histolytica, is a re-emerging public health issue owing to sexually transmitted infection (STI) in Japan. However, epidemiological data are quite limited.MethodologyTo reveal the relative prevalence of sexually transmittedE. histolyticainfection to other STIs, we conducted a cross-sectional study at a voluntary counselling and testing (VCT) centre in Tokyo. Seroprevalence ofE. histolyticawas assessed according to positivity with an enzyme-linked immunosorbent assay forE. histolytica-specific IgG in serum samples collected from anonymous VCT clients.Principal FindingsAmong 2,083 samples, seropositivity forE. histolyticawas 2.64%, which was higher than that for HIV-1 (0.34%, p < 0.001) and comparable to that for syphilis (rapid plasma reagin (RPR) 2.11%, p = 0.31). Positivity forChlamydia trachomatisin urine by transcription-mediated amplification (TMA) was 4.59%. Seropositivity forE. histolyticawas high among RPR-orTreponema pallidumhemagglutination (TPHA)-positive individuals and it was not different between clients with and without other STIs. Both seropositivity ofE. histolyticaand RPR were high among male clients. The seropositive rate for anti-E. histolyticaantibody was positively correlated with age. TMA positivity for urineC. trachomatiswas high among female clients and negatively correlated with age. Regression analysis identified that male sex, older age, and TPHA-positive results are independent risk factors ofE. histolyticaseropositivity.ConclusionsSeroprevalence ofE. histolyticawas 7.9 times higher than that of HIV-1 at a VCT centre in Tokyo, with a tendency to be higher among people at risk for syphilis infection.Author summaryAmebiasis caused byEntamoeba histolyticais an increasingly prevalent sexually transmitted infection (STI) in Japan; however, relative to other STIs, the prevalence ofE. histolyticahas not been fully assessed. We investigated the seropositivity ofE. histolyticausing serum samples from 2,083 clients of a voluntary counselling and testing centre in Tokyo.E. histolyticaseroprevalence (2.64%) was 7.9 times higher than that of HIV-1 (0.31%) and the same as that of syphilis (rapid plasma reagin: 2.11%). Logistic regression analysis showed thatE. histolyticaseroprevalence tended to be higher among individuals who were male, older, and positive inTreponema pallidumhemagglutination. These results strongly suggest that public health interventions should be considered to control sexual transmission ofE. histolyticainfection, which is currently neglected in Japan.
Transgeneratonal inheritance of ethanol preference is caused by maternal NPF repression
Authors: Bozler Julianna , Kacsoh Balint Z , Bosco Giovanni 
Published: January 2019

SummaryRapid or even anticipatory adaptation to environmental conditions can provide a decisive fitness advantage to an organism. The memory of recurring conditions could also benefit future generations, however neuronally-encoded behavior isn’t thought to be inherited across generations. We tested the possibility that environmentally triggered modifications could allow “memory” of parental experiences to be inherited. In Drosophila melanogaster, exposure to predatory wasps leads to inheritance of a predisposition for ethanol-rich food for five generations. Inhibition of Neuropeptide-F (NPF) activates germline caspases required for transgenerational ethanol preference. Further, inheritance of low NPF expression in specific regions of F1 brains is required for the transmission of this food preference: A maternally derived NPF locus is necessary for this phenomenon, implicating a maternal epigenetic mechanism of NPF-repression. Given the conserved signaling functions of NPF and its mammalian NPY homolog in drug and alcohol disorders, these observations raise the intriguing possibility of NPY-related transgenerational effects in humans.
mTOR suppresses macroautophagy during postnatal development of the striatum
Authors: Lieberman Ori J. , Pigulevskiy Irena , Post Michael R , Sulzer David , Santini Emanuela 
Published: January 2019

AbstractMacroautophagy (hereafter referred to as autophagy) plays a critical role in neuronal function related to development and degeneration. Here, we investigated whether autophagy is developmentally regulated in the striatum, a brain region implicated in neurodevelopmental disease. We demonstrate that autophagic flux is suppressed during striatal postnatal development, reaching adult levels around postnatal day 28 (P28). We also find that mTOR signaling, a key regulator of autophagy, increases during the same developmental period. We further show that mTOR signaling is responsible for suppressing autophagy, via regulation of Beclin-1 and VPS34 activity. These results demonstrate that neurons coopt metabolic signaling cascades to developmentally regulate autophagy and establish mTOR as a central node in the regulation of neuronal autophagy.
Geometric Sketching Compactly Summarizes the Single-Cell Transcriptomic Landscape
Authors: Hie Brian , Cho Hyunghoon , DeMeo Benjamin , Bryson Bryan , Berger Bonnie 
Published: January 2019

SUMMARYLarge-scale single-cell RNA-sequencing (scRNA-seq) studies that profile hundreds of thousands of cells are becoming increasingly common, overwhelming existing analysis pipelines. Here, we describe how to enhance and accelerate single-cell data analysis by summarizing the transcriptomic heterogeneity within a data set using a small subset of cells, which we refer to as a geometric sketch. Our sketches provide more comprehensive visualization of transcriptional diversity, capture rare cell types with high sensitivity, and accurately reveal biological cell types via clustering. Our sketch of umbilical cord blood cells uncovers a rare subpopulation of inflammatory macrophages, which we experimentally validatedin vitro. The construction of our sketches is extremely fast, which enabled us to accelerate other crucial resource-intensive tasks such as scRNA-seq data integration. We anticipate that our algorithm will become an increasingly essential step when sharing and analyzing the rapidly-growing volume of scRNA-seq data and help enable the democratization of single-cell omics.
Regulation of CHD2 expression by the Chaserr long noncoding RNA is essential for viability
Authors: Rom Aviv , Melamed Liliya , Goldrich Micah Jonathan , Kadir Rotem , Golan Matan , Biton Inbal , Perry Rotem Ben-Tov , Ulitsky Igor 
Published: January 2019

AbstractGenomic loci adjacent to genes encoding for transcription factors and chromatin remodelers are enriched for long non-coding RNAs (lncRNAs), but the functional importance of this enrichment is largely unclear. Chromodomain helicase DNA binding protein 2 (Chd2) is a chromatin remodeller with various reported functions in cell differentiation and DNA damage response. Heterozygous mutations in human CHD2 have been implicated in epilepsy, neurodevelopmental delay, and intellectual disability. Here we show that Chaserr, a highly conserved lncRNA transcribed from a region near the transcription start site of Chd2 and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd2 expression levels. Loss of Chaserr in mice leads to early postnatal lethality in homozygous mice, and severe growth retardation in heterozygotes. Mechanistically, loss of Chaserr leads to substantially increased Chd2 mRNA and protein levels, which in turn lead to increased transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaserr production represses Chd2 expression solely in cis, and that the phenotypic consequences of Chaserr loss are rescued when Chd2 is perturbed as well. Targeting Chaserr is thus a potentially viable strategy for increasing CHD2 levels in haploinsufficient individuals.