bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural diversity of CRISPR spacers ofThermus: evidence of local spacer acquisition and global spacer exchange
Authors: Lopatina Anna , Medvedeva Sofia , Artamonova Daria , Kolesnik Matvey , Sitnik Vasily , Ispolatov Yaroslav , Severinov Konstantin 
Published: March 2019

We investigated the diversity of CRISPR spacers ofThermuscommunities from two locations in Italy, two in Chile and one location in Russia. Among the five sampling sites, a total of more than 7200 unique spacers belonging to different CRISPR-Cas systems types and subtypes were identified. Most of these spacers are not found in CRISPR arrays of sequencedThermusstrains. Comparison of spacer sets revealed that samples within the same area (separated by few to hundreds of metres) have similar spacer sets, which appear to be largely stable at least over the course of several years. While at further distances (hundreds of kilometres and more) the similarity of spacer sets is decreased, there are still multiple common spacers inThermuscommunities from different continents. The common spacers can be reconstructed in identical or similar CRISPR arrays, excluding their independent appearance and suggesting an extensive migration of thermophilic bacteria over long distances. Several newThermusphages were isolated in the sampling sites. Mapping of spacers to bacteriophage sequences revealed examples of local acquisition of spacers from some phages and distinct patterns of targeting of phage genomes by different CRISPR-Cas systems.This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
Why put up with immunity when there is resistance: an excursion into the population and evolutionary dynamics of restriction–modification and CRISPR-Cas
Authors: Gurney James , Pleška Maroš , Levin Bruce R. 
Published: March 2019

Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction–modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions under which selection mediated by lytic phage will favour such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the number of steps in the coevolutionary arms race between the bacteria-acquiring spacers and the phage-generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered.
This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
The ethics of genome editing in non-human animals: a systematic review of reasons reported in the academic literature
Authors: de Graeff Nienke , Jongsma Karin R. , Johnston Josephine , Hartley Sarah , Bredenoord Annelien L. 
Published: March 2019

In recent years, new genome editing technologies have emerged that can edit the genome of non-human animals with progressively increasing efficiency. Despite ongoing academic debate about the ethical implications of these technologies, no comprehensive overview of this debate exists. To address this gap in the literature, we conducted a systematic review of the reasons reported in the academic literature for and against the development and use of genome editing technologies in animals. Most included articles were written by academics from the biomedical or animal sciences. The reported reasons related to seven themes: human health, efficiency, risks and uncertainty, animal welfare, animal dignity, environmental considerations and public acceptability. Our findings illuminate several key considerations about the academic debate, including a low disciplinary diversity in the contributing academics, a scarcity of systematic comparisons of potential consequences of using these technologies, an underrepresentation of animal interests, and a disjunction between the public and academic debate on this topic. As such, this article can be considered a call for a broad range of academics to get increasingly involved in the discussion about genome editing, to incorporate animal interests and systematic comparisons, and to further discuss the aims and methods of public involvement.
This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.
Stringent structural plasticity of dendritic spines revealed by two-photon glutamate uncaging in adult mouse neocortex in vivo
Authors: Noguchi Jun , Nagaoka Akira , Hayama Tatsuya , Ucar Hasan , Yagishita Sho , Takahashi Noriko , Kasai Haruo 
Published: March 2019

AbstractTwo-photon uncaging of glutamate is widely utilized to characterize structural plasticity in brain slice preparations in vitro. In this study, we investigated spine plasticity by using, for the first time, glutamate uncaging in the neocortex of adult mice in vivo. Spine enlargement was successfully induced in a smaller fraction of spines in the neocortex (22%) than in young hippocampal slices (95%), even under a low magnesium condition. Once induced, the time course and mean amplitudes of long-term enlargement were the same (81%) as those in vitro. However, low-frequency (1–2 Hz) glutamate uncaging caused spine shrinkage in a similar fraction (34%) of spines as in vitro, but spread to the neighboring spines less frequently than in vitro. Thus, we found that structural plasticity can occur similarly in the adult neocortex in vivo as in the hippocampus in vitro, although it happens stringently in a smaller subset of spines.
MS Atlas - A molecular map of brain lesion stages in progressive multiple sclerosis
Authors: Frisch Tobias , Elkjaer Maria L. , Reynolds Richard , Michel Tanja Maria , Kacprowski Tim , Burton Mark , Kruse Torben A. , Thomassen Mads , Baumbach Jan , Illes Zsolt 
Published: March 2019

AbstractMultiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder of the central nervous system with an untreatable late progressive phase in a high percentage of patients. Molecular maps of different stages of brain lesion evolution in patients with progressive MS (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate of PMS on lesion basis. The MS Atlas gives means for testing research hypotheses, validating candidate biomarkers and drug targets. The MS Atlas data base comprises comprehensive high-quality transcriptomic profiles of 73 brain white matter lesions at different stages of lesion evolution from 10 PMS patients and 25 control white matter samples from five patients with non-neurological disease. The MS Atlas was assembled from next generation RNA sequencing ofpost mortemsamples using strict, conservative preprocessing as well as advanced statistical data analysis. It comes with a user-friendly web interface, which allows for querying and interactively analyzing the PMS lesion evolution. It fosters bioinformatics methods forde novonetwork enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures. We also demonstrate how its interface can interactively condense and visualize the atlas’ content. This compendium of mechanistic PMS white matter lesion profiles is an invaluable resource to fuel future multiple sclerosis research and a new basis for treatment development.
ZBTB33 (Kaiso) methylated binding sites are associated with primed heterochromatin
Authors: Lin Quy Xiao Xuan , Rebbani Khadija , Jha Sudhakar , Benoukraf Touati 
Published: March 2019

AbstractBackgroundZBTB33, also known as Kaiso, is a member of the zinc finger and BTB/POZ family. In contrast to many transcription factors, ZBTB33 has the ability to bind both a sequence-specific consensus and methylated DNA. Although these dual binding preferences enable ZBTB33 to function as an active as well as repressive regulator of gene expression, little is known about the underlining molecular mechanisms.ResultsIn this study, we aimed to investigate the role of ZBTB33 as a methylated DNA binding factor. We took advantage of the latest releases of the ENCODE sequencing datasets, including ZBTB33 ChIP- seq, whole genome bisulfite sequencing (WGBS), histone mark ChIP-seq and sequencing assays determining the chromatin states, to characterize the chromatin landscapes surrounding methylated ZBTB33 binding sites. Interestingly, our integrative analyses demonstrated that the majority of methylated ZBTB33 binding sites were located within condensed chromatin, which are inaccessible to DNase I and Tn5 transposase. Moreover, these sites were carrying a newly revealed histone post-translational modification signature, with significant enrichment of mono-methylation at lysine 4 of histone 3 (H3K4me1) and a complete absence of other active or expected repressive histone marks.ConclusionsOverall, our analyses revealed that ZBTB33 has the unique ability to bind methylated DNA across heterochromatin in a transition state, suggesting a potential role for ZBTB33 in heterochromatin priming.
GWAS of 19,629 individuals identifies novel genetic variants for regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits
Authors: Zhao Bingxin , Luo Tianyou , Li Tengfei , Li Yun , Zhang Jingwen , Shan Yue , Wang Xifeng , Yang Liuqing , Zhou Fan , Zhu Ziliang , Zhu Hongtu 
Published: March 2019

AbstractVolumetric variations of human brain are heritable and are associated with many brain-related complex traits. Here we performed genome-wide association studies (GWAS) and post-GWAS analyses of 101 brain volumetric phenotypes using the UK Biobank (UKB) sample including 19,629 participants. GWAS identified 287 independent SNPs exceeding genome-wide significance threshold of 4.9*10−10, adjusted for testing multiple phenotypes. Gene-based association study found 142 associated genes (113 new) and functional gene mapping analysis linked 122 more genes. Many of the discovered genetic variants have previously been implicated with cognitive and mental health traits (such as cognitive performance, education, mental disease/disorders), and significant genetic correlations were detected for 29 pairs of traits. The significant SNPs discovered in the UKB sample were supported by a joint analysis with other four independent studies (total sample size 2,192), and we performed a meta-analysis of five samples to provide GWAS summary statistics with sample size larger than 20,000. Using genome-wide polygenic risk scores prediction, up to 4.36% of phenotypic variance (p-value=2.97*10−22) in the four independent studies can be explained by the UKB GWAS results. In conclusion, our study identifies many new genetic variants at SNP, locus and gene levels and advances our understanding of the pleiotropy and genetic co-architecture between brain volumes and other traits.
From bud formation to flowering: transcriptomic state defines the cherry developmental phases of sweet cherry bud dormancy
Authors: Vimont Noémie , Fouché Mathieu , Campoy José Antonio , Tong Meixuezi , Arkoun Mustapha , Yvin Jean-Claude , Wigge Philip A. , Dirlewanger Elisabeth , Cortijo Sandra , Wenden Bénédicte 
Published: March 2019

ABSTRACTBackgroundBud dormancy is a crucial stage in perennial trees and allows survival over winter to ensure optimal flowering and fruit production. Recent work highlighted physiological and molecular events occurring during bud dormancy in trees. However, they usually examined bud development or bud dormancy in isolation. In this work, we aimed to further explore the global transcriptional changes happening throughout bud development and dormancy onset, progression and release.ResultsUsing next-generation sequencing and modelling, we conducted an in-depth transcriptomic analysis for all stages of flower buds in several sweet cherry (Prunus avium L.) cultivars that are characterized for their contrasted dates of dormancy release. We find that buds in organogenesis, paradormancy, endodormancy and ecodormancy stages are defined by the expression of genes involved in specific pathways, and these are conserved between different sweet cherry cultivars. In particular, we found that DORMANCY ASSOCIATED MADS-box (DAM), floral identity and organogenesis genes are up-regulated during the pre-dormancy stages while endodormancy is characterized by a complex array of signalling pathways, including cold response genes, ABA and oxidation-reduction processes. After dormancy release, genes associated with global cell activity, division and differentiation are activated during ecodormancy and growth resumption. We then went a step beyond the global transcriptomic analysis and we developed a model based on the transcriptional profiles of just seven genes to accurately predict the main bud dormancy stages.ConclusionsOverall, this study has allowed us to better understand the transcriptional changes occurring throughout the different phases of flower bud development, from bud formation in the summer to flowering in the following spring. Our work sets the stage for the development of fast and cost effective diagnostic tools to molecularly define the dormancy stages. Such integrative approaches will therefore be extremely useful for a better comprehension of complex phenological processes in many species.
Is there an intrinsic relationship between LFP beta oscillation amplitude and firing rate of individual neurons in monkey motor cortex?
Authors: Confais Joachim , Malfait Nicole , Brochier Thomas , Riehle Alexa , Kilavik Bjørg Elisabeth 
Published: March 2019

ABSTRACTIt is a long-standing controversial issue whether an intrinsic relationship between the local field potential (LFP) beta oscillation amplitude and the spike rate of individual neurons in the motor cortex exists. Beta oscillations are prominent in motor cortical LFPs, and their relationship to the local neuronal spiking activity has been extensively studied. Many studies demonstrated that the spikes of individual neurons lock to the phase of LFP beta oscillations. However, the results concerning whether there is also an intrinsic relationship between the amplitude of LFP beta oscillations and the firing rate of individual neurons are contradictory. Some studies suggest a systematic mapping of spike rates onto LFP beta amplitude, and others find no systematic relationship. To resolve this controversy, we correlated the amplitude of LFP beta oscillations recorded in motor cortex of two male macaque monkeys with spike counts of individual neurons during visuomotor behavior, in two different manners. First, in an analysis termed task-related correlation, data obtained across all behavioral task epochs was included. These task-related correlations were frequently significant, and in majority of negative sign. Second, in an analysis termed trial-by-trial correlation, only data from a fixed pre-cue task epoch was included, and correlations were calculated across trials. Such trial-by-trial correlations were weak and rarely significant. We conclude that there is no intrinsic relationship between the firing rate of individual neurons and LFP beta oscillation amplitude in macaque motor cortex, beyond each of these signals being modulated by external factors such as the behavioral task.SIGNIFICANCE STATEMENTWe addressed the long-standing controversial issue of whether there is an intrinsic relationship between the local field potential (LFP) beta oscillation amplitude and the spike rate of individual neurons in the motor cortex. In two complementary analyses of data from macaque monkeys, we first demonstrate that the unfolding behavioral task strongly affects both the LFP beta amplitude and the neuronal spike rate, creating task-related correlations between the two signals. However, when limiting the influence of the task, by restricting our analysis to a fixed task epoch, correlations between the two signals were largely eliminated. We conclude that there is no intrinsic relationship between the firing rate of individual neurons and LFP beta oscillation amplitude in motor cortex.
Negative calorie foods: An empirical examination of what is fact or fiction
Authors: Buddemeyer Katherine M. , Alexander Ashley E. , Secor Stephen M. 
Published: March 2019

AbstractA proposed weight loss strategy is to include in one’s diet foods that are deemed “negative calorie”. In theory, negative-calorie foods are foods for which more energy is expended in their digestion and assimilation than is consumed, thereby resulting in an energy deficit. Commonly listed negative calorie foods are characterized by a high water and fiber content and little fat. Although the existence of negative calorie foods has been largely argued against, no empirical study has fully addressed the validity of foods being negative calorie. We conducted such a study using the omnivorous lizard the bearded dragon(Pogona vitticeps)and celery as the tested food. Celery tops many lists of negative calorie foods due to its high fiber and low caloric content. Following their consumption of celery meals equaling in mass to 5% of their body mass, we measured from each lizard their postprandial metabolic rates to calculate specific dynamic action (SDA). Feces and urate were collected after meals to determine the energy lost to excretion. The specific energy of the celery meals, feces, and urate was determined by bomb calorimetry. Lizards lost on average 29% and 14% of meal energy to feces and urate, respectively, and an additional 33% to SDA, leaving a net gain of 24% of the meal’s energy. When considering that only a portion of fecal energy stems from the celery meal, the net gain is expectedly higher. Although this study debunks the validity of celery and other proposed foods as negative calorie, these foods will contribute to generating a negative energy budget and thus the loss of body weight.SummaryThis empirical study refutes the existence of negative-calorie foods; however such foods will contribute to a negative energy balance, and thus the loss of body mass.
Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis
Authors: Chang Hui-Hsin , Ho Ching-Huang , Tomita Beverly , Silva Andrea A. , Sparks Jeffrey A. , Karlson Elizabeth W. , Rao Deepak A. , Lee Yvonne C. , Ho I-Cheng 
Published: March 2019

AbstractDespite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNFα or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response in a drug-specific manner.
Cerebellar involvement in learning to balance a cart-pole system
Authors: Ludolph Nicolas , Ernst Thomas M. , Mueller Oliver M. , Goericke Sophia L. , Giese Martin A. , Timmann Dagmar , Ilg Winfried 
Published: March 2019

ABSTRACTThe role of the cerebellum in error-based motor adaptation is well examined. In contrast, the involvement of the cerebellum in reward-based motor learning is less clear. In this study, we examined cerebellar involvement in a reward-based motor learning task, namely learning to control a virtual cart-pole system, over five consecutive days. Subjects with focal cerebellar lesions were compared to age-matched controls in terms of learning performance and underlying control mechanisms.Based on the overall balancing performance we have identified two subgroups of patients: (1) patients with learning performance comparable to healthy controls and (2) patients with decelerated learning, unsaturated learning progress after five days and decreased inter-manual transfer. Furthermore, we found that online learning is impaired while offline learning is partly preserved in cerebellar subjects. Regarding control mechanisms, decreased control performance was associated with impairments in predictive action timing.Voxel-wise lesion symptom mapping based on the two subgroups revealed strong associations between impairments in controlling the virtual cart-pole system and lesions in intermediate and lateral parts of lobules V and VI. These results together with previous reports suggest that the ability to predict the dynamics of the cart-pole system is an important factor for the reward-based skill acquisition process.
A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems
Authors: Vogel Jacob W. , La Joie Renaud , Grothe Michel J. , Diaz-Papkovich Alex , Doyle Andrew , Vachon-Presseau Etienne , Lepage Claude , de Wael Reinder Vos , Iturria-Medina Yasser , Bernhardt Boris , Rabinovici Gil D. , Evans Alan C. 
Published: March 2019

AbstractThe functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. When variation in this specific gene expression pattern was observed across the whole brain, a distinct anterioventral-posteriodorsal gradient was observed. Frontal, anterior temporal and brainstem regions involved in social and motivational behaviors, selectively vulnerable to frontotemporal dementia and more functionally connected to the anterior hippocampus could be clearly differentiated from posterior parieto-occipital and cerebellar regions involved in spatial cognition, selectively vulnerable to Alzheimers disease, and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single distinct molecular gradient. (148/150)