bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracking patient clusters over time enables to extract all the information available in the medico-administrative databases
Authors: Lambert Judith , Leutenegger Anne-Louise , Jannot Anne-Sophie , Baudot Anaïs 
Published: August 2022

AbstractContextIdentifying clusters (i.e., subgroups) of patients from the analysis of medico-administrative databases is particularly important to better understand disease heterogeneity. However, the complexity of these databases, in particular due to the presence of truncated longitudinal data, requires adaptation of clustering approaches.ObjectiveWe propose here cluster-tracking approaches to identify clusters of patients from longitudinal data contained in medico-administrative databases.Material and MethodsWe first cluster patients at each age using either the Markov Cluster algorithm (MCL) from patient networks or Kmeans from raw data. We then track the identified clusters over ages to construct cluster-trajectories. We compared our novel approaches with three longitudinal clustering approaches by calculating the silhouette score. As a use-case, we analyzed antithrombotic drugs prescribed from 2008 to 2018 contained in the Échantillon Généraliste des Bénéficiaires (EGB), a French national cohort.ResultsOur cluster-tracking approaches allowed us to identify several cluster-trajectories having clinical significance. Silhouette score comparison between the different approaches reveals that the best score is obtained for the cluster-tracking approaches.ConclusionThe cluster-tracking approaches are a novel and efficient alternative to identify patient clusters from medico-administrative databases by taking into account their specificities.
Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer
Authors: Morel Katherine L. , Hamid Anis A. , Falcón Beatriz G. , Nanda Jagpreet S. , Linder Simon , Bergman Andries M. , Poel Henk van der , Hofland Ingrid , Bekers Elise M. , Trostel Shana , Wilkinson Scott , Ku Anson T. , Burkhart Deborah L. , Kim Minhyung , Kim Jina , Plummer Jasmine T. , You Sungyong , Sowalsky Adam G. , Zwart Wilbert , Sweeney Christopher J. , Ellis Leigh 
Published: August 2022

AbstractPhenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance in androgen indifferent prostate tumors. It is critical to identify mechanisms and actionable targets driving phenotypic plasticity. Here, we report that loss of tristetraprolin (TTP, geneZFP36), an RNA binding protein that regulates mRNA stability increases NF-κB activation and is associated with higher rates of aggressive disease and early recurrence in primary prostate cancer (PCa). We examined the clinical and biological impact ofZFP36loss combined withPTENloss, a known driver of PCa. Combined loss ofPTENandZFP36expression was associated with increased risk of recurrence in multiple independent primary PCa cohorts, and significantly reduced overall survival and time to progression following castration in genetically engineered mouse models.ZFP36loss alters the cell state that is driven byPTENloss, demonstrated by positive enrichment of gene sets including EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3.ZFP36loss also induces enrichment of multiple gene sets involved in cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor dimethylaminoparthenolide induced significant therapeutic responses in tumors withPTENandZFP36co-loss and reversed castration resistance. This work identifies a novel molecular mechanism driving phenotypic plasticity and castration resistance through loss ofZFP36expression, that can be reversed by inhibition of NF-κB activity.
High Resolution Kinetic Characterization and Dynamic Mathematical Modeling of the RIG-I Signaling Pathway and the Antiviral Responses
Authors: Burkart Sandy S. , Schweinoch Darius , Frankish Jamie , Sparn Carola , Wüst Sandra , Urban Christian , Piras Antonio , Pichlmair Andreas , Willemsen Joschka , Kaderali Lars , Binder Marco 
Published: August 2022

ABSTRACTThe pattern recognition receptor RIG-I is essential for the recognition of viral dsRNA and the activation of a cell-autonomous antiviral response. Upon stimulation, RIG-I triggers a signaling cascade leading to the expression of cytokines, most prominently type I and III interferons (IFNs). IFNs are secreted and signal in an auto- and paracrine manner to trigger the expression of a large variety of IFN-stimulated genes, which in concert establish an antiviral state of the cell. While the topology of this pathway has been studied quite intensively, the dynamics, particularly of the RIG-I-mediated IFN induction, is much less understood. Here, we employed electroporation-based transfection to synchronously activate the RIG-I signaling pathway, enabling us to characterize the kinetics and dynamics of cell-intrinsic innate immune signaling to virus infections. By employing an A549 IFNAR1/IFNLR deficient cell line, we could analyze the difference between the primary RIG-I signaling phase and the secondary signaling phase downstream of the IFN receptors. We further used our quantitative data to set up and calibrate a comprehensive dynamic mathematical model of the RIG-I and IFN signaling pathways. This model accurately predicts the kinetics of signaling events downstream of dsRNA recognition by RIG-I as well as the feedback and signal amplification by secreted IFN and JAK/STAT signaling. We have furthermore investigated the impact of various viral immune antagonists on the signaling dynamics experimentally, and we utilized the here described modelling approach to simulate and in silico study these critical virus-host interactions. Our work provides a comprehensive insight into the signaling events occurring early upon virus infection and opens up new avenues to study and disentangle the complexity of the host-virus interface.
Microglia and astrocytes differentially endocytose exosomes facilitating alpha-Synuclein endolysosomal sorting
Authors: Pantazopoulou M. , Alexaki A. , Lamprokostopoulou A. , Delis A. , Coens A. , Melki R. , Pagakis S.N. , Stefanis L. , Vekrellis K. 
Published: August 2022

AbstractExosomes have emerged as key players in cell-to-cell communication in both physiological and pathological processes in the Central Nervous System (CNS). Thus far, the intracellular pathways involved in uptake and trafficking of exosomes within different cell types of the brain (microglia and astrocytes) are poorly understood. In our study, the endocytic processes and subcellular sorting of exosomes were investigated in primary glial cells, particularly linked with the exosome-associated α-synuclein (α-syn) transmission. Mouse microglia and astrocytic primary cultures were incubated with DiI-stained mouse brain-derived exosomes. The internalization and trafficking pathways were analysed in cells treated with pharmacological reagents that block the major endocytic pathways. Brain-derived exosomes were internalized by both glial cell types; however, uptake was more efficient in microglia than in astrocytes. Colocalization of exosomes with early and late endocytic markers (Rab5, Lamp1) indicated that exosomes are sorted to endolysosomes for subsequent processing. Treatment with Cytochalasin D, that blocks actin-dependent phagocytosis and/or macropinocytosis, inhibited exosome entry into glial cells, whereas treatment with inhibitors that strip off cholesterol from the plasma membrane, induced uptake, however differentially altered endosomal sorting. Exosome-associated fibrillar α-Syn was efficiently internalized and detected in Rab5- and Lamp1-positive compartments within microglia. Our study strongly suggests that exosomes enter glial cells through an actin network-dependent endocytic pathway and are sorted to endolysosomes for subsequent processing. Further, brain-derived exosomes are capable of mediating cell-to-glia transmission of pathological α-Syn that is also targeted to the endosomal pathway, suggesting a possible beneficial role in microglia-mediated clearance of toxic protein aggregates, present in numerous neurodegenerative diseases.
Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation
Authors: Festa Lindsay K. , Clyde Abigail E. , Long Caela C. , Roth Lindsay M. , Grinspan Judith B. , Jordan-Sciutto Kelly L. 
Published: August 2022

AbstractWhite matter deficits are a common neuropathologic finding in neurologic disorders, including HIV-associated neurocognitive disorders (HAND). In HAND, the persistence of white matter alterations despite suppressive antiretroviral (ARV) therapy suggests that ARVs may be directly contributing to these impairments. Here, we report that a frontline ARV, bictegravir (BIC), significantly attenuates remyelination following cuprizone-mediated demyelination, a model that recapitulates acute demyelination, but has no impact on already formed mature myelin. Mechanistic studies in vitro revealed that treatment with BIC leads to significant decrease in mature oligodendrocytes accompanied by lysosomal de-acidification and impairment of lysosomal degradative capacity with no alterations in lysosomal membrane permeability or total lysosome number. Activation of the endolysosomal cation channel TRPML1 prevents both lysosomal de-acidification and impairment of oligodendrocyte differentiation by BIC. Lastly, we show that de-acidification of lysosomes by compounds that raise lysosomal pH is sufficient to prevent maturation of oligodendrocytes. Overall, this study has uncovered a critical role for lysosomal acidification in modulating oligodendrocyte function and has implications for neurologic diseases characterized by lysosomal dysfunction and white matter abnormalities.Table of ContentsMain PointsThe antiretroviral, bictegravir, inhibited remyelination through OPC differentiation blockade and had no effect on mature myelinBictegravir inhibits oligodendrocyte differentiation through de-acidification of lysosomes and this was prevented via activation of the lysosomal channel TRPML1De-acidification of lysosomes by other drugs (e.g. bafilomycin A) is sufficient to inhibit oligodendrocyte maturationTable of Contents Image
Diverse responses among wild banana species to vapour pressure deficit, a solution for drought tolerance breeding?
Authors: Eyland David , Gambart Clara , Swennen Rony , Carpentier Sebastien 
Published: August 2022

1AbstractThe predicted rise in global temperature is not only affecting plant functioning directly, but is also increasing air vapour pressure deficit (VPD). The yield of banana is heavily affected by water deficit but so far breeding programs have never addressed the issue. A reduction in transpiration at high VPD has been suggested as a key drought tolerance breeding trait to avoid excessive water loss, hydraulic failure and to increase water use efficiency. In this study, stomatal and transpiration responses under increasing VPD at the leaf and whole-plant level of 8 wild banana (sub)species were evaluated, displaying significant differences in stomatal reactivity. Three different groups were identified under increasing VPD. M. acuminata spp. errans (group I), M. acuminata spp. zebrina (group II) and M. balbisiana (group II) showed the highest transpiration rate limitations to increasing VPD. In contrast to group I, group II only showed strong reductions at high VPD levels, limiting the cost of reduced photosynthesis and strongly increasing their water use efficiency. Group II genotypes thus show favourable responses for high water use efficiency in regions with high VPDs. This provides a basis for the identification of potential parent material within their wild populations for drought tolerance breeding.HighlightWild banana species respond significantly different to water deficit caused by VPD increases and differ in the rate of stomatal reduction, revealing opportunities for drought tolerance breeding.
Culture of human nasal olfactory stem cells and their extracellular vesicles as advanced therapy medicinal products
Authors: Jaloux Charlotte , Bonnet Maxime , Vogtensperger Marie , Witters Marie , Veran Julie , Giraudo Laurent , Sabatier Florence , Michel Justin , Lacroix Romaric , Chareyre Corinne , Legré Regis , Guiraudie-Capraz Gaelle , Féron François 
Published: August 2022

AbstractThe olfactory ecto-mesenchymal stem cell (OE-MSC) are mesenchymal stem cells originating from the lamina propria of the nasal mucosa. They have neurogenic and immune-modulatory properties and showed therapeutic potential in animal models of spinal cord trauma, hearing loss, Parkinsons’s disease, amnesia, and peripheral nerve injury.In this paper we designed a protocol that meet the requirements set by human health agencies to manufacture these stem cells for clinical applications.Once purified, OE-MSCs can be usedper seor expanded in order to get the extracellular vesicles (EV) they secrete. A protocol for the extraction of these vesicles was validated and the EV from the OE-MSC were functionally tested on anin vitromodel.Nasal mucosa biopsies from three donors were used to validate the manufacturing process of clinical grade OE-MSC. All stages were performed by expert staff of the cell therapy laboratory according to aseptic handling manipulations, requiring grade A laminar airflow. Enzymatic digestion provides more rapidly a high number of cells and is less likely to be contaminated. Foetal calf serum was replaced with human platelet lysate and allowed stronger cell proliferation, with the optimal percentage of platelet lysate being 10%. Cultivated OE-MSCs are sterile, highly proliferative (percentage of CFU-F progenitors was 15,5%) and their maintenance does not induce chromosomal rearrangement (karyotyping and chromosomal microarray analysis were normal). These cells express the usual phenotypic markers of OE-MSC. Purification of the EVs was performed with ultracentrifugation and size exclusion chromatography. Purified vesicles expressed the recognized markers of EVs (Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines) and promoted cell differentiation and neurite elongation in a model of neuroblastoma Neuro2a cell line.We developed a safer and more efficient manufacturing process for clinical-grade olfactory stem cells, these cells can now be used in humans. A phase I clinical trial will begin soon.An efficient protocol for the purification of the OE-MSC EVs have been validated. These EVs exert neurogenic propertiesin vitro. More studies are needed to understand the exact mechanisms of action of these EVs and prove their efficacy and safety in animal models.
Ageing impairs protein leveraging in a sex-specific manner in Drosophila melanogaster
Authors: Rushby Helen J. , Andrews Zane B. , Piper Matthew D. W. , Mirth Christen K. 
Published: August 2022

ABSTRACTModifying the relative proportions of macronutrients in an animal’s diet has noteworthy effects on its reproduction, lifelong health, and lifespan. Because of this, a wide range of animals carefully regulate their nutrient intake toward species and stage-specific targets. However, when animals are unable to reach their nutrient target from their existing food resources, they will compromise between overconsuming one nutrient and under-consuming the deficit nutrient. In this study, we used capillary feeding (CAFE) assays to understand the rules of compromise of adult fruit flies (Drosophila melanogaster) of different sex, mating status, and age when constrained to single diets. We found that young male and female D. melanogaster compromised by consuming more food on diets with low protein to carbohydrate (P:C) ratios compared to diets with high P:C ratios. Further, young male and female flies varied their carbohydrate intake significantly more than their protein intake, and female flies varied their carbohydrate intake significantly more than males. To test for effects of mating status on nutrient intake, we compared food intake of young mated and virgin females. We found that both virgin and mated females compromised by consuming more food on the low P:C diet compared to high P:C diets; however, mated females consumed more food than virgin females. As flies aged, they decreased their overall food intake and showed more modest alterations in their food intake across varying P:C diets. Further, mated females ceased to compromise for the protein deficit at a younger age than males. These findings provide new understanding about differences in protein leveraging behaviour across sexes, and how these behaviours change with age.HighlightsYoung fruit flies exhibit protein leveraging behaviour, varying their carbohydrate consumption more than proteinYoung mated female flies vary their carbohydrate consumption significantly more than young malesBoth virgin and mated female flies balance their nutrient intake similarlyAs flies age, their ability to protein leverage declines, and this occurs faster in female flies
Connexin 43 Hemichannels Regulate Mitochondrial ATP Generation, Mobilization, and Mitochondrial Homeostasis against Oxidative Stress
Authors: Zhang Jingruo , Riquelme Manuel A. , Hua Rui , Acosta Francisca M. , Gu Sumin , Jiang Jean X. 
Published: August 2022

AbstractOxidative stress is a major risk factor that causes osteocyte cell death and bone loss. Prior studies primarily focus on the function of cell surface expressed Cx43 channels. Here, we reported a new role of mitochondrial Cx43 (mtCx43) and hemichannels (HCs) in modulating mitochondria homeostasis and function in bone osteocytes under oxidative stress. In osteocyte MLO-Y4 cells, the translocation of Cx43 to mitochondria was increased under H2O2-induced oxidative stress. H2O2increased the mtCx43 level accompanied by elevated mitochondrial Cx43 HC activity determined by dye uptake assay. Cx43 knockdown (KD) by CRISPR-Cas9 lentivirus system resulted in impairment of mitochondrial function, primarily manifested as decreased ATP production. Cx43 KD had reduced intracellular reactive oxidative species (ROS) levels and mitochondrial membrane potential. Additionally, live-cell imaging results demonstrated that the proton flux was dependent upon mtCx43 HCs because its activity was specifically inhibited by an antibody targeting Cx43 C-terminus. The co-localization and interaction of mtCx43 and ATP synthase subunit F (ATP5J2) were confirmed by fluorescence resonance energy transfer (FRET) and a protein pull-down assay. Together, our study suggests that mtCx43 hemichannels regulate mitochondrial ATP generation by mediating K+, H+, and ATP transfer across the mitochondrial inner membrane and the interaction with mitochondrial ATP synthase, leading to enhancing the protection capacity of osteocytes against oxidative insults.
Human endogenous retrovirus-R envelope is a host restriction factor against severe acute respiratory syndrome-coronavirus-2
Authors: Gupta Nidhi , Ansari Shabnam , Verma Rohit , Singh Oinam N , Yadav Mukesh Kumar , Binayke Akshay , Jakhar Kamini , Mani Shailendra , Awasthi Amit , Shalimar  , Nayak Baibaswata , Ranjith-Kumar C.T. , Surjit Milan 
Published: August 2022

AbstractCoronavirus induced disease-19 (COVID-19), caused by the SARS-CoV-2 remains a major global health challenge. Human endogenous retroviruses (HERVs) represent retroviral elements that got integrated into the ancestral human genome. HERVs are important in development and diseases, including cancer, inflammation and viral infections. Here, we analyzed the expression of several HERVs in SARS-CoV-2 infected cells and observed increased activity of HERV-E, HERV-V, HERV-FRD, HERV-MER34, HERV-W and HERV-KHML2. In contrast, HERV-R-envelope was downregulated in cell-based models and COVID-19 patient PBMCs. HERV-R overexpression inhibited SARS-CoV-2 replication, suggesting its antiviral action. Further studies demonstrated the role of extracellular signal-regulated kinase (ERK) in regulating HERV-R antiviral activity. Cross-talk between the ERK and p38 MAPK controls HERV-R envelope synthesis, which in turn modulates the replication of SARS-CoV-2. These findings establish the importance of HERV-R envelope as a host restriction factor against SARS-CoV-2 and illustrate the advantage of integration and evolutionary maintenance of retroviral-elements in the human genome.
EDoF-Miniscope: pupil engineering for extended depth-of-field imaging in a fluorescence miniscope
Authors: Greene Joseph , Xue Yujia , Alido Jeffrey , Matlock Alex , Hu Guorong , Kiliç Kivilcim , Davison Ian , Tian Lei 
Published: August 2022

AbstractExtended depth of field (EDoF) microscopy has emerged as a powerful solution to greatly increase the access into neuronal populations in table-top imaging platforms. Here, we present EDoF-Miniscope, which integrates an optimized thin and lightweight binary diffractive optical element (DOE) onto the gradient refractive index (GRIN) lens of a head-mounted fluorescence miniature microscope, i.e. “miniscope”. We achieve an alignment accuracy of 70 μm to allow a 2.8X depth-of-field extension between the twin foci. We optimize the phase profile across the whole back aperture through a genetic algorithm that considers the primary GRIN lens aberrations, optical property of the submersion media, and axial intensity loss from tissue scattering in a Fourier optics forward model. Compared to other computational miniscopes, our EDoF-Miniscope produces high-contrast signals that can be recovered by a simple algorithm and can successfully capture volumetrically distributed neuronal signals without significantly compromising the speed, signal-to-noise, signal-to-background, and maintain a comparable 0.9-μm lateral spatial resolution and the size and weight of the miniature platform. We demonstrate the robustness of EDoF-Miniscope against scattering by characterizing its performance in 5-μm and 10-μm beads embedded in scattering phantoms. We demonstrate that EDoF-Miniscope facilitates deeper interrogations of neuronal populations in a 100-μm thick mouse brain sample, as well as vessels in a mouse brain. Built from off-the-shelf components augmented by a customizable DOE, we expect that this low-cost EDoF-Miniscope may find utility in a wide range of neural recording applications.