bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation restricts coordinated germline and neural fates in embryonic stem cell differentiation
Authors: Schulz Mathieu , Teissandier Aurélie , de la Mata Elena , Armand Mélanie , Iranzo Julian , El Marjou Fatima , Gestraud Pierre , Walter Marius , Kinston Sarah , Göttgens Berthold , Greenberg Maxim V.C. , Bourc’his Deborah 
Published: October 2022

ABSTRACTSomatic DNA methylation is established early during mammalian development, as embryonic cells transition from naive to primed pluripotency. This precedes the emergence of the three somatic germ layers, but also the segregation of the germline that undergoes genome-wide DNA demethylation after specification. While DNA methylation is essential for embryogenesis, the point at which it becomes critical during differentiation and whether all lineages equally depend on it is unclear. Using culture modeling of cellular transitions, we found that DNA methylation-free embryonic stem cells (ESCs) with a triple DNA methyltransferase knockout (TKO) normally progressed through the continuum of pluripotency states, but demonstrated skewed differentiation abilities towards neural versus other somatic lineages. More saliently, TKO ESCs were fully competent for establishing primordial germ cell-like cells (PGCLCs), even showing temporally extended and self-sustained capacity for the germline fate. By mapping chromatin states, we found that the neural and germline lineages are linked by a similar enhancer dynamics during priming, defined by common sets of methyl-sensitive transcription factors that fail to be decommissioned in absence of DNA methylation. We propose that DNA methylation controls the temporality of a coordinated neural-germline axis of preferred differentiation route during early development.
Species-wide genomics of kākāpō provides transformational tools to accelerate recovery
Authors: Guhlin Joseph , Lec Marissa F. Le , Wold Jana , Koot Emily , Winter David , Biggs Patrick , Galla Stephanie J. , Urban Lara , Foster Yasmin , Cox Murray P. , Digby Andrew , Uddstrom Lydia , Eason Daryl , Vercoe Deidre , Davis Tāne ,   Kākāpō Recovery Team, Howard Jason T , Jarvis Erich , Robertson Fiona E. , Robertson Bruce C. , Gemmell Neil , Steeves Tammy E. , Santure Anna W. , Dearden Peter K. 
Published: October 2022

AbstractThe kākāpō is a critically endangered, intensively managed, long-lived nocturnal parrot endemic to Aotearoa New Zealand. We generated and analyzed whole-genome sequence data for nearly all individuals living in early 2018 (169 individuals) to generate a high-quality species-wide genetic variant callset. We leverage extensive long-term metadata to quantify genome-wide diversity of the species over time and present new approaches using probabilistic programming, combined with a phenotype dataset spanning five decades, to disentangle phenotypic variance into environmental and genetic effects while quantifying uncertainty in small populations. We find associations for growth, disease susceptibility, clutch size, and egg fertility within genic regions previously shown to influence these traits in other species. Finally, we generate breeding values to predict phenotype and illustrate that active management over the past 45 years has maintained both genome-wide diversity and diversity in breeding values, and hence, evolutionary potential. We provide new pathways for informing future conservation management decisions for kākāpō, including prioritizing individuals for translocation and monitoring individuals with poor growth or high disease risk. Overall, by explicitly addressing the challenge of small sample size, we provide a template for the inclusion of genomic data that will be transformational for species recovery efforts around the globe.
Role of DEAD Box RNA helicases in low temperature adapted growth of AntarcticPseudomonas syringaeLz4W
Authors: Hussain Ashaq , Ray Malay Kumar 
Published: October 2022

AbstractNucleic acid metabolism plays an important role in adaptation of organisms to environment. For adaptation to cold environment, organisms need to overcome the impediments in complex RNA secondary structures that are highly stabilized at low temperature affecting metabolism and growth of the organisms. Employing gene disruption through homologous recombination, we investigated the role of all major DEAD box RNA helicases (rhlE, srmB, csdA, dbpAandrhlB) in cold adapted growth ofPseudomonas syringae. Our findings concluded thatsrmBanddbpAgenes are important for cold adapted growth, whereascsdAis indispensable for growth at low temperature. Helicase genesrhlBandrhlEhave no appreciable role in cold adapted growth ofPseudomonas syringae. Functional complementation studies revealed that RNA helicases don’t have any redundant functions, as the roles performed by different helicases are individual and specific.
Neglected no longer: Phylogenomic resolution of higher-level relationships in Solifugae
Authors: Kulkarni Siddharth S. , Steiner Hugh G. , Garcia Erika L. , Iuri Hernán , Jones R. Ryan , Ballesteros Jesús A. , Gainett Guilherme , Graham Matthew R. , Harms Danilo , Lyle Robin , Ojanguren-Affilastro Andrés A. , Santibañez-López Carlos E. , de Miranda Gustavo Silva , Cushing Paula E. , Gavish-Regev Efrat , Sharma Prashant P. 
Published: October 2022

AbstractConsiderable progress has been achieved in resolving higher-level relationships of Arthropoda in the past two decades, largely precipitated by advances in sequencing technology. Yet, dark branches persist in the arthropod tree of life, principally among groups that are difficult to collect, occur in cryptic habitats, or are characterized by minute body size. Among chelicerates, the mesodiverse order Solifugae (commonly called camel spiders or sun spiders) is one of the last orders of Arachnida that lacks a higher-level phylogeny altogether and has long been characterized as one of the “neglected cousins”, a lineage of arachnid orders that are comparatively poorly studied with respect to evolutionary relationships. Though renowned for their aggression, remarkable running speed, and adaptation to arid habitats, inferring solifuge relationships has been hindered by inaccessibility of diagnostic characters in most ontogenetic stages for morphological datasets, whereas molecular investigations to date have been limited to one of the 12 recognized families. In this study we generated a phylogenomic dataset via capture of ultraconserved elements (UCEs) and sampled all extant families. We recovered a well-resolved phylogeny of solifuge families, with two distinct groups of New World taxa nested within a broader Paleotropical radiation. To provide a temporal context to solifuge diversification, we estimated molecular divergence times using fossil calibrations within a least-squares framework. Solifugae were inferred to have radiated by the Permian, with divergences of most families dating to the post Paleogene-Cretaceous extinction. These results accord with a diversification history largely driven by vicariance as a result of continental breakup.
The matrisome of the murine and human dorsal root ganglion: a transcriptomal approach
Authors: Vroman Robin , Hunter Rahel , Wood Matthew J. , Davis Olivia C. , Malfait Zoë , George Dale S. , Ren Dongjun , Tavares-Ferreira Diana , Price Theodore J. , Malfait Anne-Marie , Malfait Fransiska , Miller Rachel E. , Syx Delfien 
Published: October 2022

AbstractThe extracellular matrix (ECM) is a dynamic structure composed of a large number of molecules that can be divided into six different categories and are collectively called the matrisome. The ECM plays pivotal roles in physiological and pathological processes in many tissues, including the nervous system. Intriguingly, alterations in ECM molecules/pathways are often associated with painful human conditions and murine experimental pain models. Nevertheless, mechanistic insight into the interplay of normal or defective ECM and pain is largely lacking. To expand the knowledge on ECM composition and synthesis in the peripheral nervous system, we used a transcriptomal approach to investigate the expression and cellular origin of matrisome genes in murine and human dorsal root ganglia (DRG), containing the cell bodies of sensory neurons. Bulk RNA sequencing data showed that over 60% of all matrisome genes were expressed in both murine and human DRG, with proportionally more core matrisome genes (glycoproteins, collagens, and proteoglycans) expressed compared to matrisome-associated genes (ECM-affiliated genes, ECM regulators and secreted factors). Examination of the cellular origin of matrisome expression by single cell RNA sequencing on murine DRG revealed that core matrisome genes, especially collagens, were expressed by vascular leptomeningeal-like (fibroblast) cell types whereas matrisome-associated genes were mainly expressed by neuronal cell types. We analyzed cell-cell communication networks with the CellChat R package and predicted an important role for the Collagen signaling pathway in connecting vascular cell types and nociceptors in murine tissue, which we confirmed by analysis of spatial transcriptomic data from human DRG. RNAscopein situhybridization and immunohistochemistry confirmed expression of collagens in fibroblasts surrounding nociceptors in human DRG. This study supports the idea that the DRG matrisome may contribute to neuronal signaling in both mouse and human. The identification of the cellular distribution of murine and human matrisome genes provides a framework to study the role of the ECM in peripheral nervous tissue and its effects on pain signaling.HighlightsTranscriptomal analyses of mouse and human dorsal root ganglia (DRG) revealed that over 60% of matrisome genes are expressed by murine and human dorsal root ganglia (DRG), with over 85% of the genes with orthologues overlapping between both species.Matrisome-associated genes had the highest expression in both species and included conserved expression of annexins, S100 calcium binding proteins and cathepsins.Collagens and collagen receptors are expressed by distinct cell types in murine and human DRG, suggesting that the collagen signaling pathway could be involved in cell-cell signaling.
Structural Basis for Selective Proteolysis of ADAM10 Substrates at Membrane-Proximal Sites
Authors: Lipper Colin H. , Egan Emily D. , Gabriel Khal-Hentz , Blacklow Stephen C. 
Published: October 2022

SummaryThe endopeptidase ADAM10 is a critical catalyst for regulated proteolysis of key drivers of mammalian development and physiology, and for non-amyloidogenic cleavage of the Alzheimer’s precursor protein as the primary α-secretase. ADAM10 functionin vivorequires formation of a complex with a C8-tetraspanin protein, with different ADAM10-C8-tetraspanin complexes having distinct substrate selectivity, yet the basis for such selectivity remains elusive. We present here a cryo-EM structure of a vFab-ADAM10-Tspan15 complex, which shows that Tspan15 binding relieves ADAM10 autoinhibition and positions the enzyme active site about 20 Å from the plasma membrane for membrane-proximal substrate cleavage. Cell-based assays of N-cadherin shedding establish that the positioning of the active site by the interface between the ADAM10 catalytic domain and the bound tetraspanin influences selection of the preferred cleavage site. Together, these studies reveal the molecular mechanism underlying selective ADAM10 proteolysis at membrane-proximal sites and offer a roadmap for its modulation in disease.
Antibody avidity and multi-specificity combined to confer protection against SARS-CoV-2 and resilience against viral escape
Authors: Aschner Clare Burn , Muthuraman Krithika , Kucharska Iga , Cui Hong , Prieto Katherine , Nair Manoj S. , Wang Maple , Huang Yaoxing , Christie-Holmes Natasha , Poon Betty , Lam Jessica , Sultana Azmiri , Kozak Robert , Mubareka Samira , Rubinstein John L. , Rujas Edurne , Treanor Bebhinn , Ho David D. , Jetha Arif , Julien Jean-Philippe 
Published: October 2022

AbstractSARS-CoV-2, the causative agent of COVID-19, has been responsible for a global pandemic. Monoclonal antibodies have been used as antiviral therapeutics, but have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs), and in deployment by the need for high doses. In this study, we leverage the MULTI-specific, multi-Affinity antiBODY (Multabody, MB) platform, derived from the human apoferritin protomer, to drive the multimerization of antibody fragments and generate exceptionally potent and broad SARS-CoV-2 neutralizers. CryoEM revealed a high degree of homogeneity for the core of these engineered antibody-like molecules at 2.1 Å resolution. We demonstrate that neutralization potency improvements of the MB over corresponding IgGs translates into superiorin vivoprotection: in the SARS-CoV-2 mouse challenge model, comparablein vivoprotection was achieved for the MB delivered at 30x lower dose compared to the corresponding IgGs. Furthermore, we show how MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding IgGs lose their ability to neutralize potently. Multiple mAb specificities could also be combined into a single MB molecule to expand the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.
Therapy Induced Tumor Senescence Model
Authors: Singh Ghanendra 
Published: October 2022

AbstractSenescent cell accumulation and defective clearance of the senescent cells by the immune system occur with aging and increase the prevalence of diseases like cancer. Anti-tumor therapies can induce senescence in the tumor cells. Senescence Associated Secretory Phenotypes (SASP) secretion by these senescent tumor cells activates the innate NK cells which can detect and eliminate them. Mechanisms are unclear about how does it occur? A combination of immunotherapy and senotherapy has shown the possibility to reduce the tumor burden and increase the health span. The temporal and intensity dynamics of the therapeutic dose regimen remains to be studied. Therefore, a simplified therapy-induced senescence (TIS) phenomenological model is proposed to explain the mechanism of senescent tumor cell clearance by the NK immune cells and understand the possibility of a two-punch therapy technique in regulating tumors. Interaction strength changes for the cellular population within a healthy and an aged tumor microenvironment. The simulation result shows an oscillatory behavior existing between the tumor and immune cells. Tumor heterogeneity acts as inherent noise in sustaining the tumor for relapse emergence despite therapeutic clearance. The model indicates the formation of a robust oscillatory loop between the tumor, immune, and senescence cells which they can tune by modifying the phenotypic fitness landscape through secreted factors making them resistant despite selective removal of the sensitive populations by various therapies. The model highlights the importance of modified and aged tumor microenvironment by senescence tumor cells in obstructing clearance of both senescence and tumor cells by the innate immune system. Cancer therapies along with senolytics may have a robust and effective regulatory potential over tumor and senescence cells. The model also provides a preliminary analysis of the therapy temporal and intensity dosage regimen causing a therapeutic shift in tumors.
Transforming growth factor-β promotes the postselection thymic development and peripheral function of interferon-γ-producing invariant natural killer T cells
Authors: Morgan Roxroy C. , Frank Cameron , Greger Munmun , Sigvardsson Mikael , Bartom Elizabeth T. , Kee Barbara L. 
Published: October 2022

AbstractInterferon-γ producing invariant natural killer T (iNKT1) cells are lipid reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell and thymic epithelial cell numbers or function. Here we show that a subset of thymic iNKT1 cells require transforming growth factor (TGF)-β induced signals for their development and for expression of residency associated adhesion receptors. Liver and spleen iNKT1 cells do not share this TGF-β gene signature but nonetheless TGF-β is required for optimal liver iNKT1 cell function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-β producing cells in the thymus.
Patterns of chemotherapy use and outcomes in advanced non-small-cell lung cancer in relation to age in England: A retrospective analysis of the population-based Systemic Anti-Cancer Treatment (SACT) dataset
Authors: Pilleron S. , Morris EJA. , Dodwell D. , Franks K.N. 
Published: October 2022

AbstractObjectiveWe described the patterns of chemotherapy use and outcomes in patients diagnosed with stage III or IV non-small cell lung cancer (NSCLC) in England.MethodIn this retrospective population-based study, we included 20,716 (62% stage IV) patients with NSCLC diagnosed in 2014-17 treated with chemotherapy. We used the Systemic Anti-Cancer Treatment (SACT) dataset to describe changes in treatment plan and estimated 30 and 90-day mortality rates and median, 6- and 12-month overall survival (OS) using Kaplan Meier estimator for patients aged <75 and ≥ 75 by stage. Using flexible hazard regression models we assessed the impact of age, stage, treatment intent (stage III) and performance status on survival.ResultsPatients aged ≥ 75 years were less likely to receive 2 or more regimens, more likely to have their treatment modified because of comorbidities and their doses reduced compared to younger patients. However, early mortality rates and overall survival were similar across ages, apart from the oldest patients with stage III disease.ConclusionThis observational study demonstrates that age is associated with treatment choices in an older population with advanced NSCLC in England. Although this reflecting a pre-immunotherapy period, given the median age of NSCLC patients and increasingly older population, these results suggest older patients (>75yrs) may need additional support to access more intense treatments that may influence overall survival.
Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines
Authors: Godoy-Tena Gerard , Barmada Anis , Morante-Palacios Octavio , de la Calle-Fabregat Carlos , Martins-Ferreira Ricardo , Ferreté-Bonastre Anna G. , Ciudad Laura , Ruiz-Sanmartín Adolfo , Martínez-Gallo Mónica , Ferrer Ricard , Ruiz-Rodriguez Juan Carlos , Rodríguez-Ubreva Javier , Vento-Tormo Roser , Ballestar Esteban 
Published: October 2022

AbstractCOVID-19 manifests with a wide spectrum of clinical phenotypes, ranging from asymptomatic and mild to severe and critical. Severe and critical COVID-19 patients are characterized by marked changes in the myeloid compartment, especially monocytes. However, little is known about the epigenetic alterations that occur in these cells during hyperinflammatory responses in severe COVID-19 patients. In this study, we obtained the DNA methylome and transcriptome of peripheral blood monocytes from severe COVID-19 patients. DNA samples extracted from CD14+CD15-monocytes of 48 severe COVID-19 patients and 11 healthy controls were hybridized on MethylationEPIC BeadChip arrays. In parallel, single-cell transcriptomics of 10 severe COVID-19 patients were generated. CellPhoneDB was used to infer changes in the crosstalk between monocytes and other immune cell types. We observed DNA methylation changes in CpG sites associated with interferon-related genes and genes associated with antigen presentation, concordant with gene expression changes. These changes significantly overlapped with those occurring in bacterial sepsis, although specific DNA methylation alterations in genes specific to viral infection were also identified. We also found these alterations to comprise some of the DNA methylation changes occurring during myeloid differentiation and under the influence of inflammatory cytokines. A progression of DNA methylation alterations in relation to the Sequential Organ Failure Assessment (SOFA) score was found to be related to interferon-related genes and T-helper 1 cell cytokine production. CellPhoneDB analysis of the single-cell transcriptomes of other immune cell types suggested the existence of altered crosstalk between monocytes and other cell types like NK cells and regulatory T cells. Our findings show the occurrence of an epigenetic and transcriptional reprogramming of peripheral blood monocytes, which could be associated with the release of aberrant immature monocytes, increased systemic levels of pro-inflammatory cytokines, and changes in immune cell crosstalk in these patients.
Peptides that Mimic RS repeats modulate phase separation of SRSF1, revealing a reliance on combined stacking and electrostatic interactions
Authors: Fargason Talia , De Silva Naiduwadura Ivon Upekala , King Erin , Zhang Zihan , Paul Trenton , Shariq Jamal , Zaharias Steve , Zhang Jun 
Published: October 2022

AbstractPhase separation plays crucial roles in both sustaining cellular function and perpetuating disease states. Despite extensive studies, our understanding of this process is hindered by low solubility of phase-separating proteins. One example of this is found in SR proteins. These proteins are characterized by domains rich in arginine and serine (RS domains), which are essential to alternative splicing,in vivophase separation, and a low solubility that has made these proteins difficult to study for decades. Here, we solubilize the founding member of the SR family, SRSF1, by introducing a peptide mimicking RS repeats as a co-solute. We find that this RS-mimic peptide forms interactions similar to those of the protein’s RS domain. Both interact with a combination of surface-exposed aromatic residues and acidic residues on SRSF1’s RNA Recognition Motifs (RRMs) through electrostatic and cation-pi interactions. Analysis of RRM domains spanning the human proteome indicates that RRM domains involved in phase separation have more exposed aromatic residues and that in phase-separating proteins containing RS repeats, such residues are frequently surrounded by acidic residues. In addition to opening an avenue to previously unavailable proteins, our work provides insight into how SR proteins phase separate and participate in nuclear speckles.
A Compartmentalized Model to Directional Sensing: How can an Amoeboid Cell Unify Pointwise External Signals as an Integrated Entity?
Authors: Eidi Zahra , Sadeghi Mehdi 
Published: October 2022

AbstractAfter being exposed to an external chemical attractant, several internal cellular downstream signal transduction pathways control the chemotactic machinery of eukaryotes. The spatial activation of these pathways ultimately leads to some sort of symmetry breaking around the cell periphery in the form of redistribution of several biochemicals,e.g., polymerized actin at one side of the cell for propulsion and the assembly of myosin II at nearly opposite side for retraction. In this study, we revisit the modeling of this process, which is called directional sensing, with a compartment-based design. In our model, we consider a network of excitable elements around cell circumference which are stimulated occasionally with local colored noise. The exciting elements are capable of sharing information with their close neighbors. We show that the dynamic can distinguish a temporary but enough long-lasting direction, statistically, pointing towards the gradient of external stimulants that can be deemed as the preferred orientation of the cell periphery during the directional sensing process in eukaryotes.