bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial consistency of cell growth direction during organ morphogenesis requires CELLULOSE-SYNTHASE INTERACTIVE1
Authors: Mollier Corentin , Skrzydeł Joanna , Borowska-Wykręt Dorota , Majda Mateusz , Bayle Vincent , Battu Virginie , Totozafy Jean-Chrisologue , Dulski Mateusz , Fruleux Antoine , Wrzalik Roman , Mouille Grégory , Smith Richard S. , Monéger Françoise , Kwiatkowska Dorota , Boudaoud Arezki 
Published: July 2022

AbstractExtracellular matrices generally contain fibril-like polymers that may be organized in parallel arrays. Although their role in morphogenesis has been long recognized, it is still unclear how the subcellular control of fibril synthesis translates into well-defined organ shape. Here, we addressed this question using the Arabidopsis sepal as a model organ. In plants, cell growth is driven by turgor pressure and restrained by the extracellular matrix known as the cell wall. Cellulose is the main load-bearing component of the plant cell wall and cellulose microfibrils are thought to channel growth perpendicularly to their main orientation. Given the key function of CELLULOSE SYNTHASE INTERACTIVE 1 (CSI1) in guidance of cellulose synthesis, we investigated the role of CSI1 in sepal morphogenesis. We observed that sepals fromcsi1mutants are shorter, although their newest cellulose microfibrils are more aligned compared to wild type. Surprisingly, cell growth anisotropy was similar incsi1and wild-type plants. We resolved this apparent paradox using polarized Raman microspectroscopy, live imaging of growing sepals, and bespoke mechanical assays. We found that CSI1 is required for spatial consistency of growth direction across the sepal and for the maintenance of overall organ elongation. Our work illustrates how the subcellular regulation of the extracellular matrix may control morphogenesis at multiple scales.
Biophysical ordering transitions underlie genome 3D re-organization during cricket spermiogenesis
Authors: Orsi Guillermo A. , Tortora Maxime M.C. , Horard Béatrice , Baas Dominique , Kleman Jean-Philippe , Bucevičius Jonas , Lukinavičius Gražvydas , Jost Daniel , Loppin Benjamin 
Published: July 2022

ABSTRACTSpermiogenesis is a radical process of differentiation whereby sperm cells acquire a compact and specialized morphology to cope with the constraints of sexual reproduction while preserving their main cargo, an intact copy of the paternal genome. In animals, this often involves the replacement of most histones by sperm-specific nuclear basic proteins (SNBPs). Yet, how the SNBP-structured genome achieves compaction and accommodates shaping remain largely unknown. Here, we exploited confocal, electron and super-resolution microscopy observations, coupled with polymer modeling simulations to identify the higher-order architecture of sperm chromatin in the needle-shaped nucleus of the emerging model cricket Gryllus bimaculatus. Accompanying spermatid differentiation and shaping, the SNBP-based genome was strikingly reorganized as ~25nm-thick fibers orderly coiled along the elongated nucleus axis. This chromatin spool was further found to achieve large-scale helical twisting in the final stages of spermiogenesis, favoring its ultracompaction. Through a combination of microscopy observations and polymer simulations, we revealed that these dramatic transitions may be recapitulated by a surprisingly simple biophysical principle based on a nucleated rigidification of chromatin linked to the histone-to-SNBP transition within a confined nuclear space. Our work highlights a unique, liquid crystal-like mode of higher-order genome organization in ultracompact cricket sperm completely distinct from nucleosomal chromatin, and establishes a multidisciplinary methodological framework to explore the diversity of non-canonical modes of DNA organization.SIGNIFICANCE STATEMENTAnimal sperm cells are highly compact and atypically shaped compared to other cell types. How DNA is packaged and organized in the 3D space of sperm cell nuclei to cope with these constraints is poorly understood. In this work, we identified an original and elegant solution to this problem in crickets, whereby DNA fibers orderly spool and twist to fit into ultracompact, needle-shaped sperm cells. To understand this reorganization, we modeled DNA fibers in the nucleus as polymers and found that a relatively simple mechanism through which fibers become more rigid bit by bit can largely recapitulate our observations. Our multidisciplinary work highlights a simple solution to compact DNA to extreme levels in specialized nuclei.
TROP2 represents a negative prognostic factor in colorectal adenocarcinoma and its expression is associated with features of epithelial-mesenchymal transition and invasiveness
Authors: Švec Jiří , Šťastná Monika , Janečková Lucie , Hrčkulák Dušan , Vojtěchová Martina , Onhajzer Jakub , Kříž Vítězslav , Galušková Kateřina , Šloncová Eva , Kubovčiak Jan , Pfeiferová Lucie , Hrudka Jan , Matěj Radoslav , Waldauf Petr , Havlůj Lukáš , Kolář Michal , Kořínek Vladimír 
Published: July 2022

AbstractTrophoblastic cell surface antigen 2 (TROP2) is a membrane glycoprotein overexpressed in many solid tumors with poor prognosis, including intestinal neoplasms. In our study, we show that TROP2 is expressed in preneoplastic lesions and its expression is maintained in most colorectal cancer (CRC). High TROP2 positivity correlated with lymph node metastases and poor tumor differentiation and was a negative prognostic factor. To investigate the role of TROP2 in intestinal tumors, we analyzed two mouse models with conditional disruption of the adenomatous polyposis coli (Apc) tumor suppressor gene, human adenocarcinoma samples, patient-derived organoids, and TROP2-deficient tumor cells. We found that Trop2 is produced early after Apc inactivation and its expression is associated with transcription of genes involved in epithelial-mesenchymal transition, regulation of migration, invasiveness, and extracellular matrix remodeling. A functionally similar group of genes was also enriched in TROP2-positive cells from human CRC samples. To decipher the driving mechanism of TROP2 expression, we analyzed its promoter. In human cells, this promoter was activated by β-catenin and additionally by Yes1-associated transcriptional regulator (YAP). The regulation of TROP2 expression by active YAP was verified by YAP knockdown in CRC cells. Our results suggest a possible link between aberrantly activated Wnt/β-catenin signaling, YAP, and TROP2 expression.Simple SummaryColorectal cancer (CRC) is one of the most common cancers worldwide. While systemic treatment of CRC is based on chemotherapy, subsequent therapeutic options are far less effective. Trophoblast cell surface antigen 2 (TROP2) is highly expressed in many carcinomas, including CRC, where its expression correlates with poor prognosis. Anti-TROP2-targeted therapy was approved for the treatment of breast and urothelial carcinomas. We aimed to determine whether TROP2 is a suitable target for the treatment of CRC. We demonstrated that TROP2 expression in CRC correlates with lymph node metastasis and poor tumor differentiation. Analysis of mouse tumor models, patient-derived organoids, and tumor cells revealed that TROP2 expression is associated with features related to epithelial-mesenchymal transition and invasiveness. Our results suggest that TROP2 targeting may be a promising approach, especially in the early phase of treatment.
Antibody recognition of CD4-induced open HIV-1 Env trimers
Authors: Yang Zhi , Dam Kim-Marie A. , Gershoni Jonathan M. , Zolla-Pazner Susan , Bjorkman Pamela J. 
Published: July 2022

AbstractHIV-1 envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. Here, we characterize a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i mAbs) that display characteristics of CD4i antibodies. Binding experiments demonstrate that the V2i mAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i mAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy show recognition by V2i mAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the mAbs with CD4. We also characterize CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, complexed with Env trimer and CD4. CG10 exhibits similar characteristics to the V2i antibodies: i.e., recognition of the open Env conformation, but shows direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection.ImportanceThe RV144 HIV-1 clinical vaccination trial showed mild protection against viral infection. Antibody responses to the V1V2 region of HIV-1 Env gp120 were correlated inversely with the risk of infection. In addition, antibodies targeting V1V2 have been correlated with protections from SIV and SHIV infections in non-human primates. We structurally characterized V2i antibodies directed against V1V2 isolated from HIV-1 infected humans in complex with open Env trimers bound to the host receptor CD4. We also characterized a CD4i antibody that interacts with CD4 as well as the gp120 subunit of an open Env trimer. Our study suggests how V2i and CD4i antibodies were elicited during HIV-1 infection.
Ethnic disparities in medication adherence? A systematic review examining the association between ethnicity and antidiabetic medication adherence
Authors: Asiri Rayah , Todd Adam , Robinson Anna , Husband Andy 
Published: July 2022

AbstractObjectivesAdherence to prescribed medication is an essential component of diabetes management to obtain optimal outcomes. Understanding the relationship between medication adherence and ethnicity is key in optimising treatment for all people with different chronic illnesses, including those with diabetes. The aim of this review is to examine whether the adherence to antidiabetic medications differed by ethnicity among people with diabetes.MethodsA systematic review was conducted of studies reporting adherence to antidiabetic medication amongst people from different ethnic groups. MEDLINE, Embase, CINAHL, and PsycINFO were searched from their inception to June 2021 for quantitative studies with a specific focus on studies assessing adherence to antidiabetic medications (PROSPERO: CRD42021278392). The Joanna Briggs Institute critical appraisal checklist and a second checklist designed for studies using retrospective databases were used to assess study quality. A narrative synthesis approach was used to summarize the results based on the medication adherence measures.ResultsOf 15,685 citations screened, 39 studies that included observational retrospective database research and cross-sectional studies were selected, each of which involved diverse ethnic groups from different settings. This review identified a difference in the adherence to antidiabetic medications by ethnicity in 37 studies, despite adjustment for several confounding variables that may otherwise explain these differences.ConclusionThis review revealed that adherence to antidiabetic medication differed by ethnicity. Further research is needed to explore the ethnicity-related factors that may provide an explanation for these disparities.
Engineering human Mucosal Associated Invariant T (MAIT) cells with chimeric antigen receptors for cancer immunotherapy1
Authors: Dogan Mikail , Karhan Ece , Kozhaya Lina , Placek Lindsey , Chen Xin , Yigit Mesut , Unutmaz Derya 
Published: July 2022

AbstractEngineering immune cells with chimeric antigen receptors (CAR) is a promising technology in cancer immunotherapy. Besides classical cytotoxic CD8+ T cells, innate cell types such as NK cells have also been used to generate CAR-T or CAR-NK cells. Here we devised an approach to program a non-classical cytotoxic T cell subset called Mucosal Associated Invariant T (MAIT) cells into effective CAR-T cells against B cell lymphoma and breast cancer cells. Accordingly, we expressed anti-CD19 and anti-Her2 CARs in activated primary human MAIT cells and CD8+ T cells, expanded them in vitro and compared their cytotoxicity against tumor cell targets. We show upon activation through CARs, CAR-MAIT cells exhibit high levels of cytotoxicity towards target cells, comparable to CD8+ CAR-T cells, but interestingly expressed lower levels of IFN-γ than conventional CAR CD8+ T cells. Additionally, in the presence of vitamin B2 metabolite 5-ARU, which is a conserved compound that activates MAIT cells through MHC-I related (MR1) protein, MAIT cells killed MR1-expressing target breast cancer and B cell lymphoma cell lines in a dose dependent manner. Thus, MAIT cells can be genetically edited as CAR-T cells or mobilized and expanded by MR1 ligands as an off-the-shelf novel approach to cell-based cancer immunotherapy strategies while being comparable to conventional methods in effectivity.Key PointsMAIT cells expressing CARs effectively kill CD19 and Her2 expressing targetsCAR-MAITs display strong cytotoxicity with lower TNF-γ compared to CD8+ CAR-T cells
Assembly mechanism and cryoEM structure of RecA recombination nucleofilaments from Streptococcus pneumoniae
Authors: Maud Hertzog , Noé Perry Thomas , Pauline Dupaigne , Sandra Serres , Violette Morales , Anne-Lise Soulet , Bell Jason C , Emmanuel Margeat , Stephen Kowalczykowski , Le Cam Eric , Rémi Fronzes , Patrice Polard 
Published: July 2022

AbstractRecA-mediated Homologous Recombination (HR) is a key mechanism for genome maintenance and plasticity in bacteria. It proceeds through RecA assembly into a dynamic filament on ssDNA, the presynaptic filament, which mediates DNA homology search and ordered DNA strand exchange. Here, we combined structural, single molecule and biochemical approaches to characterize the ATP-dependent assembly mechanism of the presynaptic filament of RecA from Streptococcus pneumoniae (SpRecA), in comparison to the Escherichia coli RecA (EcRecA) paradigm. EcRecA polymerization on ssDNA is assisted by the Single-Stranded DNA Binding (SSB) protein, which unwinds ssDNA secondary structures that block EcRecA nucleofilament growth. We report that neither of the two paralogous pneumococcal SSBs could assist SpRecA polymerization on ssDNA. Instead, we found that the conserved RadA helicase promotes this SpRecA nucleofilamentation in an ATP-dependent manner. This allowed us to solve the atomic structure of such a long native SpRecA nucleopolymer by cryoEM stabilized with ATPγS. It was found to be equivalent to the crystal structure of the EcRecA filament with a marked difference in how RecA mediates nucleotide orientation in the stretched ssDNA. Then, our results show that SpRecA and EcRecA HR activities are different, in correlation with their distinct ATP-dependent ssDNA binding modes.
Infection cycle and phylogeny of the Polinton-like virus Phaeocystis globosa virus virophage-14T
Authors: Roitman Sheila , Rozenberg Andrey , Lavy Tali , Brussaard Corina P. D. , Kleifeld Oded , Béjà Oded 
Published: July 2022

AbstractVirophages are small dsDNA viruses dependent on a nucleocytoplasmic large-DNA virus infection of a cellular host for replication. Putative virophages infecting algal hosts are classified together with polinton-like viruses, transposable elements widely found in algal genomes, yet the lack of isolated strains raises questions about their existence as independent entities. In this work we isolated and characterized a virophage (PgVV-14T) co-infecting Phaeocystis globosa with the Phaeocystis globosa virus-14T (PgV-14T). PgVV-14T decreases the fitness of its PgV-14T viral host, yet it does not salvage the cellular host population. We found viral-like elements resembling PgVV-14T in Phaeocystis genomes, suggesting that these virophages are capable of integrating to the cellular host genome, bridging the gap between Polinton-like viruses and virophages. This system, with a giant virus, a virophage and endogenous viral elements preying on an algal host, presents an opportunity to gain a better understanding on the evolution of eukaryotes and their viruses.
P2G3 human monoclonal antibody neutralizes SARS-CoV-2 Omicron subvariants including BA.4 and BA.5 and Bebtelovimab escape mutants
Authors: Turelli Priscilla , Fenwick Craig , Raclot Charlène , Genet Vanessa , Pantaleo Giuseppe , Trono Didier 
Published: July 2022

AbstractThe rapid evolution of SARS-CoV-2 has led to a severe attrition of the pool of monoclonal antibodies still available for COVID-19 prophylaxis or treatment. Omicron subvariants notably escape most antibodies developed so far, with Bebtelovimab last amongst clinically approved therapeutic antibodies to display still good activity against all of them including the currently dominant BA.4/BA.5. We recently described P2G3, a broadly active SARS-CoV-2 monoclonal antibody, which targets a region of Spike partly overlapping with the site recognized by Bebtelovimab. Here, we reveal that P2G3 efficiently neutralizes SARS-CoV-2 omicron subvariants including BA.4/BA.5. We further demonstrate that P2G3 neutralizes Omicron BA.2 and BA.4 mutants escaping Bebtelovimab blockade, whereas the converse is not true.FundingEU COVICIS program; private foundation advised by CARIGEST SA.
Chaperone-Directed Ribosome Repair after Oxidative Damage
Authors: Yang Yoon-Mo , Jung Youngeun , Abegg Daniel , Adibekian Alexander , Carroll Kate , Karbstein Katrin 
Published: July 2022

AbstractReactive oxygen species are ubiquitous in cells, where they damage RNA and protein. While relief mechanisms, including effects on translation, have been described, whether ribosomes are functionally compromised by oxidation, and how this damage is mitigated, remains unknown. Here we show that cysteines in ribosomal proteins, including Rps26, are readily oxidized and rendered non-functional, which is exacerbated when yeast are exposed to H2O2. Oxidized Rps26 is released from ribosomes by its chaperone Tsr2, which allows for repair of the damaged ribosomes with newly made Rps26. Ribosomes containing damaged Rpl10 or Rpl23 are similarly repaired by their chaperones, Sqt1 and Bcp1. Ablation of this pathway impairs growth, which is exacerbated under oxidative stress. These findings reveal a novel mechanism for chaperone-mediated ribosome repair with implications for aging and health.One-Sentence SummaryChaperones repair thiol-oxidized ribosomes by release of damaged components and incorporation of newly made ribosomal proteins.
Disruption of theAspergillus fumigatusRNA interference machinery alters the conidial transcriptome
Authors: Kelani Abdulrahman A. , Bruch Alexander , Rivieccio Flora , Visser Corissa , Krüger Thomas , Weaver Danielle , Pan Xiaoqing , Schäuble Sascha , Panagiotou Gianni , Kniemeyer Olaf , Bromley Michael J. , Bowyer Paul , Barber Amelia E. , Brakhage Axel A. , Blango Matthew G. 
Published: July 2022

ABSTRACTThe RNA interference (RNAi) pathway has evolved numerous functionalities in eukaryotes, with many on display in Kingdom Fungi. RNAi can regulate gene expression, facilitate drug resistance, or even be altogether lost to improve growth potential in some fungal pathogens. In the WHO fungal priority pathogen,Aspergillus fumigatus, the RNAi system is known to be intact and functional. To extend our limited understanding ofA. fumigatusRNAi, we first investigated the genetic variation in RNAi-associated genes in a collection of 217 environmental and 83 clinical genomes, where we found that RNAi components are conserved even in clinical strains. Using endogenously expressed inverted-repeat transgenes complementary to a conditionally essential gene (pabA) or a nonessential gene (pksP), we determined that a subset of the RNAi componentry is active in inverted-repeat transgene silencing in conidia and mycelium. Analysis of mRNA-seq data from RNAi double-knockout strains linked theA. fumigatusdicer-like enzymes (DclA/B) and RNA-dependent RNA polymerases (RrpA/B) to regulation of conidial ribosome biogenesis genes; however, surprisingly few endogenous small RNAs were identified in conidia that could explain this broad change. Although RNAi was not clearly linked to growth or stress response defects in the RNAi knockouts, serial passaging of RNAi knockout strains for six generations resulted in lineages with diminished spore production over time, indicating that loss of RNAi can exert a fitness cost on the fungus. Cumulatively,A. fumigatusRNAi appears to play an active role in defense against double-stranded RNA species alongside a previously unappreciated housekeeping function in regulation of conidial ribosomal biogenesis genes.
iPHoP: an integrated machine-learning framework to maximize host prediction for metagenome-assembled virus genomes
Authors: Roux Simon , Camargo Antonio Pedro , Coutinho Felipe H. , Dabdoub Shareef M. , Dutilh Bas E. , Nayfach Stephen , Tritt Andrew 
Published: July 2022

AbstractThe extraordinary diversity of viruses infecting bacteria and archaea is now primarily studied through metagenomics. While metagenomes enable high-throughput exploration of the viral sequence space, metagenome-derived genomes lack key information compared to isolated viruses, in particular host association. Different computational approaches are available to predict the host(s) of uncultivated viruses based on their genome sequences, but thus far individual approaches are limited either in precision or in recall, i.e. for a number of viruses they yield erroneous predictions or no prediction at all. Here we describe iPHoP, a two-step framework that integrates multiple methods to provide host predictions for a broad range of viruses while retaining a low (<10%) false-discovery rate. Based on a large database of metagenome-derived virus genomes, we illustrate how iPHoP can provide extensive host prediction and guide further characterization of uncultivated viruses. iPHoP is available at https://bitbucket.org/srouxjgi/iphop, through a Bioconda recipe, and a Docker container.