bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells
Authors: Follain Gautier , Osmani Naël , Mercier Luc , Garcia-Leon Maria Jesus , Busnelli Ignacio , Pichot Angélique , Paul Nicodème , Carapito Raphaël , Bahram Siamak , Lefebvre Olivier , Goetz Jacky G. 
Published: July 2020

Tumor progression and metastatic dissemination are driven by cell-intrinsic and biomechanical cues that favor the growth of life-threatening secondary tumors. We recently identified prometastatic vascular regions with blood flow profiles that are permissive for the arrest of circulating tumor cells. We have further established that such flow profiles also control endothelial remodeling, which favors extravasation of arrested CTCs. Yet, how shear forces control endothelial remodeling is unknown. In the present work, we aimed at dissecting the cellular and molecular mechanisms driving blood flow-dependent endothelial remodeling. Transcriptomic analysis revealed that blood flow modulated several signaling pathways in endothelial cells. More specifically, we observed that VEGFR signaling was significantly enhanced. Using a combination of in vitro microfluidics and intravital imaging in zebrafish embryos, we now demonstrate that the early flow-driven endothelial response can be prevented with sunitinib, a pan-inhibitor of VEGFR signaling. Embryos treated with sunitinib displayed reduced endothelial remodeling and subsequent metastatic extravasation. These results confirm the importance of endothelial remodeling as a driving force of CTC extravasation and metastatic dissemination. Furthermore, the present work suggests that therapies targeting endothelial remodeling might be a relevant clinical strategy in order to impede metastatic progression.Highlights-Flow profiles that are permissive for metastasis stimulate the VEGFR pathway-Flow-dependent VEGFR signaling favors extravasation of CTCs through endothelial remodeling-Inhibition of VEGFR signaling suppresses early flow-driven endothelial response
Identifying signaling genes in spatial single cell expression data
Authors: Li Dongshunyi , Ding Jun , Bar-Joseph Ziv 
Published: July 2020

AbstractMotivationRecent technological advances enable the profiling of spatial single cell expression data. Such data presents a unique opportunity to study cell-cell interactions and the signaling genes that mediate them. However, most current methods for the analysis of this data focus on unsupervised descriptive modeling, making it hard to identify key signaling genes and quantitatively assess their impact.ResultsWe developed aMixture ofExperts forSpatialSignaling genesIdentification (MESSI) method to identify active signaling genes within and between cells. The mixture of experts strategy enables MESSI to subdivide cells into subtypes. MESSI relies on multi-task learning using information from neighboring cells to improve the prediction of response genes within a cell. Applying the methods to three spatial single cell expression datasets, we show that MESSI accurately predicts the levels of response genes, improving upon prior methods and provides useful biological insights about key signaling genes and subtypes of excitatory neuron cells.AvailabilityMESSI is available at:https://github.com/doraadong/MESSIContactzivbj@cs.cmu.edu
Essentially leading antibody production: An investigation of amino acids, myeloma and natural V-region signal peptides in producing Pertuzumab and Trastuzumab variants
Authors: Ling Wei-Li , Su Chinh Tran-To , Lua Wai-Heng , Poh Jun-Jie , Ng Yuen-Ling , Wipat Anil , Gan Samuel Ken-En 
Published: July 2020

AbstractBoosting the production of recombinant therapeutic antibodies is crucial in both academic and industry settings. In this work, we investigated the usage of varying signal peptides by antibody genes and their roles in recombinant transient production. Comparing myeloma and the native signal peptides of both heavy and light chains in 168 antibody permutation variants, we performed a systematic analysis, finding amino acids counts to be involved in antibody production to construct a model for predicting co-transfection transient recombinant antibody production rates using the HEK293 system. The findings also provide insights into the usage of the large repertoire of antibody signal peptides.
The Drosophila MOZ homolog Enok controls Notch-dependent induction of the RUNX genelozengeindependently of its histone-acetyl transferase activity
Authors: Genais Thomas , Gigan Delhia , Augé Benoit , Moussalem Douaa , Waltzer Lucas , Haenlin Marc , Gobert Vanessa 
Published: July 2020

AbstractThe human KAT6 lysine acetyltransferase MOZ has been shown to be an essential player in the field of normal and malignant hematopoiesis. It belongs to a highly conserved family of epigenetic factors and remodels chromatin by acetylating histone tails in association with its partners of the ING5 complex. Here, we report that its Drosophila counterpart Enok is required during larval hematopoiesis to control the Notch-dependent induction of circulating crystal cells. In particularenokis essential to allow expression of the RUNX factor Lozenge (Lz) that controls the crystal cell specific transcriptional program. We demonstrate that this function involves neither the Eaf6 and Ing5 subunits of the Drosophila ING5 complex, nor Enok own acetyltransferase activity. We identify inlzthird intron a hematopoietic enhancer, which is both required to promote expression in Notch-activated crystal cell precursors in anenok-dependent manner and bound by Enok. The non-catalytic mode of action of Enok is likely conserved in MOZ/KAT6 proteins and might be of high relevance in mammalian hematopoiesis, whether normal or malignant.
Modelling white matter in gyral blades as a continuous vector field
Authors: Cottaar Michiel , Bastiani Matteo , Boddu Nikhil , Glasser Matthew , Haber Suzanne , van Essen David C. , Sotiropoulos Stamatios N. , Jbabdi Saad 
Published: July 2020

1AbstractMany brain imaging studies aim to measure structural connectivity with diffusion tractography. However, biases in tractography data, particularly near the boundary between white matter and cortical grey matter can limit the accuracy of such studies. When seeding from the white matter, streamlines tend to travel parallel to the convoluted cortical surface, largely avoiding sulcal fundi and terminating preferentially on gyral crowns. When seeding from the cortical grey matter, streamlines generally run near the cortical surface until reaching deep white matter. These so-called “gyral biases” limit the accuracy and effective resolution of cortical structural connectivity profiles estimated by tractography algorithms, and they do not reflect the expected distributions of axonal densities seen in invasive tracer studies or stains of myelinated fibres. We propose an algorithm that concurrently models fibre density and orientation using a divergence-free vector field within gyral blades to encourage an anatomically-justified streamline density distribution along the cortical white/grey-matter boundary while maintaining alignment with the diffusion MRI estimated fibre orientations. Usingin vivodata from the Human Connectome Project, we show that this algorithm reduces tractography biases. We compare the structural connectomes to functional connectomes from resting-state fMRI, showing that our model improves cross-modal agreement. Finally, we find that after parcellation the changes in the structural connectome are very minor with slightly improved interhemispheric connections (i.e, more homotopic connectivity) and slightly worse intrahemispheric connections when compared to tracers.
Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
Authors: Schloer Sebastian , Brunotte Linda , Goretzko Jonas , Mecate-Zambrano Angeles , Korthals Nadia , Gerke Volker , Ludwig Stephan , Rescher Ursula 
Published: July 2020

AbstractThe Corona Virus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective, and globally available pharmaceuticals that inhibit SARS-CoV-2 entry and ameliorate COVID-19. In this study, we explored the use of small compounds acting on the homeostasis of the endolysosomal host-pathogen interface, to fight SARS-CoV-2 infection. We find that fluoxetine, a widely used antidepressant and a functional inhibitor of acid sphingomyelinase (FIASMA), efficiently inhibited the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects and also exerted potent antiviral activity against two currently circulating influenza A virus subtypes, an effect which was also observed upon treatment with the FIASMAs amiodarone and imipramine. Mechanistically, fluoxetine induced both impaired endolysosomal acidification and the accumulation of cholesterol within the endosomes. As the FIASMA group consists of a large number of small compounds that are well-tolerated and widely used for a broad range of clinical applications, exploring these licensed pharmaceuticals may offer a variety of promising antivirals for host-directed therapy to counteract enveloped viruses, including SARS-CoV-2 and COVID 19.
Charged Pore-lining Residues are Required for Normal Channel Kinetics in the Eukaryotic Mechanosensitive Ion Channel MSL1
Authors: Schlegel Angela M. , Haswell Elizabeth S. 
Published: July 2020

ABSTRACTMechanosensitive (MS) ion channels are widespread mechanisms for cellular mechanosensation that can be directly activated by membrane tension. The well-studied MscS family of MS ion channels is found in bacteria, archaea, and plants. MscS-Like (MSL)1 is localized to the inner mitochondrial membrane ofArabidopsis thaliana, where it is required for normal mitochondrial responses to oxidative stress. LikeEscherichia coliMscS, MSL1 has a pore-lining helix that is kinked. However, in MSL1 this kink is comprised of two charged pore-lining residues, R326 and D327. Using single channel patch-clamp electrophysiology inE. coli, we show that altering the size and charge of R326 and D327 leads to dramatic changes in open state dwell time. Modest changes in gating pressure and open state stability were also observed while no effects on channel rectification or conductance were detected. MSL1 channel variants had differing physiological function inE. colihypoosmotic shock assays, without clear correlation between function and particular channel characteristics. Taken together, these results demonstrate that altering pore-lining residue charge and size disrupts normal channel state stability and gating transitions, and led us to propose the “sweet spot” model. In this model, the transition to the closed state is facilitated by attraction between R326 and D327 and repulsion between R326 residues of neighboring monomers. In the open state, expansion of the channel reduces inter-monomeric repulsion, rendering open state stability influenced mainly by attractive forces. This work provides insight into how unique charge-charge interactions can be combined with an otherwise conserved structural feature to help modulate MS channel function.
Computational and experimental characterization of the novel ECM glycoprotein SNED1 and prediction of its interactome
Authors: Vallet Sylvain D. , Davis Martin N. , Barqué Anna , Ricard-Blum Sylvie , Naba Alexandra 
Published: July 2020

ABSTRACTThe extracellular matrix (ECM) protein SNED1 has been shown to promote breast cancer metastasis and control neural crest cell-specific craniofacial development, but the cellular and molecular mechanisms by which it does so remain unknown. ECM proteins exert their functions by binding to cell surface receptors, sequestering growth factors, and interacting with other ECM proteins, actions that can be predicted using knowledge of protein’s sequence, structure and post-translational modifications. Here, we combined in-silico and in-vitro approaches to characterize the physico-chemical properties of SNED1 and infer its putative functions. To do so, we established a mammalian cell system to produce and purify SNED1 and its N-terminal fragment, which contains a NIDO domain. We have determined experimentally SNED1’s potential to be glycosylated, phosphorylated, and incorporated into insoluble ECM produced by cells. In addition, we used biophysical and computational methods to determine the secondary and tertiary structures of SNED1 and its N-terminal fragment. The tentative ab-initio model we built of SNED1 suggests that it is an elongated protein presumably able to bind multiple partners. Using computational predictions, we identified 114 proteins as putative SNED1 interactors. Pathway analysis of the newly-predicted SNED1 interactome further revealed that binding partners of SNED1 contribute to signaling through cell surface receptors, such as integrins, and participate in the regulation of ECM organization and developmental processes. Altogether, we provide a wealth of information on an understudied yet important ECM protein with the potential to decipher its functions in physiology and diseases.
Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions
Authors: Kumbhar Ramhari , Perren Jullian , Gong Fade , Corujo David , Medina Frank , Matouschek Andreas , Buschbeck Marcus , Miller Kyle M. 
Published: July 2020

AbstractThe histone demethylase KDM5A removes histone H3 lysine 4 methylation, which is involved in transcription and DNA damage responses (DDR). While DDR functions of KDM5A have been identified, how KDM5A recognizes DNA lesion sites within chromatin is unknown. Here, we identify two factors that act upstream of KDM5A to promote its association with DNA damage sites. We have identified a non-canonical poly(ADP-ribose), (PAR), binding region unique to KDM5A. Loss of the PAR-binding region or treatment with PAR polymerase (PARP) inhibitors (PARPi) blocks KDM5A-PAR interactions and DNA repair functions of KDM5A. The histone variant macroH2A1.2 is also specifically required for KDM5A recruitment and functions at DNA damage sites, including homology-directed repair of DNA double-strand breaks and repression of transcription at DNA breaks. Overall, this work reveals the importance of PAR-binding and macroH2A1.2 in KDM5A recognition of damage sites that drive transcriptional and repair activities at DNA breaks within chromatin that are essential for maintaining genome integrity.SummaryThe histone demethylase KDM5A demethylates H3K4 to promote repair and transcriptional responses at DNA breaks. We identified poly(ADP-ribose)-binding and macroH2A1.2 as modulators of KDM5A association with DNA damage sites, revealing how KDM5A engages DNA breaks within chromatin.
RNA-binding protein RBM3 negatively regulates innate lymphoid cells (ILCs) and lung inflammation
Authors: Badrani Jana H. , Amadeo Michael , Cavagnero Kellen , Naji Luay H. , Lund Sean J. , Leng Anthea , Lacasa Lee , Strohm Allyssa , Kim Hyojoung , Baum Rachel E. , Khorram Naseem , Mondal Monalisa , Seumois Grégory , Pilotte Julie , Vanderklish Peter W. , Doherty Taylor A. 
Published: July 2020

AbstractInnate lymphoid cells (ILCs) promote lung inflammation through cytokine production in diseases such as asthma. RNA-binding proteins (RBPs) are critical post-transcriptional regulators of cellular function, including inflammatory responses, though the role of RBPs in innate lymphoid cells is unknown. Here, we demonstrate that RNA-binding motif 3 (RBM3) is one of the most highly expressed RBPs in Thy1.2+ lung ILCs after fungal allergen challenge and is further induced by epithelial cytokines TSLP and IL-33 in both human and mouse ILCs. Single (rbm3−/−) and double (rbm3−/−rag2−/−) knockout mice exposed via the airway to the asthma-associated fungal allergen Alternaria alternata displayed increases in eosinophilic lung inflammation and ILC activation compared to control mice. In addition to increased Th2 cytokine production, rbm3−/− ILCs produced elevated IL-17A. The negative regulation by RBM3 in ILC responses was direct as purified rbm3−/− ILCs were hyperinflammatory in vitro and in vivo after stimulation with IL-33. Transcriptomic analysis by RNA-sequencing of rbm3−/− lung ILCs showed increased type 2 and 17 cytokines as well as global expression differences in critical cytokines, receptors, transcription factors, and survival transcripts compared with WT ILCs. Intriguingly, these transcript changes did not correlate with the presence of AU-rich elements (AREs), which RBM3 is known to bind. Thus, regulation of ILC responses by RNA-binding proteins offers novel mechanistic insight into lung ILC biology and ILC-driven inflammatory diseases.
Modulation of the mTOR pathway plays a central role in dendritic cell functions after Echinococcus granulosus antigen recognition
Authors: Rodrigues Christian Rodriguez , Nicolao María Celeste , Chop Maia , Plá Natalia , Massaro Mora , Loos Julia , Cumino Andrea C. 
Published: July 2020

1.AbstractImmune evasion is a hallmark of persistent echinococcal infection, comprising modulation of innate immune cells and antigen-specific T cell responses. However, recognition ofEchinococcus granulosusby dendritic cells (DCs) is a key determinant of the host’s response to this parasite. Given that mTOR signaling pathway has been described as a regulator linking metabolism and immune function in DCs, we reported for the first time in these cells, global translation levels, antigen uptake, phenotype, cytokine transcriptional levels, and splenocyte priming activity upon recognition of the hydatid fluid (HF) and the highly glycosylated laminar layer (LL). We found that LL induced a slight up-regulation of CD86 and MHC II in DCs and also stimulated the production of IL-6 and TNF-α. By contrast, HF did not increase the expression of any co-stimulatory molecules, but also down-modulated CD40 and stimulated the expression of the anti-inflammatory cytokine IL-10. Both parasitic antigens promoted protein synthesis through mTOR activation. The use of rapamycin decreased the expression of the cytokines tested, empowered the down-modulation of CD40 and also reduced splenocyte proliferation. Finally, we showed thatE. granulosusantigens increase the amounts of LC3-positive structures in DCs which play critical roles in the presentation of these antigens to T cells.
Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories
Authors: Su Yapeng , Chen Daniel , Lausted Christopher , Yuan Dan , Choi Jongchan , Dai Cheng , Voillet Valentin , Scherler Kelsey , Troisch Pamela , Duvvuri Venkata R. , Baloni Priyanka , Qin Guangrong , Smith Brett , Kornilov Sergey , Rostomily Clifford , Xu Alex , Li Jing , Dong Shen , Rothchild Alissa , Zhou Jing , Murray Kim , Edmark Rick , Hong Sunga , Jones Lesley , Zhou Yong , Roper Ryan , Mackay Sean , O’Mahony D. Shane , Dale Christopher R , Wallick Julie A , Algren Heather A , Michael Zager A , Magis Andrew , Wei Wei , Price Nathan D. , Huang Sui , Subramanian Naeha , Wang Kai , Hadlock Jennifer , Hood Leroy , Aderem Alan , Bluestone Jeffrey A. , Lanier Lewis L. , Greenberg Phil , Gottardo Raphael , Davis Mark M. , Goldman Jason D. , Heath James R. ,   the ISB-Swedish COVID19 Biobanking Unit
Published: July 2020

SUMMARYHost immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+and CD4+T cells, and cytotoxic CD4+T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.
Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1
Authors: Pokrishevsky Edward , DuVal Michèle G. , McAlary Luke , Louadi Sarah , Pozzi Silvia , Roman Andrei , Plotkin Steven S , Dijkstra Anke , Julien Jean-Pierre , Allison W. Ted , Cashman Neil R. 
Published: July 2020

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). Co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein G85R-GFP in HEK293FT cells, and promotes synergistic axonopathy in zebrafish. This pathological interaction is dependent upon natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in HEK293FT cells, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in HEK293FT cells, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.