bluuebunny/crossref_metadata_2025_split huggingface dataset:
G-Quadruplexes Act as Sequence Dependent Chaperones via Protein Oligomerization
Authors: Begeman Adam , Litberg Theodore J. , Bourne Jennifer , Xuan Zhenyu , Horowitz Scott 
Published: November 2019

AbstractMaintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent aggregation up to 300-fold more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences’ effects on aggregation, we demonstrate that the holdase chaperone effect of nucleic acids is highly sequence dependent. Quadruplexes are found to have especially potent effects on aggregation with many different proteins via quadruplex:protein oligomerization. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as Fragile X and Amyotrophic lateral sclerosis (ALS).
Bacterial quorum sensing allows graded and bimodal cellular responses to variations in population density
Authors: Rattray Jennifer B. , Thomas Stephen A. , Wang Yifei , Molotkova Evgeniya , Gurney James , Varga John J. , Brown Sam P. 
Published: November 2019

AbstractQuorum sensing (QS) is a mechanism of cell–cell communication that connects gene expression to environmental conditions (e.g. density) in many bacterial species, mediated by diffusible signal molecules. Current functional studies focus on a dichotomy of QS on/off (or, quorate / sub-quorate) states, overlooking the potential for intermediate, graded responses to shifts in the environment. Here, we track QS regulated protease (lasB) expression and show that Pseudomonas aeruginosa can deliver a graded behavioral response to fine-scale variation in population density, on both the population and single-cell scales. On the population scale, we see a graded response to variation in environmental population density. On the single-cell scale, we see significant bimodality at higher densities, with separate OFF and ON sub-populations that respond differentially to changes in density; static OFF cells and increasing intensity of expression among ON cells. Together these results indicate that QS can tune gene expression to graded environmental change, with no critical cell mass or ‘quorum’ at which behavioral responses are activated on either the individual cell or population scale. In an infection context, our results indicate there is not a hard threshold separating sub-quorate ‘stealth’ mode and a quorate ‘attack’ mode.
Cyclic peptides can engage a single binding pocket through multiple, entirely divergent modes
Authors: Patel Karishma , Walport Louise J , Walshe James L , Solomon Paul , Low Jason K K , Tran Daniel H , Mouradian Kevork S , Silva Ana P G , Wilkinson-White Lorna , Matthews Jacqueline M , Mitchell Guss J , Payne Richard J , Passioura Toby , Suga Hiroaki , Mackay Joel P 
Published: November 2019

AbstractCyclic peptide display screening techniques can identify drug leads and biological probes with exceptional affinity and specificity. To date, however, the structural and functional diversity encoded in such peptide libraries remains unexplored. We have used the Random nonstandard Peptide Integrated Discovery (RaPID) system to develop cyclic peptide inhibitors of several acetyllysine-binding bromodomains from the Bromodomain and Extra-Terminal domain (BET) family of epigenetic regulators. These peptides have very high affinities for their targets and exhibit extraordinary selectivity (up to 106-fold), making them the highest-affinity and most specific BET-binding molecules discovered to date. Crystal structures of 13 distinct peptide-bromodomain complexes, which all target the acetyllysine-binding pocket, reveal remarkable diversity in both peptide structure and binding mode, and include both α-helical and β-sheet type structures. The peptides can exhibit a high degree of structural pre-organization and bivalent binding of two BDs by one peptide was common, flagging the potential for a new direction in inhibitor design that could bring stronger discrimination between BET-family paralogues. Our data demonstrate for the first time the enormous potential held in these libraries to provide a wide array of modes against a single target, maximizing the opportunity to attain high potency and specificity ligands to a wide variety of proteins.
Learning mutational signatures and their multidimensional genomic properties with TensorSignatures
Authors: Vöhringer Harald , van Hoeck Arne , Cuppen Edwin , Gerstung Moritz 
Published: November 2019

AbstractMutational signature analysis is an essential part of the cancer genome analysis toolkit. Conventionally, mutational signature analysis extracts patterns of different mutation types across many cancer genomes. Here we present TensorSignatures, an algorithm to learn mutational signatures jointly across all variant categories and their genomic context. The analysis of 2,778 primary and 3,824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that practically all signatures operate dynamically in response to various genomic and epigenomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis, which is detected in 7 different cancer types. The analysis also unmasks replication- and double strand break repair-driven APOBEC mutagenesis, which manifests with differential numbers and length of mutation clusters indicating a differential processivity of the two triggers. As a fourth example, TensorSignatures detects a signature of somatic hypermutation generating highly clustered variants around the transcription start sites of active genes in lymphoid leukaemia, distinct from a more general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types.Key findingsSimultaneous inference of mutational signatures across mutation types and genomic features refines signature spectra and defines their genomic determinants.Analysis of 6,602 cancer genomes reveals pervasive intra-genomic variation of mutational processes.Distinct mutational signatures found in quiescent and active regions of the genome reveal differential repair and mutagenicity of UV- and tobacco-induced DNA damage.APOBEC mutagenesis produces two signatures reflecting highly clustered, double strand break repair-initiated and lowly clustered replication-driven mutagenesis, respectively.Somatic hypermutation in lymphoid cancers produces a strongly clustered mutational signature localised to transcription start sites, which is distinct from a weakly clustered translesion synthesis signature found in multiple tumour types.
Reconciling global priorities for conserving biodiversity habitat
Authors: Mokany K. , Ferrier S. , Harwood T.D. , Ware C. , Di Marco M. , Grantham H.S. , Venter O. , Hoskins A.J. , Watson J.E.M. 
Published: November 2019

AbstractDegradation and loss of natural habitat is the major driver of the current global biodiversity crisis. Most habitat conservation efforts to date have targeted small areas of highly threatened habitat, but emerging debate suggests retaining large intact natural systems may be just as important. We reconcile these perspectives by integrating fine-resolution global data on habitat condition and species assemblage turnover, to identify Earth’s high-value biodiversity habitat. These are areas in better condition than most other locations once supporting a similar assemblage of species, and are found within both intact regions and human dominated landscapes. However, only 18.6 % of this high-value habitat is currently protected globally. Averting permanent biodiversity loss requires clear spatially explicit targets for retaining these unprotected high-value habitats.
Quantitative Detection of Cell Activity by Measuring the Fluctuation of Intracellular Motility
Authors: Sakuma Morito , Kondo Yuichi , Higuchi Hideo 
Published: November 2019

AbstractThe measurement of cell activity changes during damage is important to understand the process of cell death and evaluate the effect of medicines. To evaluate cell activity generally, we extended the method of intensity fluctuation in which intensity change in the pixel induced by the movement of organelles was calculated. Cancer, endothelial and iPS cells were damaged by reactive oxygen species (ROS) generated by a fluorescent dye (IR700), hydrogen peroxide, and ultraviolet light. The intensity fluctuation in damaged cells gradually decreased independent of the kind of cell, indicating that the decrease in the fluctuation is a general phenomenon in damaged cells. The rupture of vesicles and mitochondria in the cells were observed upon ROS production. The motility of purified kinesin and dynein which transport vesicles and organelles was inhibited by ROS. These suggest that ROS and cytotoxic molecules spreading from ruptured organelles contribute to the reduction in cell activity which brings about the decrease in the motility and intensity fluctuation of organelles driven by kinesin and dynein.
Computing Skin Cutaneous Melanoma Outcome from the HLA-alleles and Clinical Characteristics
Authors: Dhall Anjali , Patiyal Sumeet , Kaur Harpreet , Bhalla Sherry , Arora Chakit , Raghava G.P.S. 
Published: November 2019

AbstractHuman Leukocyte Antigen (HLA) is an essential component of the immune system which stimulates immune cells to provide protection and defense against cancer. More than thousands of HLA alleles have been reported in the literature; but, only a specific set of HLA alleles expressed in an individual. Recognition of cancer-associated mutations by the immune system depends on the presence of a particular set of alleles, that elicit an immune response to fight against cancer. It indicates that the occurrence of specific HLA alleles also affects the outcome of the cancer patients. In the current study, prediction models have been developed using 415 skin cutaneous melanoma (SKCM) patients for predicting the overall survival of patients from their HLA-alleles. It has been observed that, the presence of certain superalleles in the patients, is responsible for improved overall survival which were referred as favourable superalleles like HLA-B*55 (HR=0.15, 95% CI 0.034 to 0.67), HLA-A*01 (HR=0.5, 95% CI 0.3 to 0.8). In contrast, presence of certain superalleles in the patients is responsible for their poor survival, those superalleles were referred as unfavourable superalleles such as HLA-B*50 (HR=2.76, 95% CI 1.284 to 5.941), HLA-DRB1*12 (HR=3.44, 95% CI 1.64 to 7.2). We developed prediction models using 14 HLA-superalleles and five clinical characteristics for predicting high-risk SKCM patients and achieve HR=4.52 (95% CI 3.088-6.609) with p-value = 8.01E-15. Lastly, we provide a web-based service to community for predicting the risk in SKCM patients (https://webs.iiitd.edu.in/raghava/skcmhrp/)
Low iron-induced small RNA BrrF regulates central metabolism and oxidative stress responses inBurkholderia cenocepacia
Authors: Sass Andrea , Coenye Tom 
Published: November 2019

AbstractBrrF is a Fur-regulated small RNA highly upregulated inBurkholderia cenocepaciaunder conditions of iron depletion. Its computationally predicted targets include iron-containing enzymes of the tricarboxylic acid (TCA) cycle such as aconitase and succinate dehydrogenase, as well as iron-containing enzymes responsible for the oxidative stress response, such as superoxide dismutase and catalase. Phenotypic and gene expression analysis of BrrF deletion and overexpression mutants show that the regulation of these genes is BrrF-dependent. Expression ofacnA,fumA,sdhAandsdhCwas downregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. TCA cycle genes not predicted as target for BrrF were not affected in the same manner by iron depletion. Likewise, expression ofsodBandkatBwas dowregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. BrrF overexpression reduced aconitase and superoxide dismutase activities and increased sensitivity to hydrogen peroxide. All phenotypes and gene expression changes of the BrrF deletion mutant could be complemented by overexpressing BrrFin trans. Overall, BrrF acts as a regulator of central metabolism and oxidative stress response, possibly as an iron-sparing measure to maintain iron homeostasis under conditions of iron starvation.ImportanceRegulatory small RNAs play an essential role in maintaining cell homeostasis in bacteria in response to environmental stresses such as iron starvation. Prokaryotes generally encode a large number of RNA regulators, yet their identification and characterisation is still in its infancy for most bacterial species.Burkholderia cenocepaciais an opportunistic pathogen with high innate antimicrobial resistance, which can cause the often fatal cepacia syndrome in individuals with cystic fibrosis. In this study we characterise a small RNA which is involved in the response to iron starvation, a condition that pathogenic bacteria are likely to encounter in the host.
Exploring groundwater microbial communities for natural attenuation potential of micropollutants
Authors: Aldas-Vargas Andrea , Hauptfeld Ernestina , Hermes Gerben D.A. , Atashgahi Siavash , Smidt Hauke , Rijnaarts Huub H.M. , Sutton Nora B. 
Published: November 2019

AbstractGroundwater is a key water resource, with 45.7% of all drinking water globally being extracted from groundwater. Maintaining good groundwater quality is thus crucial to secure drinking water. Micropollutants, such as pesticides, threaten groundwater quality which can be mitigated by biodegradation. Hence, exploring microbial communities in aquifers used for drinking water production is essential for understanding micropollutants biodegradation capacity. This study aimed at understanding the interaction between groundwater geochemistry, pesticide presence, and microbial communities in aquifers used for drinking water production. Two groundwater monitoring wells located in the northeast of The Netherlands and at 500 m distance from each other were sampled in 2014, 2015, 2016 and 2018. In both wells, water was extracted from five discrete depths ranging from 13 to 54 m and used to analyze geochemical parameters, pesticide concentrations and microbial community dynamics using 16S rRNA gene sequencing and qPCR. Groundwater geochemistry was stable throughout the study period and pesticides were heterogeneously distributed at low concentrations (μg/L range). Integration of the groundwater chemical and microbial data showed that geochemical parameters and pesticides exerted selective pressure on microbial communities. Furthermore, microbial communities in both wells showed a more similar composition in the deeper part of the aquifer as compared to shallow sections, suggesting vertical differences in hydrological connection. This study provides initial insights into microbial community composition and distribution in groundwater systems in relation to geochemical parameters. This information can contribute for the implementation of bioremediation technologies that guarantee safe drinking water production from clean aquifers.Importance sectionGroundwater is an essential source of drinking water. However, its quality is threathened by the presence of micropollutants. Certain microorganisms are capable of degrading micropollutants. However, groundwater is an unexplored environment, where the biodegradation potential of naturally-present microorganisms is unknown. We thus explore how groundwater microbial ecology in shaped by groundwater composition, namely geochemical parameters and micropollutants. This is a first step towards understanding which microbial communities and environmental conditions support natural attenuation of micropollutants. This study thus provides a first step towards developing in situ bioremediation strategies to remove micropollutants from groundwater used for drinking water production.
Genome-enabled prediction models for black tea (Camellia sisnesnsis) quality and drought tolerance traits
Authors: Koech Robert. K. , Malebe Pelly M. , Nyarukowa Christopher , Mose Richard , Kamunya Samson M. , Loots Theodor , Apostolides Zeno 
Published: November 2019

SummaryGenomic selection in tea (Camellia sinensis) breeding has the potential to accelerate efficiency of choosing parents with desirable traits at the seedling stage.The study evaluated different genome-enabled prediction models for black tea quality and drought tolerance traits in discovery and validation populations. The discovery population comprised of two segregating tea populations (TRFK St. 504 and TRFK St. 524) with 255 F1 progenies and 56 individual tea cultivars in validation population genotyped using 1 421 DArTseq markers.Two-fold cross-validation was used for training the prediction models in discovery population, and the best prediction models were consequently, fitted to the validation population.Of all the four based prediction approaches, putative QTLs (Quantitative Trait Loci) + annotated proteins + KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathway-based prediction approach, showed robustness and usefulness in prediction of phenotypes.Extreme Learning Machine model had better prediction ability for catechin, astringency, brightness, briskness, and colour based on putative QTLs + annotated proteins + KEGG pathway approach.The percent variables of importance of putatively annotated proteins and KEGG pathways were associated with the phenotypic traits. The findings has for the first time opened up a new avenue for future application of genomic selection in tea breeding.
Dynamic expression of MMP28 during cranial morphogenesis
Authors: Gouignard Nadege , Theveneau Eric , Saint-Jeannet Jean-Pierre 
Published: November 2019

AbstractMatrix metalloproteinases (MMP) are a large family of proteases comprising 24 members in vertebrates. They are well known for their extracellular matrix remodelling activity. MMP28 is the last member of the family to be discovered. It is a secreted MMP involved in wound healing, immune system maturation, cell survival and migration. MMP28 is also expressed during embryogenesis in human and mouse. Here we describe the detailed expression profile of MMP28 inXenopus laevisembryos. We show that MMP28 is expressed maternally and accumulates at neurula and tailbud stages specifically in the cranial placode territories adjacent to migrating neural crest cells. As a secreted MMP, MMP28 may be required in normal neural crest-placode interactions.
In vivodiversification of target genomic sites using processive T7 RNA polymerase-base deaminase fusions blocked by RNA-guided dCas9
Authors: Álvarez Beatriz , Mencía Mario , de Lorenzo Víctor , Fernández Luis Ángel 
Published: November 2019

AbstractDiversification of specific DNA segments typically involvein vitrogeneration of large sequence libraries and their introduction in cells for selection. Alternativein vivomutagenesis systems on cells often show deleterious offsite mutations and restricted capabilities. To overcome these limitations, we have developed anin vivoplatform to diversify specific DNA segments based on protein fusions between various base deaminases (BD) and the T7 RNA polymerase (T7RNAP) that recognizes a cognate promoter oriented towards the target sequence. The transcriptional elongation of these fusions generates transitions C to T or A to G on both DNA strands and in long DNA segments. To delimit the boundaries of the diversified DNA, the catalytically dead Cas9 (dCas9) is tethered with custom-designed crRNAs as a “roadblock” for BD-T7RNAP elongation. While the efficiency of this platform is demonstrated inE. coli, the system can be adapted to a variety of bacterial and eukaryotic hosts.
Discovery of the First Human Retro-Giant Virus: Description of its morphology, retroviral kinase and ability to induce tumours in mice
Authors: Lusi Elena Angela , Caicci Federico 
Published: November 2019

AbstractBackgroundThe study of retroviruses dates back to the early 1900s during investigations on neoplastic diseases in chickens. Subsequently, Robert Gallo reported the first human retrovirus HLTV in 1980. What we report here is not an archetypal retrovirus, but the discovery of an oncogenic giant microbial agent with a mega-genome, where the transforming retroviral nature co-exists with multiple archaeal oncogenes.MethodsAfter their isolation from human T cells Leukaemia, these organisms were examined at electron microscopy, tested for reverse transcriptase activity, fully sequenced, used for transformation tests on NIH-3T3 cells in vitro and tumours formation in mice. Same type of particles were also isolated from Canine Transmissible Venereal Tumour (CTVT), the oldest contagious cancer in nature.ResultsEM showed the presence of giant viral particles displaying retroviral antigens. These microbial entities harbour in their mega-genome a transforming retroviral kinase, cell-based oncogenes and have reverse transcriptase activity. The purified viral particles transformed NIH-3T3 cells and induced metastatic tumours in nude mice, three weeks post infection. Ruling out the possible presence of filterable retroviruses, a filtered supernatant did not display RT activity and did not transforms.ConclusionsWe discovered an ancestral microbial agent, acutely transforming. For its giant dimensions, the ability to retain the Gram stain, the presence of a mega-genome and its retroviral nature, we tentatively named the agent Retro-Giant-Virus (RGV). However, distinct from amoeba giant Mimiviruses, this transforming human agent has a different nature and does not require for its isolation amoeba co-culture, since amoeba is not its natural host.The morphology, biology and genetic features allocate this mammalian giant microbe halfway in between a classic oncogenic virus and an infectious cancer cell. Its transforming nature goes with its constant ability to induce tumours formation in mice.
Family History of Depression is Associated with Alterations in Task-Dependent Connectivity between the Cerebellum and Ventromedial Prefrontal Cortex
Authors: Tepfer Lindsey J. , Alloy Lauren B. , Smith David V. 
Published: November 2019

AbstractBackgroundA family history of major depressive disorder (MDD) increases the likelihood of a future depressive episode, which itself poses a significant risk for disruptions in reward processing and social cognition. However, it is unclear whether a family history of MDD is associated with alterations in the neural circuitry underlying reward processing and social cognition.MethodsWe subdivided 279 participants from the Human Connectome Project into three groups: 71 with a lifetime history of MDD, 103 with a family history of MDD (FH), and 105 healthy controls (HC). We then evaluated task-based fMRI data on a social cognition and a reward processing task and found a region of the ventromedial prefrontal cortex (vmPFC) that responded to both tasks, independent of group. To investigate whether the vmPFC shows alterations in functional connectivity between groups, we conducted psychophysiological interaction (PPI) analyses using the vmPFC as a seed region.ResultsWe found that FH (relative to HC) was associated with increased sadness scores, and MDD (relative to both FH and HC) was associated with increased sadness and MDD symptoms. Additionally, the FH group had increased vmPFC functional connectivity within the nucleus accumbens, left dorsolateral PFC, and subregions of the cerebellum relative to HC during the social cognition task.ConclusionsThese findings suggest that aberrant neural mechanisms among those with a familial risk of MDD may underlie vulnerability to altered social cognition.