bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates
Authors: Walters Jewell N. , Schouest Blake , Patel Ami , Reuschel Emma L. , Schultheis Katherine , Parzych Elizabeth , Maricic Igor , Gary Ebony N. , Purwar Mansi , Andrade Viviane M. , Doan Arthur , Elwood Dustin , Eblimit Zeena , Nguyen Brian , Frase Drew , Zaidi Faraz I. , Kulkarni Abhijeet , Generotti Alison , Kim J Joseph , Humeau Laurent M. , Ramos Stephanie J. , Smith Trevor R.F. , Weiner David B. , Broderick Kate E. 
Published: October 2021

SUMMARYThe enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.
Biology-inspired data-driven quality control for scientific discovery in single-cell transcriptomics
Authors: Subramanian Ayshwarya , Alperovich Mikhail , Yang Yiming , Li Bo 
Published: October 2021

AbstractQuality control (QC) of cells, a critical step in single-cell RNA sequencing data analysis, has largely relied on arbitrarily fixed data-agnostic thresholds on QC metrics such as gene complexity and fraction of reads mapping to mitochondrial genes. The few existing data-driven approaches perform QC at the level of samples or studies without accounting for biological variation in the commonly used QC criteria. We demonstrate that the QC metrics vary both at the tissue and cell state level across technologies, study conditions, and species. We propose data-driven QC (ddqc), an unsupervised adaptive quality control framework that performs flexible and data-driven quality control at the level of cell states while retaining critical biological insights and improved power for downstream analysis. On applyingddqcto 6,228,212 cells and 835 mouse and human samples, we retain a median of 39.7% more cells when compared to conventional data-agnostic QC filters. Withddqc, we recover biologically meaningful trends in gene complexity and ribosomal expression among cell-types enabling exploration of cell states with minimal transcriptional diversity or maximum ribosomal protein expression. Moreover,ddqcallows us to retain cell-types often lost by conventional QC such as metabolically active parenchymal cells, and specialized cells such as neutrophils or gastric chief cells. Taken together, our work proposes a revised paradigm to quality filtering best practices - iterative QC, providing a data-driven quality control framework compatible with observed biological diversity.
A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity
Authors: Gómez-Carballa Alberto , Rivero-Calle Irene , Pardo-Seco Jacobo , Gómez-Rial José , Rivero-Velasco Carmen , Rodríguez-Núñez Nuria , Barbeito-Castiñeiras Gema , Pérez-Freixo Hugo , Cebey-López Miriam , Barral-Arca Ruth , Rodriguez-Tenreiro Carmen , Dacosta-Urbieta Ana , Bello Xabier , Pischedda Sara , Currás-Tuala María José , Viz-Lasheras Sandra , Martinón-Torres Federico , Salas Antonio ,   GEN-COVID (www.gencovid.eu) study group
Published: October 2021

AbstractBackgroundCOVID-19 symptoms range from mild to severe illness; the cause for this differential response to infection remains unknown. Unravelling the immune mechanisms acting at different levels of the colonization process might be key to understand these differences.Methods and findingsWe carried out a multi-tissue (nasal, buccal and blood;n= 156) gene expression analysis of immune-related genes from patients affected by different COVID-19 severities, and healthy controls through the nCounter technology. We then used a differential expression approach and pathways analysis to detect tissue specific immune severity signals in COVID-19 patients.Mild and asymptomatic cases showed a powerful innate antiviral response in nasal epithelium, characterized by activation of interferon (IFN) pathway and downstream cascades, successfully controlling the infection at local level. In contrast, weak macrophage/monocyte driven innate antiviral response and lack of IFN signalling activity were shown in severe cases. Consequently, oral mucosa from severe patients showed signals of viral activity, cell arresting and viral dissemination to the lower respiratory tract, which ultimately could explain the exacerbated innate immune response and impaired adaptative immune responses observed at systemic level. Results from saliva transcriptome suggest that the buccal cavity might play a key role in SARS-CoV-2 infection and dissemination in patients with worse prognosis.ConclusionsWe found severity-related signatures in patient tissues mainly represented by genes involved in the innate immune system and cytokine/chemokine signalling. Local immune response could be key to determine the course of the systemic response and thus COVID-19 severity. Our findings provide a framework to investigate severity host gene biomarkers and pathways that might be relevant to diagnosis, prognosis, and therapy.
Transferability of Psychological Interventions from Disaster-Exposed Employees to Healthcare Workers Working during the COVID-19 Pandemic
Authors: Treacy Sean , O’Donnell Shane , Gavin Blánaid , Schloemer Tamara , Quigley Etain , Adamis Dimitrios , Nicholas Fiona Mc , Hayden John C. 
Published: October 2021

AbstractBackgroundThe COVID-19 Pandemic had a significant negative impact on the mental health of healthcare workers. Evidence-based interventions that could be used to mitigate this impact are lacking in the literature. This review aims to evaluate psychological interventions used for employees following previous disasters and assess the transferability of these interventions to a healthcare setting during the COVID-19 pandemic.MethodsIntervention information from a previously published systematic review of the literature published up to 2015 was extracted, and an additional search of studies published from 2015-2020 was conducted. Studies were assessed for transferability using a checklist derived from the PIET-T process model.ResultsInterventions from eighteen studies were assessed for transferability (including three studies identified in an updated literature search). Interventions established as most transferable included resilience training, meditation/mindfulness interventions, and cognitive behavioural therapy. Psychological debriefing was transferable but as it is contrary to current recommendations is not deemed appropriate for adoption.ImplicationsSeveral existing interventions have the potential to be utilised within the COVID-19 context/pandemic. More research needs to be undertaken in this area to assess these interventions upon transfer.
The impact of epistasis in the heterosis and combining ability analyses
Authors: Viana José Marcelo Soriano 
Published: October 2021

AbstractThe current theoretical knowledge concerning the influence of epistasis on heterosis is based on simplified multiplicative model. The objective of this study was to assess the impact of epistasis in the heterosis and combining ability analyses, assuming additive model, hundreds of genes, linkage disequilibrium (LD), dominance, and seven types of digenic epistasis. We developed the quantitative genetics theory for supporting the simulation of the individual genotypic values in nine populations, the selfed populations, the 36 interpopulation crosses, 180 doubled haploids (DHs) and their 16,110 crosses, assuming 400 genes in 10 chromosomes of 200 cM. Epistasis only affects population heterosis if there is LD. Only additive x additive and dominance x dominance epistasis can affect the components of the heterosis and combining ability analyses of populations. Both analyses can lead to completely wrong inferences regarding the identification of the superior populations, the populations with greater differences of gene frequencies, and the populations with maximum variability, when the number of interacting genes and the magnitude of the epistatic effects are high. There was a decrease in the average heterosis by increasing the number of epistatic genes and the magnitude of their epistatic effects. The same results are generally true for the combining ability analysis of DHs. Surprisingly, the combining ability analyses of subsets of 20 DHs showed no significant average impact of epistasis on the identification of the most divergent ones, even assuming a high number of epistatic genes and great magnitude of their effects. However, a significant negative effect can occur.Statements and DeclarationsThe author has no relevant financial or non-financial interests to disclose. The author has no competing interests to declare that are relevant to the content of this article. The author certifies that he has no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The author has no financial or proprietary interests in any material discussed in this article.
The Loroxanthin cycle: A new type of xanthophyll cycle in green algae (Chlorophyta)
Authors: van den Berg T E , Croce R. 
Published: October 2021

SummaryXanthophyll cycles have proven to be major contributors to photoacclimation for many organisms. This work describes a light-driven xanthophyll cycle operating in the chlorophyte Chlamydomonas reinhardtii and involving the xanthophylls Lutein (L) and Loroxanthin (Lo). Pigments were quantified during a switch from high to low light and at different time points from cells grown in Day/night cycle. Trimeric LHCII was purified from cells acclimated to high or low light and their pigment content and spectroscopic properties were characterized. The Lo/(L+Lo) ratio in the cells varies by a factor of 10 between cells grown in low or high light leading to a change in the Lo/(L+Lo) ratio in trimeric LHCII from 0.5 in low light to 0.07 in high light. Trimeric LhcbMs binding Loroxanthin have 5±1% higher excitation energy transfer from carotenoid to Chlorophyll as well as higher thermo- and photostability than trimeric LhcbMs that only bind Lutein. The Loroxanthin cycle operates on long time scales (hours to days) and likely evolved as a shade adaptation. It has many similarities with the Lutein-epoxide - Lutein cycle of plants.
ACTN2mutant causes proteopathy in human iPSC-derived cardiomyocytes
Authors: Zech Antonia T. L. , Prondzynski Maksymilian , Singh Sonia R. , Orthey Ellen , Alizoti Erda , Busch Josefine , Madsen Alexandra , Behrens Charlotta S. , Mearini Giulia , Lemoine Marc D. , Krämer Elisabeth , Mosqueira Diogo , Virdi Sanamjeet , Indenbirken Daniela , Depke Maren , Salazar Manuela Gesell , Völker Uwe , Braren Ingke , Pu William T. , Eschenhagen Thomas , Hammer Elke , Schlossarek Saskia , Carrier Lucie 
Published: October 2021

AbstractGenetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T)ACTN2gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut present a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by thisACTN2variant, which may contribute to humanACTN2-associated cardiomyopathies.
Tubular lysosome induction couples animal starvation to healthy aging
Authors: Villalobos Tatiana V. , Ghosh Bhaswati , Alam Sanaa , Butsch Tyler J. , Mercola Brennan M. , Ramos Cara D. , Das Suman , Eymard Eric D. , Bohnert K. Adam , Johnson Alyssa E. 
Published: October 2021

AbstractDietary restriction promotes longevity via autophagy activation. However, changes to lysosomes underlying this effect remain unclear. Using the nematode Caenorhabditis elegans, we show that induction of autophagic tubular lysosomes, which occurs upon dietary restriction or mTOR inhibition, is a critical event linking reduced food intake to lifespan extension. We find that starvation induces tubular lysosomes not only in affected individuals but also in well-fed descendants, and the presence of gut tubular lysosomes in well-fed progeny is predictive of enhanced lifespan. Furthermore, we demonstrate that expression of Drosophila SVIP, a tubular-lysosome activator in flies, artificially induces tubular lysosomes in well-fed worms and improves C. elegans health in old age. These findings identify tubular lysosomes as a new class of lysosomes that couples starvation to healthy aging.One-Sentence SummaryTubular lysosome induction promotes healthy aging.
Salmonella exploits OmpR to switch essential morphogenetic peptidoglycan synthases in response to intracellular cues
Authors: López-Escarpa David , Castanheira Sónia , García-del Portillo Francisco 
Published: October 2021

AbstractEssential peptidoglycan synthases, like penicillin binding proteins 2 and 3 (PBP2/PBP3) of Escherichia coli, define shape by orchestrating cell elongation and division, respectively. Despite being intensively studied as drug targets, the regulatory rules governing their production remain poorly understood. During infection, the closely related pathogen Salmonella enterica serovar Typhimurium downregulates PBP2/PBP3 production and replace them with alternative peptidoglycan synthases, PBP2SAL/PBP3SAL, absent in E. coli. The bases for such switch in morphogenetic proteins are unknown. Here, we show that the S. Typhimurium regulator OmpR triggers PBP2SAL and PBP3SAL expression responding solely to acid pH and define a shared motif present in upstream regions of the PBP2SAL- and PBP3SAL-coding genes sufficient for such control. The elimination of PBP2/PBP3 in infection conditions is however multifactorial, requiring acidity, high osmolarity and being favoured by OmpR and the Prc protease. Remarkably, we found that E. coli loses the essential PBP3 required for cell division when exposed to both acidity and high osmolarity, the environmental cues encountered by intracellular S. Typhimurium. Therefore, OmpR played a central role in the evolution of this pathogen when co-opting the regulation of PBP2SAL/PBP3SAL and, consequently, promoting a new morphogenetic cycle that made possible increasing progeny inside acidic eukaryotic phagosomes.SignificanceSome enzymes that participate in peptidoglycan metabolism are present exclusively in bacterial pathogens and modify its structure to limit immune recognition. The intracellular pathogen Salmonella enterica serovar Typhimurium is the only example known to date in which a “substitution” of essential peptidoglycan enzymes involved in cell division and elongation takes place during infection. The data presented here support instability of PBP3 in environments with acidity and high osmolarity as a probable selective pressure that promoted the fixation of alternative morphogenetic enzymes. This was possible due to the control that OmpR exerted over these new foreign functions. The acquisition of enzymes like PBP2SAL and PBP3SAL therefore represent a “quantum leap” evolutionary event in S. Typhimurium that made possible the colonization of acidic intracellular niches.
Investigating pathogenicity and virulence of Staphylococcus pettenkoferi: an emerging pathogen
Authors: Plumet Lucile , Ahmad-Mansour Nour , Huc-Brandt Sylvaine , Magnan Chloé , Yahiaoui-Martinez Alex , Kissa Karima , Pantel Alix , Lavigne Jean-Philippe , Molle Virginie 
Published: October 2021

AbstractStaphylococcus pettenkoferi is a coagulase-negative Staphylococcus identified in 2002 that has been implicated in human diseases as an opportunistic pathogenic bacterium. Its multiresistant character is becoming a major health problem, yet the pathogenicity of S. pettenkoferi is poorly characterized. In this study, pathogenicity of a S. pettenkoferi clinical isolate from diabetic foot osteomyelitis was compared to a Staphylococcus aureus strain in various in vitro and in vivo experiments. Growth kinetics were compared against S. aureus and bacteria survival was assessed in the RAW 264.7 murine macrophage cell line, the THP-1 human leukemia monocytic cell line and the HaCaT human keratinocyte cell line. Ex vivo analysis were performed in whole blood survival assays, and in vivo assays via the infection model of zebrafish embryos. Moreover, whole-genome analysis was performed. Our results showed that S. pettenkoferi was able to survive in human blood, human keratinocytes, murine macrophages, and human macrophages. S. pettenkoferi demonstrated its virulence by causing substantial embryo mortality in the zebrafish model. Genomic analysis revealed virulence factors such as biofilm- (e.g., icaABCD; rsbUVW) and regulator- (e.g., agr, mgrA, sarA, saeS) encoding genes well characterized in S. aureus. This study thus advances the knowledge of this under investigated pathogen and validates the zebrafish infection model for this bacterium.
Mecp2 deletion results in profound alterations of developmental and adult functional connectivity
Authors: Rahn Rachel M. , Yen Allen , Chen Siyu , Gaines Seana H. , Bice Annie R. , Brier Lindsey M. , Swift Raylynn G. , Lee LeiLani , Maloney Susan E. , Culver Joseph P. , Dougherty Joseph D. 
Published: October 2021

AbstractAs a regressive neurodevelopmental disorder with a well-established genetic cause, Rett Syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into Mecp2’s role in functional circuit development. Thus, we applied optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex prior to symptom onset as well as during decline. We found that FC was profoundly disrupted in Mecp2 males both in juvenile development and early adulthood. Female Mecp2 mice displayed a subtle homotopic contralateral increase in motor cortex as juveniles but not in adulthood, where instead parietal regions were implicated. Additionally, conditional rescue studies indicated FC phenotypes are driven by excitatory neurons. Altogether, the female results identify subtle candidate translatable biomarkers of disease progression, while the male results indicate MeCP2 protein is needed in a circuit-specific manner for FC.
Defined microenvironments trigger in vitro gastrulation in human pluripotent stem cells
Authors: Srivastava Pallavi , Romanazzo Sara , Ireland Jake , Nemec Stephanie , Molley Thomas G. , Jayathilaka Pavithra , Pandzic Elvis , Yeola Avani , Chandrakanthan Vashe , Pimanda John , Kilian Kristopher 
Published: October 2021

AbstractEmbryogenesis is orchestrated through local morphogen gradients and endometrial constraints that give rise to the three germ layers in a well-defined assembly. In vitro models of embryogenesis have been demonstrated by treating pluripotent stem cells in adherent or suspension culture with soluble morphogens and small molecules, which leads to tri-lineage differentiation. However, treatment with exogenous agents override the subtle spatiotemporal changes observed in vivo that ultimately underly the human body plan. Here we demonstrate how microconfinement of pluripotent stem cells on hydrogel substrates catalyses gastrulation-like events without the need for supplements. Within six hours of initial seeding, cells at the boundary show elevated cytoskeletal tension and yes-associated protein (YAP) activity, which leads to changes in cell and nuclear morphology, epithelial to mesenchymal transition, and emergence of defined patterns of primitive streak containing SRY-Box Transcription Factor 17 (SOX17)+ T/BRACHYURY+ cells. Immunofluorescence staining, transcript analysis, and the use of pharmacological modulators reveal a role for mechanotransduction-coupled non-canonical wingless-type (WNT) signalling in promoting epithelial to mesenchymal transition and multilayered organization within the colonies. These microscale gastruloids were removed from the substrate and encapsulated in 3D hydrogels, where biomaterials properties correspond to maintenance and spatial positioning of the primitive streak. Together, this approach demonstrates how materials alone can nurture embryonic gastrulation, thereby providing an in vitro model of early development.