bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues
Authors: Kastan Nathaniel , Gnedeva Ksenia , Alisch Theresa , Petelski Aleksandra A. , Huggins David J. , Chiaravalli Jeanne , Aharanov Alla , Shakked Avraham , Tzahor Eldad , Nagiel Aaron , Segil Neil , Hudspeth A. J. 
Published: February 2020

SummaryHippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs1–3. Using a high-throughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yap-dependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the substance fosters both the G1-S and G2-M checkpoint transitions and yields supporting cells capable of transdifferentiation. Upon withdrawal of the compound, a subset of supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. Viral transfection of Atoh1 induces the expression of hair cellspecific proteins in progeny. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.
The chloroplast ribonucleoprotein CP33B quantitatively binds thepsbAmRNA
Authors: Teubner Marlene , Lenzen Benjamin , Espenberger Lucas Bernal , Fuss Janina , Nickelsen Jörg , Krause Kirsten , Ruwe Hannes , Schmitz-Linneweber Christian 
Published: February 2020

AbstractChloroplast RNAs are stabilized and processed by a multitude of nuclear-encoded RNA binding proteins, often in response to external stimuli like light and temperature. A particularly interesting RNA based regulation occurs with thepsbAmRNA, which shows light-dependent translation. Recently, the chloroplast ribonucleoprotein CP33B was identified as a ligand of thepsbAmRNA. We here characterized the interaction of CP33B with chloroplast RNAs in greater detail using a combination of RIP-chip, quantitative dot-blot, and RNA-Bind-n-Seq experiments. We demonstrate that CP33B preferspsbAover all other chloroplast RNAs and associates with vast majority of thepsbAtranscript pool. The RNA sequence target motif determinedin vitrodoes not fully explain CP33B’s preference forpsbA, suggesting that there are other determinants of specificityin vivo.
The evolution of sex is tempered by costly hybridization inBoechera(rock cress)
Authors: Rushworth Catherine A. , Mitchell-Olds Tom 
Published: February 2020

AbstractEven after decades of research, the evolution of sex remains an enigma in evolutionary biology. Typically, research addresses the costs of sex and asexuality to characterize the circumstances in which one reproductive system is more favorable. Yet surprisingly few studies address the influence of common traits that are obligately correlated with asexuality, including hybridization and polyploidy; even though these traits have substantial impacts on selective patterns. In particular, hybridization is well-known to alter trait expression; these alterations may themselves represent a cost of sex. We examined the role of reproductive isolation in the formation of de novo hybrid lineages between two widespread species in the ecological model systemBoechera. Of 664 crosses betweenBoechera strictaandBoechera retrofracta, 17% of crosses produced F1 fruits. This suggests that postmating prezygotic barriers, i.e. pollen-pistil interactions, form the major barrier to hybrid success in this system. These interactions are asymmetrical, with 110 F1 fruits produced whenB. strictawas the maternal parent. This asymmetry was confirmed using a chloroplast phylogeny of wild-collectedB. stricta,B. retrofracta, and hybrids, which showed that most hybrids have aB. strictachloroplast haplotype. We next compared fitness of F2 hybrids and selfed parentalB. strictalines, finding that F2 fitness was reduced by substantial hybrid sterility. Our results suggest that multiple reproductively isolating barriers likely influence the formation and fitness of hybrid lineages in the wild, and that these costs of hybridization likely have profound impacts on the costs of sex in the natural environment.
Cryopreservation of midbrain dopaminergic neural cells differentiated from human embryonic stem cells
Authors: Drummond Nicola J. , Dolt Karamjit Singh , Canham Maurice A. , Kilbride Peter , Morris G. John , Kunath Tilo 
Published: February 2020

AbstractRecent advancements in protocols to differentiate human pluripotent stem cells into midbrain dopaminergic (mDA) neurons has improved the ability to model Parkinson’s disease (PD) in a dish, and has provided a scalable source of donor cells for emerging PD cell replacement therapy (CRT). However, to facilitate reproducibility, collaboration, and clinical trials it would be highly beneficial to cryopreserve committed mDA neural precursors cells in a ready-to-use format. In terms of cell manufacturing for PD CRT trials, a cryopreserved transplantation-ready mDA cell product would provide a critical opportunity for quality control, efficacy testing, and safety assessments. To address this challenge, we have compared six (6) different clinical-grade cryopreservation media and different freezing conditions for mDA neural precursor cells differentiated from two human embryonic stem cell (ESC) lines, MasterShef7 and RC17. Significant differences in cell viability were observed at 24h post-thawing, but no differences were observed immediately upon thawing. This highlights the need to check cell viability over the first 24h after thawing, and that viability of freshly thawed cells is insufficient to gauge the success of a cryopreservation protocol. Considerable apoptosis occurs in the first 24h post-thawing, and significant differences between cryopreservation procedures were only revealed during this time period. The presence of ROCK inhibitors improved cell viability at 24h for all conditions tested. A faster cooling rate of 1-2°C/min was significantly better than 0.5°C/min for all conditions tested, while rapid thawing at 37°C was not always superior to slow thawing at 4°C. Indeed, the optimal cryopreservation and thawing conditions in this study, as determined by 24h post-thaw viability, were cells frozen in PSC Cryopreservation medium at a cooling rate of 1°C/min and slow thawing at 4°C. These conditions permitted recovery of 60%-70% live cells at 24h with respect to the starting number of cryopreserved cells. Importantly, cryopreservation of mDA neural precursor cells did not alter their potential to resume differentiation into mDA neurons.HighlightsFirst systematic comparison of multiple clinical-grade cryopreservation media for human ESC-derived mDA neural precursor cellsDifferences in cell viability were observed at 24h after thawing, but not immediately upon thawingCooling rates of 1°C/min or 2°C/min were significantly better than 0.5°C/min for all cryopreservation conditions testedA slow thawing condition at 4°C was significantly better than quick thawing at 37°C for cells frozen in PSC Cryopreservation mediumCryopreservation of mDA cells does not significantly alter their potential to differentiate into mDA neurons
Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease
Authors: Piras Ignazio S. , Bleul Christiane , Schrauwen Isabelle , Talboom Joshua , Llaci Lorida , De Both Matthew D. , Naymik Marcus A. , Halliday Glenda , Bettencourt Conceicao , Holton Janice L. , Serrano Geidy E. , Sue Lucia I. , Beach Thomas G. , Stefanova Nadia , Huentelman Matthew J. 
Published: February 2020

AbstractMultiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n=66) and healthy controls (HC;n=66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n= 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis of MSA-C showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for theQKIgene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and an enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes,APPandPSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.
The Landscape of Mutational Mosaicism in Autistic and Normal Human Cerebral Cortex
Authors: Rodin Rachel E. , Dou Yanmei , Kwon Minseok , Sherman Maxwell A. , D’Gama Alissa M. , Doan Ryan N. , Rento Lariza M. , Girskis Kelly M. , Bohrson Craig L. , Kim Sonia N. , Luquette Lovelace J. , Gulhan Doga C. ,   Brain Somatic Mosaicism Network, Park Peter J. , Walsh Christopher A. 
Published: February 2020

AbstractAlthough somatic mutations have well-established roles in cancer and certain focal epilepsies, the extent to which mutational mosaicism shapes the developing human brain is poorly understood. Here we characterize the landscape of somatic mutations in the human brain using ultra-deep (~250×) whole-genome sequencing of brains from 59 autism spectrum disorder (ASD) cases and 15 controls. We observe a mean of 26 (±10, range 10-60) somatic single nucleotide variants (sSNVs) per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This rate suggests that a typical individual possesses ~80 sSNVs present in ≥2% of cells—comparable to the number ofde novogermline mutations per generation—with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. Although limited by sample size, ASD brains show an excess of somatic mutations in neural enhancer sequences compared to controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.
Varying thermal exposure, host-plant traits and oviposition behaviour across vegetation ecotones
Authors: Vives-Ingla Maria , Sala-Garcia Javier , Stefanescu Constantí , Peñuelas Josep , Carnicer Jofre 
Published: February 2020

ABSTRACTVegetation cover generates local microclimatic gradients in the understorey, being especially pronounced at narrow ecotones linking open and forested habitats (open–closed ecotones). They provide key habitats for multiple insect communities and may largely determine the exposure of herbivorous insects to the increasing impacts of climate change. We report parallel measurements of microclimatic variables, multiple host-plant traits, and oviposition behaviour in Mediterranean populations of twoPierisbutterflies across ecotones of vegetation cover. Open microhabitats were significantly warmer, drier, and more exposed to thermal amplification, which increased temperatures to values affecting insect larval survival. Host plants advanced their reproductive phenology and were shorter. Open microhabitats also inhibited the development of shade-adapted plants (e.g.Alliaria petiolata), decreasing fruit production. In contrast, the reproduction of sun-adapted host plants (e.g.Lepidium draba) was vigorous in the open microhabitats and completely inhibited in closed microhabitats, which were exclusively inhabited by non-reproductive ramets. Key plant traits for the selection of oviposition sites by butterflies, such as foliar water and chlorophyll contents, varied significantly across the open– closed ecotones. Foliar water content was always lower in the open microhabitats, whereas foliar chlorophyll gradients differed between sun- and shade-adapted plants. The oviposition behavior ofPierisbutterflies across the ecotones differed significantly between the thermotolerant species (P. rapae, preferentially selecting open microhabitats) and the thermosensitive species (P. napi, selecting microhabitats protected by vegetation cover), matching the values of thermal susceptibility estimated from parallel heat tolerance assays of the populations. The larvae of the thermotolerantPierisspecies grew under completely different thermal conditions due to differential microhabitat selection, indicating marked interspecific differences in thermal exposure (5–10 °C). These results suggest that the impacts of global warming in these communities will likely be mediated by open–closed ecotones, which determine pronounced local variability in thermal exposure, oviposition placement, and host-plant traits affecting larval performance in summer.
A Casz1 - NuRD complex regulates temporal identity transitions in neural progenitors
Authors: Mattar Pierre , Jolicoeur Christine , Shah Sujay , Cayouette Michel 
Published: February 2020

AbstractNeural progenitor cells alter their output over developmental time to generate different types of neurons and glia in the correct sequences and proportions. A number of ‘temporal identity factors’ that control transitions in progenitor competence have been identified, but the molecular mechanisms underlying their function remain unclear. Here, we asked how the transcription factorCasz1, the mammalian orthologue ofDrosophila castor,regulates competence during retinal neurogenesis. We show thatCasz1is required to control the transition between neurogenesis and gliogenesis. Using BioID proteomics, we reveal that Casz1 interacts with the nucleosome remodeling and deacetylase (NuRD) complex in retinal cells. Finally, we show that both the NuRD and the polycomb repressor complexes are required for Casz1 to promote the rod fate and suppress gliogenesis. As other temporal identity factors have been found to interact with the NuRD complex in other contexts, we propose that these factors might act through a common biochemical process to regulate neurogenesis.
Harnessing tumor immune ecosystem dynamics to personalize radiotherapy
Authors: Daniel Grass G. , Alfonso Juan C.L. , Welsh Eric , Ahmed Kamran A. , Teer Jamie K. , Harrison Louis B. , Cleveland John L. , Mulé James J. , Eschrich Steven A. , Enderling Heiko , Torres-Roca Javier F. 
Published: February 2020

AbstractRadiotherapy is a pillar of cancer care and augments the response to immunotherapies. However, little is known regarding the relationships between the tumor immune ecosystem (TIES) and intrinsic radiosensitivity, and a pressing question in oncology is how to optimize radiotherapy to improve patient responses to immune therapies. To address this challenge, we profiled over 10,000 primary tumors for their metrics of radiosensitivity and immune cell infiltrate (ICI), and applied a new integrated in silico model that mimics the dynamic relationships between tumor growth, ICI flux and the response to radiation. We then validated this model with a separate cohort of 59 lung cancer patients treated with radiotherapy. These analyses explain radiation response based on its effect on the TIES and quantifies the likelihood that radiation can promote a shift to anti-tumor immunity. Dynamic modeling of the relationship between tumor radiosensitivity and the TIES may provide opportunity to personalize combined radiation and immunotherapy approaches.
Insight into motility-dependent pathogenicity of the zoonotic spirocheteLeptospira
Authors: Xu Jun , Koizumi Nobuo , Nakamura Shuichi 
Published: February 2020

AbstractBacterial motility is crucial for many pathogenic species in the process of invasion and/or dissemination. The spirochete bacteriaLeptospiraspp. cause symptoms, such as hemorrhage, jaundice, and nephritis, in diverse mammals including humans. Although loss-of-motility attenuate the spirochete, the mechanism of the motility-dependent pathogenicity is unknown. Here, focusing on thatLeptospiraspp. swim in liquid and crawl on solid surfaces, we investigated the spirochetal dynamics on the host tissues by infecting cultured kidney cells from various species with pathogenic and nonpathogenic leptospires. We found that, in the case of the pathogenic leptospires, a larger fraction of bacteria attached to the host cells and persistently traveled long distances using the crawling mechanism. Our results associate the kinetics and kinematic features of the spirochetal pathogens with their virulence.One Sentence SummaryAdhesivity and crawling motility over host tissue surfaces are closely related to the pathogenicity of a zoonotic spirochete.
A population-level invasion by transposable elements triggers genome expansion in a fungal pathogen
Authors: Oggenfuss Ursula , Badet Thomas , Wicker Thomas , Hartmann Fanny E. , Singh Nikhil K. , Abraham Leen N. , Karisto Petteri , Vonlanthen Tiziana , Mundt Christopher C. , McDonald Bruce A. , Croll Daniel 
Published: February 2020

AbstractGenome evolution is driven by the activity of transposable elements (TEs). The spread of TEs can have deleterious effects including the destabilization of genome integrity and expansions. However, the precise triggers of genome expansions remain poorly understood because genome size evolution is typically investigated only among deeply divergent lineages. Here, we use a large population genomics dataset of 284 individuals from populations across the globe ofZymoseptoria tritici, a major fungal wheat pathogen. We built a robust map of genome-wide TE insertions and deletions to track a total of 2,456 polymorphic loci within the species. We show that purifying selection substantially depressed TE frequencies in most populations but some rare TEs have recently risen in frequency and likely confer benefits. We found that specific TE families have undergone a substantial genome-wide expansion from the pathogen’s center of origin to more recently founded populations. The most dramatic increase in TE insertions occurred between a pair of North American populations collected in the same field at an interval of 25 years. We find that both genome-wide counts of TE insertions and genome size have increased with colonization bottlenecks. Hence, the demographic history likely played a major role in shaping genome evolution within the species. We show that both the activation of specific TEs and relaxed purifying selection underpin this incipient expansion of the genome. Our study establishes a model to recapitulate TE-driven genome evolution over deeper evolutionary timescales.
General Framework for Tracking Neural Activity Over Long-Term Extracellular Recordings
Authors: Chaure Fernando Julian , Rey Hernan Gonzalo 
Published: February 2020

AbstractThe recent advances in the chronic implantation of electrodes have allowed the collection of extracellular activity from neurons over long periods of time. To fully take advantage of these recordings, it is necessary to track single neurons continuously, particularly when their associated waveform changes over time. Multiple spike sorting algorithms can track drifting neurons but they do not perform well in conditions like a temporary increase in the noise level and changes in the number of detectable neurons. In this work, we present Tracking_Graph, a general framework to track neurons under these conditions. Tracking_Graph can be implemented with different spike sorting algorithms, allowing the experimenter to use the algorithm best fitted for their setup. The main idea behind Tracking_Graph is the blockwise analysis of the recording and application of a classification algorithm to match spikes to templates in different segments, leading to a directional metric that can be used to link clusters across blocks. Moreover, the algorithm can detect and fix sorting errors (splits and merges) in isolated blocks. We compared an implementation of Tracking_Graph with other algorithms using long-term simulations and obtained superior performance in all the metrics.
Microtubule attachment and centromeric tension shape the protein architecture of the human kinetochore
Authors: Kukreja Alexander A. , Kavuri Sisira , Joglekar Ajit. P 
Published: February 2020

SummaryThe nanoscale protein architecture of the kinetochore, a complex protein machine, plays an integral role in the molecular mechanisms underlying its functions in chromosome segregation. However, defining this architecture in human cells remains challenging because of the large size and compositional complexity of the kinetochore. Here, we use Förster Resonance Energy Transfer to reveal the architecture of individual kinetochore-microtubule attachments in human cells. We find that the microtubule-binding domains of the Ndc80 complex cluster at the microtubule plus-end. This clustering occurs only after microtubule attachment, and it increases proportionally with centromeric tension. Surprisingly, this clustering is independent of the organization and number of centromeric receptors for Ndc80. Moreover, Ndc80 clustering is similar in yeast and human kinetochores despite significant differences in their centromeric organizations. These and other data suggest that the microtubule-binding interface of the human kinetochore behaves like a flexible “lawn” despite being nucleated by repeating biochemical subunits.
A Generalized Discrete Dynamic Model for Human Epidemics
Authors: Zhang Wenjun , Chen Zeliang , Lu Yi , Guo Zhongmin , Qi Yanhong , Wang Guoling , Lu Jiahai 
Published: February 2020

AbstractA discrete dynamic model for human epidemics was developed in present study. The model included major parameters as transmission strength and its decline parameters, mean incubation period, hospitalization time, non-hospitalization daily mortality, non-hospitalization daily recovery rate, and hospitalization proportion, etc. Sensitivity analysis of the model indicated the total cumulative cases significantly increased with initial transmission strength, hospitalization time. The total cumulative cases significantly decreased with transmission strength’s decline and hospitalization proportion, and linearly decreased with non-hospitalization daily mortality and non-hospitalization daily recovery rate. In a certain range, the total cumulative cases significantly increased with mean incubation period. Sensitivity analysis demonstrated that dynamic change of transmission strength is one of the most important and controllable factors. In addition, reducing the delay for hospitalization is much effective in weakening disease epidemic. Non-hospitalization recovery rate is of importance for enhancing immunity to recover from the disease.