bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systems analysis reveals ageing-related perturbations in retinoids and sex hormones in Alzheimer’s and Parkinson’s diseases
Authors: Lam Simon , Hartmann Nils , Benfeitas Rui , Zhang Cheng , Arif Muhammad , Turkez Hasan , Uhlén Mathias , Englert Christoph , Knight Robert , Mardinoglu Adil 
Published: June 2021

AbstractNeurodegenerative diseases (NDDs), including Alzheimer’s (AD) and Parkinson’s diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analyse transcriptomic data from AD and PD patients, and stratify these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identify retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrate that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.
Mapping RNA-binding proteins in human B cells and T cells upon differentiation
Authors: Zandhuis Nordin D. , Nicolet Benoit P. , Wolkers Monika C. 
Published: June 2021

ABSTRACTB cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease. Lymphocyte differentiation relies on the appropriate timing and dosage of regulatory molecules, and post-transcriptional gene regulation (PTR) is a key player herein. PTR includes the regulation through RNA-binding proteins (RBPs), which control the fate of RNA and its translation into proteins. To date, a comprehensive RBP expression map throughout lymphocyte differentiation is lacking. Using transcriptome and proteome analyses, we here provide an RBP expression map for human B cells and T cells. We observed that even though the overall RBP expression is conserved, the relative RBP expression is distinct between B cells and T cells. Differentiation into effector and memory cells alters the RBP expression, resulting into preferential expression of different classes of RBPs. For instance, whereas naïve T cells express high levels of translation-regulating RBPs, effector T cells preferentially express RBPs that modulate mRNA stability. Lastly, we found that cytotoxic CD8+and CD4+T cells express a common RBP repertoire. Combined, our study reveals a cell type-specific and differentiation-dependent RBP expression landscape in human lymphocytes, which will help unravel the role of RBPs in lymphocyte function.
RNA polymerase II is recruited to DNA double-strand breaks for dilncRNA transcription inDrosophila
Authors: Böttcher Romy , Schmidts Ines , Nitschko Volker , Duric Petar , Förstemann Klaus 
Published: June 2021

AbstractDNA double-strand breaks are among the most toxic lesions that can occur in a genome and their faithful repair is thus of great importance. Recent findings have uncovered local transcription that initiates at the break and forms a non-coding transcript, called damage-induced long non-coding RNA (dilncRNA), which helps to coordinate the DNA transactions necessary for repair. We provide nascent RNA sequencing-based evidence that RNA polymerase II transcribes the dilncRNA inDrosophilaand that this is more efficient for DNA breaks in an intron-containing gene, consistent with the higher damage-induced siRNA levels downstream of an intron. The spliceosome thus stimulates recruitment of RNA polymerase II to the break, rather than merely promoting the annealing of sense and antisense RNA to form the siRNA precursor. In contrast, RNA polymerase III nascent RNA libraries did not contain reads corresponding to the cleaved loci and selective inhibition of RNA polymerase III did not reduce the yield of damage-induced siRNAs. Finally, the damage-induced siRNA density was unchanged downstream of a T8 sequence, which terminates RNA polymerase III transcription. We thus found no evidence for a participation of RNA polymerase III in dilncRNA transcription in cultured Drosophila cells.
Remote cortical perturbation dynamically changes the network solutions to given tactile inputs in neocortical neurons
Authors: Etemadi Leila , Enander Jonas M.D. , Jörntell Henrik 
Published: June 2021

AbstractThe neocortex is a widely interconnected neuronal network. All such networks have a connectivity structure, which limits the possible combinations of neuronal activations across it. In this sense, the network can be said to contain solutions, i.e., for each given external input the cortex may yield a specific combination of neuronal activations/output. If the cortex has a variety of states, a given input could result in a range of possible outputs. There will also be a vast range of outputs that are not possible due to the network structure. Here we use intracellular recordings in SI neurons to show that remote intracortical electrical perturbation can impact such constraints on the responses to given tactile input patterns. Whereas each given tactile input pattern induced a wide set of preferred response states, when combined with cortical perturbation they induced response states that did not otherwise occur. The findings indicate that the physiological network structure can dynamically change as the state of any given cortical region changes, thereby enabling a very rich, multifactorial, perceptual capability.
The long arm of childhood socioeconomic deprivation on mid- to later-life cognitive trajectories: A cross-cohort analysis
Authors: Tsang Ruby S. M. , Gallacher John E. , Bauermeister Sarah 
Published: June 2021

AbstractINTRODUCTIONEarlier studies of the effects of childhood socioeconomic status (SES) on later life cognitive function consistently report a social gradient in later life cognitive function. Evidence for their effects on cognitive decline is, however, less clear.METHODSThe sample consists of 5,324 participants in the Whitehall II Study, 8,572 in the Health and Retirement Study, and 1,413 in the Kame Project, who completed self-report questionnaires on their early-life experiences and underwent repeated cognitive assessments. We characterised cognitive trajectories using latent class mixed models, and explored associations between childhood SES and latent class membership using logistic regressions.RESULTSWe identified distinct trajectories classes for all cognitive measures examined. Childhood socioeconomic deprivation was associated with an increased likelihood of being in a lower trajectory class.DISCUSSIONOur findings support the notions that cognitive ageing is a heterogeneous process and early-life circumstances may have lasting effects on cognition across the life-course.Research in contextSystematic review: We reviewed the literature on childhood socioeconomic status (SES) as a predictor for cognitive decline in mid- to later-life using PubMed. Studies generally reported lower childhood SES is associated with poorer baseline cognition, but not a faster rate of decline. These studies generally focused on the mean rate of decline in the population; no study to date has explored associations between childhood SES and different cognitive trajectories. Relevant studies have been appropriately cited.Interpretation: Our findings suggest that cognitive trajectories differ between individuals and across cognitive domains. Individuals of lower childhood SES were more likely to be in a lower cognitive trajectory class, which may or may not involve more rapid decline.Future directions: Future studies should include more cognitive outcomes and longer follow-ups, as well as investigate the impact of social mobility to further improve our understanding on how early-life circumstances influence cognitive decline.
Molecular dissection of pro-fibrotic signaling identifies the mechanism underlying IL11-driven fibrosis gene translation, reveals non-specific effects of STAT3 and suggests a new mechanism of action for nintedanib
Authors: Widjaja Anissa A. , Viswanathan Sivakumar , Jinrui Dong , Singh Brijesh K. , Tan Jessie , Ting Joyce Goh Wei , Lamb David , Shekeran Shamini G , George Benjamin L , Schafer Sebastian , Carling David , Adami Eleonora , Cook Stuart A. 
Published: June 2021

AbstractIn fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signalling pathways downstream of IL11 are contentious and both STAT3 and ERK have been implicated. Here we show that TGFβ1- or IL11-induced ERK activation is consistently associated with fibrogenesis whereas STAT3 phosphorylation (pSTAT3) is unrelated to fibroblast activation. Surprisingly, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, non-specifically increases pSTAT3 in Il11ra1 null mouse fibroblasts. Pharmacologic inhibition of STAT3 prevents TGFβ1-induced fibrogenesis but this effect was found to reflect fibroblast dysfunction due to severe proteotoxic ER stress. In contrast, inhibition of MEK/ERK prevented fibrosis in the absence of ER stress. TGFβ1-stimulated ERK/mTOR/P70RSK-driven protein translation was IL11-dependent and selectivity for pro-fibrotic protein synthesis was ascribed to an EPRS-related mechanism. In TGFβ1-stimulated fibroblasts, the anti-fibrotic drug nintedanib caused dose-dependent ER stress, reduced pSTAT/pERK and inhibited pro-fibrotic protein translation, similarly to generic STAT3 inhibitors or ER stressors. Pirfenidone, while anti-fibrotic, had no effect on ER stress whereas anti-IL11 inhibited the ERK/mTOR axis while reducing ER stress. These studies discount a specific role for STAT3 in pro-fibrotic signaling, suggest a novel mechanism of action for nintedanib and prioritise further the IL11 pathway as a therapeutic target for fibrosis.
An ancient antimicrobial protein co-opted by a fungal plant pathogen for in planta mycobiome manipulation
Authors: Snelders Nick C. , Petti Gabriella C. , van den Berg Grardy C. M. , Seidl Michael F. , Thomma Bart P.H.J. 
Published: June 2021

ABSTRACTMicrobes typically secrete a plethora of molecules to promote niche colonization. Soil-dwelling microbes are well-known producers of antimicrobials that are exploited to outcompete microbial co-inhabitants. Also plant pathogenic microbes secrete a diversity of molecules into their environment for niche establishment. Upon plant colonization, microbial pathogens secrete so-called effector proteins that promote disease development. While such effectors are typically considered to exclusively act through direct host manipulation, we recently reported that the soil-borne fungal xylem-colonizing vascular wilt pathogen Verticillium dahliae exploits effector proteins with antibacterial properties to promote host colonization through the manipulation of beneficial host microbiota. Since fungal evolution preceded land plant evolution, we now speculate that a subset of the pathogen effectors involved in host microbiota manipulation evolved from ancient antimicrobial proteins of terrestrial fungal ancestors that served in microbial competition prior to the evolution of plant pathogenicity. Here, we show that V. dahliae has co-opted an ancient antimicrobial protein as effector, named VdAMP3, for mycobiome manipulation in planta. We show that VdAMP3 is specifically expressed to ward off fungal niche competitors during resting structure formation in senescing mesophyll tissues. Our findings indicate that effector-mediated microbiome manipulation by plant pathogenic microbes extends beyond bacteria and also concerns eukaryotic members of the plant microbiome. Finally, we demonstrate that fungal pathogens can exploit plant microbiome-manipulating effectors in a life-stage specific manner, and that a subset of these effectors has evolved from ancient antimicrobial proteins of fungal ancestors that likely originally functioned in manipulation of terrestrial biota.SIGNIFICANCE STATEMENTMicrobes secrete a diversity of molecules into their environment to mediate niche colonization. During host ingress, plant pathogenic microbes secrete effector proteins that facilitate disease development, many of which deregulate host immune responses. We recently demonstrated that plant pathogens additionally exploit effectors with antibacterial activities to manipulate beneficial plant microbiota to promote host colonization. Here, we show that the fungal pathogen Verticillium dahliae has co-opted an ancient antimicrobial protein, that likely served in microbial competition in terrestrial environments before land plants existed, as effector for the manipulation of fungal competitors during host colonization. Thus, we demonstrate that pathogen effector repertoires comprise antifungal proteins, and speculate such effectors could be exploited for the development of novel antimycotics.
Dimensional reduction of phenotypes from 53,000 mouse models reveals a diverse landscape of gene function
Authors: Konopka Tomasz , Vestito Letizia , Smedley Damian 
Published: June 2021

AbstractAnimal models have long been used to study gene function and the impact of genetic mutations on phenotype. Through the research efforts of thousands of research groups, systematic curation of published literature, and high-throughput phenotyping screens, the collective body of knowledge for the mouse now covers the majority of protein-coding genes. We here collected data for over 53,000 mouse models with mutations in over 15,000 genomic markers and characterized by more than 254,000 annotations using more than 9,000 distinct ontology terms. We investigated dimensional reduction and embedding techniques as means to facilitate access to this diverse and high-dimensional information. Our analyses provide the first visual maps of the landscape of mouse phenotypic diversity. We also summarize some of the difficulties in producing and interpreting embeddings of sparse phenotypic data. In particular, we show that data preprocessing, filtering, and encoding have as much impact on the final embeddings as the process of dimensional reduction. Nonetheless, techniques developed in the context of dimensional reduction create opportunities for explorative analysis of this large pool of public data, including for searching for mouse models suited to study human diseases.
Adaptive diversification in the cellular circadian behavior of Arabidopsis leaf- and root-derived cells
Authors: Nakamura Shunji , Oyama Tokitaka 
Published: June 2021

ABSTRACTThe plant circadian system is based on self-sustained cellular oscillations and is utilized to adapt to daily and seasonal environmental changes. The cellular circadian clocks in the above- and belowground plant organs are subjected to diverse local environments. Individual cellular clocks are affected by other cells/tissues in plants, and the intrinsic properties of cellular clocks remain to be elucidated. In this study, we showed the circadian properties of leaf- and root-derived cells of a CCA1::LUC Arabidopsis transgenic plant and demonstrated that the cells in total isolation from other cells harbor a genuine circadian clock. Quantitative and statistical analyses for individual cellular bioluminescence rhythms revealed a difference in amplitude and precision of light/dark entrainment between the two cell-types, suggesting that leaf-derived cells have a clock with a stronger persistence against fluctuating environments. Circadian systems in the leaves and roots are diversified to adapt to their local environments at the cellular level.
Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states
Authors: Rodriguez-Algarra Francisco , Seaborne Robert A E , Danson Amy F , Yildizoglu Selin , Yoshikawa Harunori , Law Pui Pik , Ahmad Zakaryya , Maudsley Victoria A , Brew Ama , Holmes Nadine , Ochôa Mateus , Hodgkinson Alan , Marzi Sarah J , Pradeepa Madapura M , Loose Matthew , Holland Michelle L , Rakyan Vardhman K 
Published: June 2021

AbstractBackgroundRibosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed.ResultsUsing a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during ageing only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are <5%.ConclusionsOur work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases.
Detection of Xanthomonas translucens pv. undulosa from wheat by quantitative PCR
Authors: Sarkes Alian , Yang Yalong , Dijanovic Snezana , Harding Michael W. , Feindel David , Feng Jie 
Published: June 2021

AbstractA probe-based quantitative PCR (qPCR) protocol was developed for detection and evaluation of the wheat bacterial leaf streak pathogen Xanthomonas translucens pv. undulosa (Xtu). The protocol can also detect X. translucens pv. translucens (Xtt), but can’t differentiate the two pathovars. When tested on DNA from plant, non-target bacteria and culture of microorganisms from wheat seeds, the qPCR showed a high specificity. On purified Xtu DNA, the qPCR was more sensitive than a loop-mediated isothermal amplification (LAMP) assay. When DNA samples from a set of serial dilutions of Xtu cells were tested, the qPCR method could repeatedly generate quantification cycle (Cq) values from the dilutions containing ≥1,000 cells. Since 2 µL of the total of 50 µL DNA was used in one reaction, one qPCR reaction could detect the presence of the bacteria in samples containing as few as 40 bacterial cells. The qPCR could detect the bacteria from both infected seed and leaf tissues. For seed testing, a protocol for template preparation was standardized, which allowed one qPCR reaction to test DNA from the surface of one seed. Thus, the qPCR system could theoretically detect Xtu and/or Xtt in samples where the bacteria had an average concentration ≥40 cells per seed.
Rpi-amr3 confers resistance to multiple Phytophthora species by recognizing a conserved RXLR effector
Authors: Lin Xiao , Olave-Achury Andrea , Heal Robert , Witek Kamil , Karki Hari S. , Song Tianqiao , Wu Chih-hang , Adachi Hiroaki , Kamoun Sophien , Vleeshouwers Vivianne G. A. A. , Jones Jonathan D. G. 
Published: June 2021

AbstractDiverse pathogens from the genus Phytophthora cause disease and reduce yields in many crop plants. Although many Resistance to Phytophthora infestans (Rpi) genes effective against potato late blight have been cloned, few have been cloned against other Phytophthora species. Most Rpi genes encode nucleotide-binding domain, leucine-rich repeat-containing (NLR) proteins, that recognize RXLR effectors. However, whether NLR proteins can recognize RXLR effectors from multiple different Phytophthora pathogens has rarely been investigated. Here, we report the effector AVRamr3 from P. infestans that is recognized by Rpi-amr3 from S. americanum. We show here that AVRamr3 is broadly conserved in many different Phytophthora species, and that recognition of AVRamr3 homologs enables resistance against multiple Phytophthora pathogens, including P. parasitica and P. palmivora. Our findings suggest a novel path to identifying R genes against important plant pathogens.
Variability in white matter structure relates to hallucination proneness
Authors: Johnson Joseph F. , Schwartze Michael , Belyk Michel , Pinheiro Ana P. , Kotz Sonja A. 
Published: June 2021

AbstractHallucinations are a prominent transdiagnostic psychiatric symptom but are also prevalent in individuals who do not require clinical care. Moreover, persistent psychosis-like experience in otherwise healthy individuals may be related to increased risk to transition to a psychotic disorder. This suggests a common etiology across clinical and non-clinical individuals along a multidimensional psychosis continuum that may be detectable in structural variations of the brain. The current diffusion tensor imaging study assessed healthy individuals to identify possible differences in white matter associated with hallucination proneness (HP). This approach circumvents potential confounds related to medication, hospitalization, and disease progression common in clinical individuals. We determined how HP relates to white matter integrity in selected association, commissural, and projection fiber pathways putatively linked to psychosis. Increased HP was associated with enhanced fractional anisotropy (FA) in the right uncinate fasciculus, the right anterior and posterior arcuate fasciculus, and the corpus callosum. Although FA in cortico-cerebellar pathways revealed no relationship, streamline quantity between the left cerebellum and the right motor cortex positively correlated with HP. These findings support the notion of a psychosis continuum, providing first evidence of structural white matter variability associated with HP in healthy individuals. Furthermore, alterations in the targeted pathways likely indicate an association between HP-related structural variations and the putative salience and attention mechanisms that these pathways subserve.
CREB repressor in mushroom body enhances Drosophila LTM formation
Authors: Chen Chun-Chao , Lin Hsuan-Wen , Feng Kuan-Lin , Jhang Ruei-Yu , Chen Linyi , de Belle J. Steven , Tully Tim , Chiang Ann-Shyn 
Published: June 2021

AbstractLong-term memory (LTM) requires learning-induced synthesis of new proteins allocated to specific neurons and synapses in a neural circuit. Not all learned information, however, becomes permanent memory. How the brain gates relevant information into LTM remains unclear. In Drosophila adults, a single training session in an olfactory aversive task is not sufficient to induce protein synthesis-dependent LTM. Instead, multiple spaced training sessions are required. Here, we report that initial learning induces neural activity in the early α/β subset of Kenyon cells of the mushroom body (MB), and output from these neurons inhibits LTM formation. Specifically in response to spaced training, Schnurri activates CREBB expression which then appears to suppress the inhibitory output from MB. One training session can enhance LTM formation when this inhibitory effect is relieved. We propose that learning-induced protein synthesis and spaced training-induced CREBB act antagonistically to modulate output from early α/β MB neurons during LTM formation.