bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycogen Synthase Kinase 3 regulates the genesis of the rare displaced ganglion cell retinal subtype
Authors: Kisseleff Elena , Vigouroux Robin J , Hottin Catherine , Lourdel Sophie , Shah Parth , Chédotal Alain , Perron Muriel , Swaroop Anand , Roger Jerome E 
Published: January 2021

ABSTRACTGlycogen Synthase Kinase 3 (GSK) proteins (GSK3α and GSK3β) are key mediators of signaling pathways, with crucial roles in coordinating fundamental biological processes during neural development. Here we show that the complete loss of GSK3 signaling in mouse retinal progenitors leads to microphthalmia with broad morphological defects. Both proliferation of retinal progenitors and neuronal differentiation are impaired and result in enhanced cell death. A single wild-type allele of eitherGsk3αorGsk3βis able to rescue these phenotypes. In this genetic context, all cell types are present with a functional retina. However, we unexpectedly detect a large number of cells in the inner nuclear layer expressing retinal ganglion cell (RGC)-specific markers (called displaced RGCs, dRGCs) when at least one allele ofGsk3αis expressed. Excess dRGCs lead to increased number of axons projecting into the ipsilateral medial terminal nucleus, an area of the brain belonging to the non-image-forming visual circuit and poorly targeted by RGCs in wild-type retina. Transcriptome analysis and optomotor response assay suggest that at least a subset of dRGCs inGsk3mutant mice are direction-selective RGCs. Our study thus uncovers a unique role of GSK3 in controlling the genesis of dRGCs, a rare and poorly characterized retinal cell type.
Defining the Caprin-1 interactome in unstressed and stressed conditions
Authors: Vu Lucas , Ghosh Asmita , Tran Chelsea , Tebung Walters Aji , Sidibé Hadjara , Garcia-Mansfield Krystine , David-Dirgo Victoria , Sharma Ritin , Pirrotte Patrick , Bowser Robert , Velde Christine Vande 
Published: January 2021

AbstractCytoplasmic stress granules (SGs) are dynamic non-membranous foci containing translationally arrested mRNA and RNA binding proteins that form in response to a variety of cellular stressors. SGs may evolve into the cytoplasmic inclusions observed in many neurodegenerative diseases. Recent studies have examined the SG proteome by interrogating the interactome of G3BP1, a core SG protein. To gain further insight into the SG proteome, we employed an immunoprecipitation coupled with mass spectrometry approach of endogenous Caprin-1 in HeLa cells under unstressed or stressed conditions. Overall, we identified ~1,500 proteins that interact with Caprin-1. Interactors under stressed conditions were primarily annotated to the ribosome, spliceosome, and RNA transport pathways. We validated four Caprin-1 interactors that localized to arsenite-induced SGs: ANKHD1, Talin-1, GEMIN5, and SNRNP200. We also validated these stress-induced interactions in SH-SY5Y cells and determined that SNRNP200 also associated with osmotic and thermal induced SGs. Finally, we identified SNRNP200 in cytoplasmic aggregates in ALS spinal cord and motor cortex. Collectively, our findings provide the first description of the Caprin-1 protein interactome, identify novel cytoplasmic SG components, and reveal a SG protein in cytoplasmic aggregates in ALS patients. Proteomic data collected in this study are available via ProteomeXchange with identifier PXD023271.
On the role of arkypallidal and prototypical neurons for phase transitions in the external pallidum
Authors: Gast Richard , Gong Ruxue , Schmidt Helmut , Meijer Hil G.E. , Knösche Thomas R. 
Published: January 2021

AbstractThe external pallidum (GPe) plays a central role for basal ganglia functions and dynamics and, consequently, has been included in most computational studies of the basal ganglia. These studies considered the GPe as a homogeneous neural population. However, experimental studies have shown that the GPe contains at least two distinct cell types (prototypical and arkypallidal cells). In this work, we provide in silico insight into how pallidal heterogeneity modulates dynamic regimes inside the GPe and how they affect the GPe response to oscillatory input.We derive a mean-field model of the GPe system from a microscopic spiking neural network of recurrently coupled prototypical and arkypallidal neurons. Using bifurcation analysis, we examine the influence of the intra-pallidal connectivity on the GPe dynamics. We find that under healthy conditions, the inhibitory coupling determines whether the GPe is close to either a bi-stable or an oscillatory regime. Furthermore, we show that oscillatory input to the GPe, arriving from subthalamic nucleus or striatum, leads to characteristic patterns of cross-frequency coupling observed at the GPe. Based on these findings, we propose two different hypotheses of how dopamine depletion at the GPe may lead to phase-amplitude coupling between the parkinsonian beta rhythm and a GPe-intrinsic gamma rhythm. Finally, we show that these findings generalize to realistic spiking neural networks of sparsely coupled type-I excitable GPe neurons.Significant StatementOur work provides (a) insight into the theoretical implications of a dichotomous GPe organization for its macroscopic dynamic regimes, and (b) an exact mean-field model that allows for future investigations of the relationship between GPe spiking activity and local field potential fluctuations. We identify the major phase transitions that the GPe can undergo when subject to static or periodic input and link these phase transitions to the emergence of synchronized oscillations and cross-frequency coupling in the basal ganglia. Due to the close links between our model and experimental findings on the structure and dynamics of prototypical and arkypallidal cells, our results can be used to guide both experimental and computational studies on the role of the GPe for basal ganglia dynamics in health and disease.
A syntenin-deficient microenvironment educates AML for aggressiveness
Authors: Leblanc R , Fares J , Goubard A , Castellano R , Camoin L , Balzano M , Ghossoub R , Bou-Tayeh B , Fauriat C , Vey N , Borg JP , Collette Y , Aurrand-Lions M , David G , Zimmermann P 
Published: January 2021

AbstractIn acute myeloid leukemia (AML), the stromal microenvironment plays a prominent role in promoting tumor cell survival and progression. Although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin, a multi-domain PDZ protein, controls both the trafficking and signaling of key molecules involved in intercellular communication. Therefore, we aimed to clarify the role of environmental syntenin in the progression of AML. Byin vivoapproaches in syngeneic mice, we demonstrate that a syntenin-deficient environment reprograms AML blasts to survive independently of the stroma. Up-regulation of EEF1A2 in the blasts controls this gain of cell survival. Furthermore, usingex vivoco-culture systems, we show that syntenin-deficient bone marrow stromal cells (BMSC) enhance the survival of different types of AML cells, including patient samples, and suffice to educate syngeneic AML, recapitulating micro-environmental effects observedin vivo.We establish that syntenin-deficiency causes an increase of eIF5A and autophagy-related factors in BMSC, and provide evidence that the inhibition of autophagy prevents syntenin-deficient BMSC to stimulate AML survival. Altogether, these findings indicate that host-syntenin in the BM microenvironment acts as a repressor of AML aggressiveness.Key points-A syntenin-deficient host reprograms AML blasts, enhancing total protein synthesis and cell survival pathways-Autophagy in the syntenin-deficient microenvironment is responsible for the gain of AML cell survival
BMP pathway antagonism byGrem1regulates epithelial cell fate in intestinal regeneration
Authors: Koppens Martijn AJ , Davis Hayley , Valbuena Gabriel N , Mulholland Eoghan J , Nasreddin Nadia , Colombe Mathilde , Antanaviciute Agne , Biswas Sujata , Friedrich Matthias , Lee Lennard ,   Oxford IBD cohort investigators, Wang Lai Mun , Koelzer Viktor H , East James E , Simmons Alison , Winton Douglas J , Leedham Simon J 
Published: January 2021

ABSTRACTIn the intestine, the homeostatic effect of Bone Morphogenetic Protein (BMP) on cell fate has predominantly been inferred through pathway inactivation. Here, we assessed the impact of autocrineBmp4expression on secretory cell fate. Ligand exposure reduced proliferation, expedited terminal differentiation, abrogated long-term secretory cell survival and prevented dedifferentiation. As stem cell plasticity is required for regenerative adaptive reprogramming, we spatiotemporally mapped and functionally explored BMP’s role in epithelial restitution. Following ulceration, physiological attenuation of BMP signalling arose through upregulation of the secreted antagonist,Grem1,from topographically distinct populations of stromal cells. Concomitant expression supported functional compensation, followingGrem1deletion from tissue-resident fibroblasts. BMP pathway manipulation showed that antagonist-mediated BMP attenuation was obligatory, but functionally sub-maximal, as regeneration was impaired or enhanced by epithelial overexpression ofBmp4orGrem1respectively. Mechanistically,Bmp4abrogated regenerative stem cell reprogramming, despite a convergent impact of YAP/TAZ on cell fate in remodelled wounds.
Functionnectome: a framework to analyse the contribution of brain circuits to fMRI
Authors: Nozais Victor , Forkel Stephanie J. , Foulon Chris , Petit Laurent , Thiebaut de Schotten Michel 
Published: January 2021

AbstractIn recent years, the field of functional neuroimaging has moved away from a pure localisationist approach of isolated functional brain regions to a more integrated view of these regions within functional networks. However, the methods used to investigate functional networks rely on local signals in grey matter and are limited in identifying anatomical circuitries supporting the interaction between brain regions. Mapping the brain circuits mediating the functional signal between brain regions would propel our understanding of the brain’s functional signatures and dysfunctions. We developed a novel method to unravel the relationship between brain circuits and functions: The Functionnectome. The Functionectome combines the functional signal fromfMRI with white matter circuits’ anatomy to unlock and chart the first maps of functional white matter. To showcase this new method’s versatility, we provide the first functional white matter maps revealing the joint contribution of connected areas to motor, working memory, and language functions. The Functionnectome comes with an open-source companion software and opens new avenues into studying functional networks by applying the method to already existing dataset and beyond taskfMRI.
Extracellular Matrix Dysfunction in Sorsby Patient-Derived Retinal Pigment Epithelium
Authors: Engel Abbi L. , Wang YeKai , Khuu Thomas H. , Worrall Emily , Manson Megan A. , Lim Rayne R. , Knight Kaitlen , Yanagida Aya , Qi Jian Hua , Ramakrishnan Aravind , Weleber Richard G , Klein Michael L. , Wilson David J. , Anand-Apte Bela , Hurley James B. , Du Jianhai , Chao Jennifer R. 
Published: January 2021

AbstractSorsby Fundus Dystrophy (SFD) is a rare form of macular degeneration that is clinically similar to age-related macular degeneration (AMD), and a histologic hallmark of SFD is a thick layer of extracellular deposits beneath the retinal pigment epithelium (RPE). Previous studies of SFD patient-induced pluripotent stem cell (iPSC) derived RPE differ as to whether these cultures recapitulate this key clinical feature by forming increased drusenoid deposits. The primary purpose of this study is to examine whether SFD patient-derived iPSC-RPE form basal deposits similar to what is found in affected family member SFD globes and to determine whether SFD iPSC RPE may be more oxidatively stressed. We performed a careful comparison of iPSC RPE from three control individuals, multiple iPSC clones from two SFD patients’ iPSC RPE, and post-mortem eyes of affected SFD family members. We also examined the effect of CRISPR-Cas9 gene correction of the S204CTIMP3mutation on RPE phenotype. Finally, targeted metabolomics analysis with liquid chromatography and mass spectrometry analysis and stable isotope-labeled metabolite analysis was performed to determine whether SFD RPE are more oxidatively stressed. We found that SFD iPSC-RPE formed significantly more sub-RPE deposits (∼6-90 μm in height) compared to control RPE at 8 weeks. These deposits were similar in composition to the basal laminar drusen found in SFD family member globes by immunofluorescence staining and TEM imaging. S204CTIMP3correction by CRISPR-Cas9 gene editing in SFD iPSC RPE cells resulted in significantly reduced basal laminar and sub-RPE calcium deposits. We detected a ∼18-fold increase in TIMP3 accumulation in the extracellular matrix (ECM) of SFD RPE, and targeted metabolomics showed that intracellular 4-hydroxyproline, a major breakdown product of collagen, is significantly elevated in SFD RPE, suggesting increased ECM turnover. Finally, SFD RPE cells have decreased intracellular reduced glutathione and were found to be more vulnerable to oxidative stress. Our findings suggest that elements of SFD pathology can be demonstrated in culture which may lead to insights into disease mechanisms.
Easymap: a user-friendly software package for rapid mapping by sequencing of point mutations and large insertions
Authors: Lup Samuel Daniel , Wilson-Sánchez David , Andreu-Sánchez Sergio , Micol José Luis 
Published: January 2021

ABSTRACTMapping-by-sequencing strategies combine next-generation sequencing (NGS) with classical linkage analysis, allowing rapid identification of the causal mutations of the phenotypes exhibited by mutants isolated in a genetic screen. Computer programs that analyze NGS data obtained from a mapping population of individuals derived from a mutant of interest in order to identify a causal mutation are available; however, the installation and usage of such programs requires bioinformatic skills, modifying or combining pieces of existing software, or purchasing licenses. To ease this process, we developed Easymap, an open-source program that simplifies the data analysis workflows from raw NGS reads to candidate mutations. Easymap can perform bulked segregant mapping of point mutations induced by ethyl methanesulfonate (EMS) with DNA-seq or RNA-seq datasets, as well as tagged-sequence mapping for large insertions, such as transposons or T-DNAs. The mapping analyses implemented in Easymap have been validated with experimental and simulated datasets from different plant and animal model species. Easymap was designed to be accessible to all users regardless of their bioinformatics skills by implementing a user-friendly graphical interface, a simple universal installation script, and detailed mapping reports, including informative images and complementary data for assessment of the mapping results.One sentence summaryEasymap is a versatile user-friendly software tool that facilitates mapping-by-sequencing of large insertions and point mutations in plant and animal genomes
Enhanced Solid Tumor Recognition and T cell Stemness with SynNotch CAR Circuits
Authors: Hyrenius-Wittsten Axel , Su Yang , Park Minhee , Garcia Julie M. , Perry Nathaniel , Montgomery Garrett , Liu Bin , Roybal Kole T. 
Published: January 2021

ABSTRACTThe lack of highly tumor-specific antigens limits the development of engineered T cell therapeutics because of life-threatening “on-target/off-tumor” toxicities. Here we identify ALPPL2 as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma. ALPPL2 can act as a sole target for chimeric antigen receptor (CAR) therapy or be combined with tumor-associated antigens such as MCAM or mesothelin in synthetic Notch (synNotch) CAR combinatorial antigen circuits. SynNotch CAR T cells display superior tumor control when compared to CAR T cells to the same antigens by prevention of CAR-mediated tonic signaling allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable target for multiple solid tumors and demonstrate the multi-faceted therapeutic benefits of synNotch CAR T cells.ONE SENTENCE SUMMARYSynNotch CAR circuits targeting novel solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion.
The dysregulated Pink1-Drosophila mitochondrial proteome is partially corrected with exercise
Authors: Ebanks Brad , Ingram Thomas L , Katyal Gunjan , Ingram John R , Moisoi Nicoleta , Chakrabarti Lisa 
Published: January 2021

AbstractOne of the genes which has been linked to the onset of juvenile/early onset Parkinson’s disease (PD) is PINK1. There is evidence that supports the therapeutic potential of exercise in the alleviation of PD symptoms. It is possible that exercise may enhance synaptic plasticity, protect against neuro-inflammation and modulate L-Dopa regulated signalling pathways. We explored the effects of exercise onPink1deficientDrosophila melanogasterwhich undergo neurodegeneration and muscle degeneration. We used a ‘power-tower’ type exercise platform to deliver exercise activity toPink1-and age matched wild-type flies. Mitochondrial proteomic profiles responding to exercise were obtained. Of the 516 proteins identified, 105 proteins had different levels betweenPink1-and wild-type (WT) non-exercisedD. melanogaster. Gene ontology enrichment analysis and STRING network analysis highlighted proteins and pathways with altered expression within the mitochondrial proteome. Comparison of thePink1-exercised proteome to WT proteomes showed that exercising thePink1-flies caused their proteomic profile to return towards wild-type levels.
Global transcriptional response ofMethylorubrum extorquensto formaldehyde stress expands the role of EfgA and is distinct from antibiotic translational inhibition
Authors: Bazurto Jannell V. , Riazi Siavash , D’Alton Simon , Deatherage Daniel E. , Bruger Eric L. , Barrick Jeffrey E. , Marx Christopher J. 
Published: January 2021

ABSTRACTThe potency and indiscriminate nature of formaldehyde reactivity upon biological molecules make it a universal stressor. However, some organisms such asMethylorubrum extorquenspossess means to rapidly and effectively mitigate formaldehyde-induced damage. EfgA is a recently identified formaldehyde sensor predicted to halt translation in response to elevated formaldehyde as a means to protect cells. Herein, we investigate growth and changes in gene expression to understand howM. extorquensresponds to formaldehyde with and without the EfgA-formaldehyde-mediated translational response, and how this mechanism compares to antibiotic-mediated translation inhibition. These distinct mechanisms of translation inhibition have notable differences: they each involve different specific players and in addition, formaldehyde also acts as a general, multi-target stressor and a potential carbon source. We present findings demonstrating that in addition to its characterized impact on translation, functional EfgA allows for a rapid and robust transcriptional response to formaldehyde and that removal of EfgA leads to heightened proteotoxic and genotoxic stress in the presence of increased formaldehyde levels. We also found that many downstream consequences of translation inhibition were shared by EfgA-formaldehyde- and kanamycin-mediated translation inhibition. Our work uncovered additional layers of regulatory control enacted by functional EfgA upon experiencing formaldehyde stress, and further demonstrated the importance this protein plays at both transcriptional and translational levels in this model methylotroph.
SLTRiP induces long lasting and protective T-cell memory response
Authors: Quadiri Afshana , Kashif Mohammad , Kalia Inderjeet , Singh Agam Prasad 
Published: January 2021

AbstractMajor developments have been made in the past many years to characterize and explore potential vaccine candidates that can induce host immune responses against parasite. These advances were based on the fact that the induction of host immune responses could effectively target parasite at different stages of its life cycle and thus, abrogatePlasmodiuminfections. The role of T-cells against malaria comes from initial studies on rodents showing these cells could inhibit parasite development during pre-erythrocytic stages. Since then, the importance of the cellular immune responses against malaria has been increasingly emphasized, especially for vaccine development against pre-erythrocytic stages. Previous work in our laboratory has confirmed that SLTRiP confers protection against the pre-erythrocytic stage ofPlasmodiumgrowth in rodents. Here we report that the protection is mainly due to cell mediated immune responses andPbSLTRiP specific cellular memory responses could be efficiently recalled in mice challenged withP. bergheiparasites even after a year following immunization. Our results thereby, highlight the role of the T cell response involved in protection. Characterization of T-cells by intracellular cytokine staining (ICS) revealed that the induced T cells were polyfunctional and involved in secretion of pro-inflammatory cytokines which mediate anti-parasitic activity. The findings contribute to our understanding of the immunological mechanisms underlying the protective vaccines.
Strain variation inBacillus cereusbiofilms and their susceptibility to extracellular matrix-degrading enzymes
Authors: Lim Eun Seob , Baek Seung-Youb , Oh Taeyoung , Koo Minseon , Lee Joo Young , Kim Hyun Jung , Kim Joo-Sung 
Published: January 2021

AbstractBacillus cereusis a foodborne pathogen and can form biofilms on food contact surfaces, which causes food hygiene problems. While it is necessary to understand strain-dependent variation to effectively control these biofilms, strain-to-strain variation in the structure ofB cereusbiofilms is poorly understood. In this study,B. cereusstrains from tatsoi and the ATCC 10987 reference strain were incubated at 30°C to form biofilms in the presence of the extracellular matrix-degrading enzymes DNase I, proteinase K, dispase II, cellulase, amyloglucosidase, and α-amylase to assess the susceptibility to these enzymes. The four strains exhibited four different patterns in terms of biofilm susceptibility to the enzymes as well as morphology of surface-attached biofilms or suspended cell aggregates. DNase I inhibited the biofilm formation of strains ATCC 10987 and BC4 but not of strains BC10 and BC72. This result suggests that some strains may not have extracellular DNA, or their extracellular DNA may be protected in their biofilms. In addition, the strains exhibited different patterns of susceptibility to protein- and carbohydrate-degrading enzymes. While other strains were resistant, strains ATCC 10987 and BC4 were susceptible to cellulase, suggesting that cellulose or its similar polysaccharides may exist and play an essential role in their biofilm formation. Our compositional analysis of strains ATCC 10987 and BC4 suggested that the physicochemical properties of their biofilms are distinct, as calculated by the carbohydrate to protein ratio. Taken together, our study suggests that the extracellular matrix ofB. cereusbiofilms may be highly diverse and provides insight into the diverse mechanisms of biofilm formation amongB. cereusstrains.