bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genome ofLitomosoides sigmodontisilluminates the origins of Y chromosomes in filarial nematodes
Authors: Stevens Lewis , Kieninger Manuela , Chan Brian , Wood Jonathan M D , de la Rosa Pablo Gonzalez , Allen Judith , Blaxter Mark 
Published: August 2023

AbstractHeteromorphic sex chromosomes are usually thought to have originated from a pair of autosomes that acquired a sex-determining locus and subsequently stopped recombining, leading to degeneration of the sex-limited chromosome. In contrast, in rhabditid nematodes, sex is determined by an X-chromosome counting mechanism and males are hemizygous for one or more X chromosomes (XX/X0). Some species of filarial nematodes, including important parasites of humans, have heteromorphic XX/XY systems. It has been assumed that sex is determined by a Y-linked locus in these species. However, karyotypic analyses suggested that filarial Y chromosomes are derived from the unfused autosome following an X-to-autosome fusion. Here, we generated a chromosome-level reference genome forLitomosoides sigmodontis, a filarial nematode with the ancestral filarial karyotype and sex determination mechanism (XX/X0). We mapped the assembled chromosomes to the rhabditid nematode ancestral linkage (or Nigon) elements. We found that theL. sigmodontisX chromosome was formed from a fusion of NigonX (the ancestrally X-linked element) and NigonD (ancestrally autosomal) that occurred in the last common ancestor of all filarial nematodes. In the two filarial lineages with XY systems, the X chromosomes were formed from two recent and independent fusions of the ancestral X chromosome with different autosomal Nigon elements. In both lineages, the region shared by the neo-X and neo-Y chromosomes is within the ancestrally autosomal portion of the X, confirming that the filarial Y chromosomes are derived from unfused autosomes. Sex determination in XY filarial nematodes therefore likely continues to operateviathe ancestral X-chromosome counting mechanism, rather thanviaa neo-Y-linked sex-determining locus.
DOCK2-deficiency causes defects in anti-viral T cell responses and poor control of herpes simplex virus infection
Authors: Randall Katrina L. , Flesch Inge E.A. , Mei Yan , Miosge Lisa A. , Aye Racheal , Yu Zhijia , Domaschenz Heather , Hollett Natasha A. , Russell Tiffany A. , Stefanovic Tijana , Wong Yik Chun , Goodnow Christopher C. , Bertram Edward M. , Enders Anselm , Tscharke David C. 
Published: August 2023

AbstractThe expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defence against infectious diseases. However, patients with these diseases are by definition rare. In addition, any analysis is complicated by treatments and co-morbid infections requiring the use of mouse models for detailed investigations. Here we develop a mouse model of DOCK2 immunodeficiency and demonstrate that these mice have delayed clearance of herpes simplex virus type 1 (HSV-1) infections. Further, we found that they have a critical, cell intrinsic role of DOCK2 in the clonal expansion of anti-viral CD8+T cells despite normal early activation of these cells. Finally, while the major deficiency is in clonal expansion, the ability of primed and expanded DOCK2-deficient CD8+T cells to protect against HSV-1-infection is also compromised. These results provide a contributing cause for the frequent and devastating viral infections seen in DOCK2-deficient patients and improve our understanding of anti-viral CD8+T cell immunity.
Elucidating the Membrane Binding Process of a Disordered Protein: Dynamic Interplay of Anionic Lipids and the Polybasic Region
Authors: Alavizargar Azadeh , Gass Maximilian , Krahn Michael P. , Heuer Andreas 
Published: August 2023

AbstractIntrinsically disordered regions of proteins are responsible for many biological processes such as in the case of liver kinase LKB1 – a serine/threonine kinase, relevant for cell proliferation and cell polarity. LKB1 itself becomes fully activated upon recruitment to the plasma membrane by binding of its disordered C-terminal polybasic motif consisting of eight lysines/arginines to phospholipids. Here we present extensive molecular dynamics (MD) simulations of the polybasic motif interacting with a model membrane composed of phosphatidylcholin (POPC) and phosphatidic acid (PA) and cell culture experiments. Protein-membrane binding effects are due to the electrostatic interactions between the polybasic amino acids and PAs. For significant binding the first three lysines turn out to be dispensable, which was also recapitulated in cell culture using transfected GFP-LKB1 variants. LKB1-membrane binding results in a non-monotonous changes in the structure of the protein as well as of the membrane, in particular accumulation of PAs and reduced thickness at the protein-membrane contact area. The protein-lipid binding turns out to be highly dynamic due to an interplay of PA-PA repulsion and protein-PA attraction. The thermodynamics of this interplay is captured by a statistical fluctuation model, which allows the estimation of both energies. Quantification of the significance of each polar amino acid in the polybasic provides detailed insights into the molecular mechanism of the protein-membrane binding of LKB1. These results can be likely transferred to other proteins, which interact by intrinsically disordered polybasic regions with anionic membranes.
A type VII secretion system toxin functioning as a biofilm-specific intercellular signal inBacillus subtilis
Authors: Kobayashi Kazuo 
Published: August 2023

AbstractBiofilms are cooperative bacterial communities, in which diffusible signal-mediated quorum sensing coordinates the activities of member cells. However, limited diffusion in extracellular polymeric substance (EPS)-filled biofilms suggests existence of another intercellular signaling mechanism that is more adapted to the biofilm environment. Here, I demonstrate that theyfjAoperon ofBacillus subtilisencodes one such signaling mechanism. TheyfjAoperon was induced by the two-component system DegSU, which controls biofilm development. Deleting theyfjAoperon resulted in increased expression of DegSU-regulated genes under nutrient-rich conditions, hastening the onset of sporulation in biofilms. TheyfjAoperon encoded the type VII secretion system effector toxin YFJ in addition to its related proteins. YFJ toxin-mediated intercellular competition required EPS components which promote close cell-cell association, suggesting that the contact-dependent YFJ toxin system functions specifically in biofilms. The YFJ toxin also functioned as an intercellular signal that controlled the activity of DegSU. I propose that the YFJ toxin system is a biofilm-specific intercellular signaling mechanism that controls cell fate in biofilms in response to nutrient conditions and population size.
Body weight, gonadectomy, and other risk factors for diagnosis of osteoarthritis in companion dogs
Authors: Graves Jessica L , McKenzie Brennen A , Koch Zane , Naka Alexander , Spofford Nathaniel , Morrison JoAnn 
Published: August 2023

AbstractOBJECTIVETo evaluate age, sex, body weight, breed, neuter status, and age at neutering as risk factors for diagnosis of osteoarthritis in companion dogsANIMALSDogs seen as patients at Banfield Pet Hospital in the United States from 1998-2019 with a date of death in 2019. The final cohort consisted of 131,140 dogs.METHODSIn this retrospective cohort study, Cox proportional hazard models were used to test for associations between osteoarthritis incidence and age at baseline, sex, maximum body weight, maximum body condition score, neuter status, and age at neutering. The same model was used to test these associations in 12 representative breeds, chosen based on breed weight and sample size.RESULTSOlder age, higher adult body weight, gonadectomy, and younger age at gonadectomy were significantly associated with higher risks of osteoarthritis in the total cohort and in all 12 breeds evaluated. Higher body condition score and sex were also significantly associated with osteoarthritis but with minimal effect sizes in the overall cohort, and these risk factors were not consistently significant in all breeds tested.CLINICAL RELEVANCEThese results will assist veterinarians in identifying dogs at higher risk for osteoarthritis and applying appropriate diagnostic, preventative, and treatment interventions. An understanding of potentially modifiable risk factors, such as body condition, and neutering, will support evidence-based discussions with dog owners about risk management in individual patients.
An unconventional mechanism of IL-1β secretion that requires Type I IFN in lupus monocytes
Authors: Caielli Simone , Balasubramanian Preetha , Rodriguez-Alcazar Juan , Balaji Uthra , Wan Zurong , Baisch Jeanine , Smitherman Cynthia , Walters Lynnette , Sparagana Paola , Nehar-Belaid Djamel , Marches Radu , Nassi Lorien , Stewart Katie , Fuller Julie , Banchereau Jacques F. , Gu Jinghua , Wright Tracey , Pascual Virginia 
Published: August 2023

AbstractSystemic Lupus Erythematosus (SLE) is characterized by autoreactive B cell activation, upregulation of Type I Interferon (IFN) and widespread inflammation. Mitochondrial nucleic acids (NAs) are increasingly recognized as triggers of IFN1. Thus, defective removal of mitochondria from mature red blood cells (Mito+RBCs), a feature of SLE, contributes to IFN production by myeloid cells2. Here we identify blood monocytes (Mo) that have internalized RBCs and co-express IFN-stimulated genes (ISGs) and interleukin-1β (IL-1β) in SLE patients with active disease. We show that ISG expression requires the interaction between Mito+RBC-derived mitochondrial DNA (mtDNA) and cGAS, while IL-1β production entails Mito+RBC-derived mitochondrial RNA (mtRNA) triggering of RIG-I-like receptors (RLRs). This leads to the cytosolic release of Mo-derived mtDNA that activates the NLRP3 inflammasome. Importantly, IL-1β release depends on the IFN-inducible myxovirus resistant protein 1 (MxA), which enables the translocation of this cytokine into a trans-Golgi network (TGN)-mediated unconventional secretory pathway. Our study highlights a novel and synergistic pathway involving IFN and the NLRP3 inflammasome in SLE.
In vitroimpact of fluconazole on oral microbial communities, bacterial growth and biofilm formation
Authors: Dornelas-Figueira Louise Morais , Ricomini Filho Antônio Pedro , Junges Roger , Åmdal Heidi Aarø , Cury Altair Antoninha Del Bel , Petersen Fernanda Cristina 
Published: August 2023

AbstractAnti-fungal agents are widely used to specifically eliminate infections by fungal pathogens. However, the specificity of anti-fungal agents has been challenged by a few studies demonstrating anti-bacterial inhibitory effects against Mycobateria and Streptomyces species. Here we evaluated for the first time the potential effect of fluconazole, the most clinically used antifungal agent, on a human oral microbiota biofilm model. The results showed that biofilm viability on blood and mitis-salivarius agar media was progressively increased in the presence of fluconazole at clinically relevant concentrations, despite of a reduction in biomass. Target PCR revealed higher proportions ofVeillonella atypica, Veillonella disparandLactobacillusspp. in the fluconazole treated samples compared to the control, whileFusobacterium nucleatumwas reduced andStreptococcusspp was not significantly affected. Further, we tested the potential impact of fluconazole using single-species models. Our results usingStreptococcus mutansandStreptococcus mitisluciferase reporters showed thatS. mutansplanktonic growth was not significantly affected by fluconazole, while forS, mitisplanktonic growth, but not biofilm viability, was inhibited at the highest concentration. Fluconazole effects onS. mitisbiofilm biomass were concentration and time-dependent. Exposure for 48h to the highest concentration of fluconazole was associated withS. mitisbiofilms with the most increased biomass. Potential growth inhibitory effects were further tested using four non-streptococcal species. Among these, planktonic growth of bothEscherichia coliandGranulicatella adiacenswere inhibited by fluconazole. Conclusions: The data indicate bacterial responses to fluconazole that extend to a broader range of bacterial species than previously anticipated from the literature, with the potential to disturb microbial biofilm communities. Future studies are warranted to further identify the breath of species for which growth may be impacted by anti-fungal agents, and possible mechanisms involved.
Gbx2 controls amacrine cell dendrite stratification through Robo1/2 receptors
Authors: Kerstein Patrick C. , Agreda Yessica Santana , Curran Bridget M. , Ma Le , Wright Kevin M. 
Published: August 2023

SUMMARYWithin the neuronal classes of the retina, amacrine cells (ACs) exhibit the greatest neuronal diversity in morphology and function. We show that the selective expression of the transcription factorGbx2is required for cell fate specification and dendritic stratification of an individual AC subtype in the mouse retina. We identify Robo1 and Robo2 as downstream effectors that when deleted, phenocopy the dendritic misprojections seen inGbx2mutants. Slit1 and Slit2, the ligands of Robo receptors, are localized to the OFF layers of the inner plexiform layer where we observe the dendritic misprojections in bothGbx2andRobo1/2mutants. We show that Robo receptors also are required for the proper dendritic stratification of additional AC subtypes, such as Vglut3+ ACs. These results show both that Gbx2 functions as a terminal selector in a single AC subtype and identify Slit-Robo signaling as a developmental mechanism for ON-OFF pathway segregation in the retina.
Ice nucleation proteins self-assemble into large fibres to trigger freezing at near 0 °C
Authors: Hansen Thomas , Lee Jocelyn C. , Reicher Naama , Ovadia Gil , Guo Shuaiqi , Guo Wangbiao , Liu Jun , Braslavsky Ido , Rudich Yinon , Davies Peter L. 
Published: August 2023

AbstractIn nature, frost can form at a few degrees below 0 °C. However, this process requires the assembly of tens of thousands of ice-like water molecules that align together to initiate freezing at these relatively high temperatures. Water ordering on this scale is mediated by the ice nucleation proteins of common environmental bacteria likePseudomonas syringaeandP. borealis. However, individually, these 100-kDa proteins are too small to organize enough water molecules for frost formation, and it is not known how giant, megadalton-sized multimers, which are crucial for ice nucleation at high sub-zero temperatures, form. The ability of multimers to self-assemble was suggested when the transfer of an ice nucleation protein gene intoEscherichia coliled to efficient ice nucleation. Here we demonstrate that a positively-charged sub-domain at the C-terminal end of the central beta-solenoid of the ice nucleation protein is crucial for multimerization. Truncation, relocation, or change of the charge of this subdomain caused a catastrophic loss of ice nucleation ability. Cryo-electron tomography of the recombinantE. colishowed that the ice nucleation protein multimers form fibres that are ∼ 5 nm across and up to 200 nm long. A model of these fibres as an overlapping series of antiparallel dimers can account for all their known properties and suggests a route to making cell-free ice nucleators for biotechnological applications.
Positive feedback regulation ofPparγ1svandPparγ2during adipogenesis in 3T3-L1 cells
Authors: Takenaka Yasuhiro , Kakinuma Yoshihiko , Inoue Ikuo 
Published: August 2023

AbstractWe have previously identified the novel splicing variant of mousePparγ(Pparγ1sv) and proposed the synergistic regulation of the early stage of adipocyte differentiation byPparγ1svandPparγ2. Here, we report the finding of PPARγ-binding sites within thePparγgene locus and its importance in adipogenesis and propose the positive feedback regulation ofPparγ1svandPparγ2expression during the adipocyte differentiation of 3T3-L1 cells.
Curved crease origami and topological singularities at a cellular scale enable hyper-extensibility ofLacrymaria olor
Authors: Flaum Eliott , Prakash Manu 
Published: August 2023

AbstractEukaryotic cells undergo dramatic morphological changes during cell division, phagocytosis and motility. Fundamental limits of cellular morphodynamics such as how fast or how much cellular shapes can change without harm to a living cell remain poorly understood. Here we describe hyper-extensibility in the single-celled protistLacrymaria olor, a 40µm cell which is capable of reversible and repeatable extensions (neck-like protrusions) up to 1500µm in 30 seconds. We discover that a unique and intricate organization of cortical cytoskeleton and membrane enables these hyper-extensions that can be described as the first cellular scale curved crease origami. Furthermore, we show how these topological singularities including d- cones and twisted domain walls provide a geometrical control mechanism for the deployment of membrane and microtubule sheets as they repeatably spool thousands of time from the cell body. We lastly build physical origami models to understand how these topological singularities provide a mechanism for the cell to control the hyper-extensile deployable structure. This new geometrical motif where a cell employs curved crease origami to perform a physiological function has wide ranging implications in understanding cellular morphodynamics and direct applications in deployable micro-robotics.Significance statementHere we present the discovery of curved crease origami at the scale of a single cell. We show how topological singularities in the origami (d-cones) and twist walls in microtubule ribbons control deployment of a hyper-extensile neck in a single-celled protist. Our work establishes a direct link between geometry and cell behavior, connecting form and function of cellular morphodynamics.
Bronchoconstriction damages airway epithelia by excess crowding-induced extrusion
Authors: Bagley Dustin C. , Russell Tobias , Ortiz-Zapater Elena , Fox Kristina , Redd Polly F. , Joseph Merry , Deering-Rice Cassandra , Reilly Christopher , Parsons Maddy , Rosenblatt Jody 
Published: August 2023

ABSTRACTAsthma is deemed an inflammatory disease, yet the defining diagnostic symptom is mechanical bronchoconstriction. We previously discovered a conserved process that drives homeostatic epithelial cell death in response to mechanical cell crowding called cell extrusion(1, 2). Here, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion. While relaxing airways with the rescue treatment albuterol did not impact these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these symptoms. Our findings propose a new etiology for asthma, dependent on the mechanical crowding of a bronchoconstrictive attack. Our studies suggest that blocking epithelial extrusion, instead of ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
Rapid and unbiased enrichment of extracellular vesicles via meticulously engineered peptide
Authors: Wang Le , Gong Zhou , Wang Ming , Liang Yi-Zhong , Zhao Jing , Xie Qi , Wu Xiao-Wei , Li Qin-Ying , Zhang Cong , Ma Li-Yun , Zheng Si-Yang , Jiang Ming , Yu Xu , Xu Li 
Published: August 2023

AbstractExtracellular vesicles (EVs) have garnered significant attention in biomedical applications, particularly as biomarkers and therapeutic agents for cancer diagnosis and treatment. However, the rapid, efficient, and unbiased separation of EVs from complex biological fluids remains a challenge due to their heterogeneity and low abundance concentration in biofluids. Herein, we report a novel approach to reconfigure and modify an artificial insertion peptide for the rapid isolation of EVs in 20 min with ∼ 80% recovery. By inserting the peptide into the phospholipid bilayer of EVs, our method enables the unbiased isolation of EVs. Moreover, our approach demonstrates exceptional anti-interference capability and achieves a high purity of EVs comparable to standard ultracentrifugation and other methods. Importantly, we show that the isolated EVs could be directly applied for downstream protein and nucleic acids analyses, including proteomics analysis, exome sequencing analysis, as well as the detection of EGFR and KRAS gene mutation in clinical plasma samples. Our approach offers new possibilities for utilizing EVs in cancer diagnostics through liquid biopsy, as well as in various other biomedical applications.
RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis
Authors: Quiroz Erik J. , Kim Seongjae , Gautam Lalit K. , Borok Zea , Kintner Christopher , Ryan Amy L. 
Published: August 2023

AbstractA core pathophysiologic feature underlying many respiratory diseases is multiciliated cell dysfunction, leading to inadequate mucociliary clearance. Due to the prevalence and highly variable etiology of mucociliary dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in a complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelia, however this does not apply to all cell types, nor does it occur evenly across all cells in the same cell population. In this study we further investigated how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells, we identify RBL2 as a repressor of the transcriptional activity of Multicilin. Knockdown of RBL2 in submerged cultures or phosphorylation of RBL2 in response to apical air exposure, in the presence of Multicilin, allows multiciliogenesis to progress. These data demonstrate a dynamic interaction between RBL2 and Multicilin that regulates the capacity of cells to differentiate and multiciliate. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases with impaired mucociliary clearance.
Unlocking the gender diversity–group performance link: the moderating role of relative cultural distance
Authors: Andrieu Guillaume , Montani Francesco , Setti Ilaria , Sommovigo Valentina 
Published: August 2023

PurposeThis study aims to shed light on the relationship between gender diversity and group performance by considering the moderating role of relative cultural distance. Drawing from the categorization–elaboration model (CEM), the authors hypothesize that gender-diverse collaborative learning groups perform better when a low level of relative cultural distance in country-level individualism–collectivism or power distance exists among group members.Design/methodology/approachTo test this hypothesis, the authors conducted a study on 539 undergraduate students organized into 94 groups. The assessment of group performance was based on scores given by external raters.FindingsThe authors found that relative cultural distance significantly moderated the gender diversity–group performance relationship such that gender diversity was positively related to group performance when the collaborative learning group included members who similarly valued individualism–collectivism or power distance (i.e. relative cultural distance was low) and was negatively related to group performance when the collaborative learning group comprised members who differently valued individualism–collectivism or power distance (i.e. relative cultural distance was high).Originality/valueThis study contributes to understanding when gender diversity is positively associated with group performance by expanding the range of previously examined diversity dimensions to include relative cultural distance in country-level individualism–collectivism and power distance.