bluuebunny/crossref_metadata_2025_split huggingface dataset:
The COVID19 pandemic has changed women’s experiences of pregnancy in the UK
Authors: Sturrock Sarah , Turner Kim , Lee-Wo Chelone , Greening Vanessa , Khalil Asma , Heath Paul T , Doare Kirsty Le 
Published: November 2021

AbstractIntroductionDuring the SARS-CoV-2 pandemic, maternity care has been substantially altered to reduce transmission of the SARS-CoV-2 virus. Many antenatal services are now restricted or delivered online, and visiting has been restricted during labour and in the postnatal period.MethodsWe conducted an online survey from 1st August to 31st December 2020 to investigate the experiences of women who were pregnant or breastfeeding in the UK during the SARS-CoV-2 pandemic. The survey included 55 open and closed questions and required 5 minutes to complete. We publicised the survey using social media.ResultsWe received 96 responses, including 66 currently pregnant women and 22 women who were pregnant during the pandemic. The response rate was 70.1% of survey views. We found mixed experiences of the impact of the pandemic on antenatal and perinatal care, notably with some women feeling visiting restrictions were insufficient and others feeling they were too strict. Twenty-nine women received no information about COVID-19, and 6 women found it very difficult to find information. Thirty-nine women would have liked to have more information about breastfeeding after a pregnancy affected by COVID-19, and 37 women wanted more information about antibody persistence and transfer.DiscussionAdditional support is required for pregnant and lactating women during the current pandemic. Provision of information and support, including via social media, may improve women’s experiences of pregnancy in the current environment.SignificanceMaternity services in the UK have been significantly restructured to prevent transmission of the SARS-CoV-2 virus, including restrictions to in-person antenatal care, and perinatal visiting. It is not fully known how these changes are perceived by pregnant and breastfeeding women.Reactions to changes in antenatal care are mixed, including whether restrictions were too lenient or too strict. Most women underwent online antenatal care in addition in-person visits. Some received no information about COVID-19, and a significant proportion of women would have liked more information, particularly regarding antibody transfer and benefits of breastfeeding during the pandemic.Ethical statementThis study was approved by North East - Newcastle & North Tyneside 1 Research Ethics Committee
A SARS-CoV-2 variant of concern triggers Fc effector function with increased cross-reactivity
Authors: Richardson Simone I. , Manamela Nelia P. , Motsoeneng Boitumelo M. , Kaldine Haajira , Ayres Frances , Makhado Zanele , Mennen Mathilda , Skelem Sango , Williams Noleen , Sullivan Nancy J. , Misasi John , Gray Glenda G. , Bekker Linda-Gail , Ueckermann Veronica , Rossouw Theresa M. , Boswell Michael T. , Ntusi Ntobeko A. B. , Burgers Wendy A. , Moore Penny L. 
Published: November 2021

SummarySARS-CoV-2 variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with decreased disease severity and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta infection triggered responses with significantly improved Fc cross-reactivity against global VOCs compared to either D614G infected or Ad26.COV2.S vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence impacts Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.
Targeting SerpinE1 reverses cellular features of Hutchinson-Gilford progeria syndrome
Authors: Catarinella Giorgia , Nicoletti Chiara , Bracaglia Andrea , Procopio Paola , Salvatori Illari , Taggi Marilena , Ferri Alberto , Valle Cristiana , Canipari Rita , Puri Pier Lorenzo , Latella Lucia 
Published: November 2021

AbstractHutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal disease caused by Lamin A mutation, leading to altered nuclear architecture, loss of perinuclear heterochromatin and deregulated gene expression. HGPS patients eventually die by coronary artery disease and cardiovascular alterations. However, how deregulated transcriptional networks at the cellular level impact on the systemic disease phenotype is currently unclear. We have performed a longitudinal genome-wide analysis of gene expression in primary HGPS fibroblasts from patients at two sequential stages of disease that revealed a progressive activation of Rho signaling and SerpinE1, also known as Plasminogen Activator Inhibitor (PAI-1). siRNA-mediated downregulation or pharmacological inhibition of SerpinE1 by TM5441 could revert key pathological features of HGPS in patient-derived fibroblasts, including re-activation of cell cycle progression, reduced DNA damage signaling, decreased expression of pro-fibrotic genes and recovery of mitochondrial defects. These effects were accompanied by reduced levels of Progerin and correction of nuclear abnormalities. These data point to SerpinE1 as a novel potential effector of HGPS pathogenesis and target for therapeutic interventions.
Parental genomes segregate into different blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts
Authors: De Coster Tine , Masset Heleen , Tšuiko Olga , Catteeuw Maaike , Dierckxsens Nicolas , Debrock Sophie , Peeraer Karen , Smits Katrien , Van Soom Ann , Vermeesch Joris Robert 
Published: November 2021

AbstractThe zygotic division enables two haploid genomes to segregate into two biparental diploid blastomeres. This fundamental tenet was challenged by the observation that blastomeres with different genome ploidy or parental genotypes can coexist within individual embryos. We hypothesized that whole parental genomes can segregate into distinct blastomere lineages during the first division through “heterogoneic division”. Here, we map the genomic landscape of 82 blastomeres from 25 embryos that underwent multipolar zygotic division. The coexistence of androgenetic and diploid or polyploid blastomeres with or without anuclear blastomeres, and androgenetic and gynogenetic blastomeres within the same embryo proofs the existence of heterogoneic division. We deduced distinct segregation mechanisms and demonstrate these genome-wide segregation errors to persist to the blastocyst stage in both human and cattle. Genome-wide zygotic segregation errors contribute to the high incidence of embryonic arrest and provide an overarching paradigm for the development of mixoploid and chimeric individuals and moles.
Internal state dependent control of feeding behaviour via hippocampal ghrelin signalling
Authors: Wee Ryan W. S. , Mishchanchuk Karyna , AlSubaie Rawan , MacAskill Andrew F. 
Published: November 2021

ABSTRACTHunger is an internal state that not only invigorates feeding, but also acts as a contextual cue for the higher-order control of anticipatory feeding-related behaviour. The ventral hippocampus is a brain region crucial for differentiating optimal behaviour across different contexts, but how internal context such as hunger influence hippocampal circuits to define behaviour is not known. Pyramidal neurons in the ventral hippocampus, including the ventral CA1/subiculum border (vS) express the receptor for the peripheral hunger hormone ghrelin, and ghrelin is known to cross the blood brain barrier and directly influence hippocampal circuitry. But how ghrelin influences vS has not been directly investigated. In this study, we used a combination of electrophysiology, optogenetics andin vivocalcium imaging in mice to investigate the role of vS during feeding behaviour across different states of hunger. We found that activity of a unique subpopulation of vS neurons that project to the nucleus accumbens (vS-NAc) increased when animals approached and investigated food, and this activity inhibited the transition to begin eating. Increases in peripheral ghrelin reduced vS-NAc activity during this anticipatory phase of feeding behaviour by increasing the postsynaptic influence of inhibition, and promoted the initiation of eating. Furthermore, this peripheral ghrelin-induced inhibition required postsynaptic expression of the ghrelin receptor GHSR1a in vS-NAc neurons, and removal of GHSR1a from vS-NAc neurons impaired ghrelin-induced changes in feeding-related behaviour. Together, these experiments define a ghrelin-sensitive hippocampal circuit that informs the decision to eat based on internal state.
Injectable Nanoporous Microgels Generate Vascularized Constructs and Support Bone Regeneration in Critical-sized Defects
Authors: Patrick Matthew D. , Keys Jeremy F. , Sureshkumar Harshini , Annamalai Ramkumar T. 
Published: November 2021

AbstractLarge and aberrant bone fractures require ossification and concomitant vascularization for proper healing. Evidence indicates that osteogenesis and vessel growth are coupled in bone fractures. Although the synergistic role of endothelial cells has been recognized, vascularizing large bone grafts remains a challenge and has apprehended the clinical translation of engineered bone constructs. Here, we describe a facile method to fabricate vascularized constructs using chitosan and gelatin-based microgels that promote osteogenesis of human mesenchymal stromal cells (MSC) while supporting endothelial sprouting and network formation. The microgels are enzymatically degradable and had a high hydration rate with a volume swelling ratio of ~560% and a polymer density of ~430 mg/cm3, which is comparable to that of native skeletal tissues. AFM indentation of the surface showed an average Young’s modulus of 189 kPa, falling in a range that is conducive to both osteogenesis and vasculogenesis. The osteogenic microgel containing chitosan, gelatin, and hydroxyapatite, mimicking the bone matrix, supported robust attachment, proliferation, and differentiation of MSC. On the other hand, the vasculogenic microgels containing only gelatin, enriched endothelial phenotype and enabled vascular networks formation when embedded in 3D matrices. Combining the two types of microgels created a hybrid construct that sustained the functions of both osteogenic and vasculogenic microgels and enhanced one another. Using a murine model, we also show that the osteogenic microgels regenerate bone in a critical-sized defect with >95% defect closure by week 12. These multifunctional microgels can be administered minimally invasively and can conformally fill large bone defects. This work lays the foundation to establish principles of designing multiphasic scaffolds with tissue-specific biophysical and biochemical properties for regenerating vascularized and interfacial tissues.
Assessment of AI-based Protein Structure Prediction for the NLRP3 Target
Authors: Yin Jian , Lei Junkun , Yu Jialin , Cui Weiren , Zhou Yifan , Feng Hua , Deng Jason , Su Wenji , Kuai Letian 
Published: November 2021

AbstractThe recent success of AlphaFold and RoseTTAFold has demonstrated the values of AI methods in predicting highly accurate protein structures. Despite the advances, their roles in the context of small-molecule drug discovery need to be thoroughly explored. In this study, we evaluated whether the AI-based models can lead to reliable three-dimensional structures of protein-ligand complexes. The structure we predicted was NLRP3, a challenging protein target in terms of obtaining the three-dimensional model both experimentally and computationally. The conformation of the binding pockets generated by the AI models were carefully characterized and compared with experimental structures. Further molecular docking results indicated that AI-predicted protein structures combined with molecular dynamics simulations can be useful in small-molecule drug discovery.
Organizing Principles of Astrocytic Nanoarchitecture in the Mouse Cerebral Cortex
Authors: Salmon Christopher K. , Syed Tabish A. , Kacerovsky J. Benjamin , Alivodej Nensi , Schober Alexandra L. , Pratte Michael T. , Rosen Michael P. , Green Miranda , DasGupta Adario , Vali Hojatollah , Mandato Craig A. , Siddiqi Kaleem , Murai Keith K. 
Published: November 2021

SUMMARYAstrocytes have complex roles in central nervous system (CNS) health and disease. Underlying these roles is an elaborate architecture based on frequent, extremely fine, but seemingly haphazard branches, as well as prominent features including tripartite synaptic complexes and perivascular endfeet. While broad categories of structures in astrocytes are known, the fundamental building blocks that compose them and their organizing principles have yet to be adequately defined. This is largely due to the absence of high-resolution datasets that can reveal nanoscopic features of astrocytes (i.e. 10-20nm diameter in x, y, and z) and a lack of computational approaches that can effectively interrogate astrocyte shape, organization, and nanoarchitecture. Here, we produced and analyzed multiple, high-resolution datasets of layer 2/3 mouse somatosensory cortex using focused ion beam scanning electron microscopy (8nm intervals) and computer vision approaches to provide a principled, quantitative analysis of astrocytic nanoarchitecture. A decomposition of astrocytes into fundamental ‘parts’ led to the discovery of unique structural components, recurring structural motifs, and assembly of parts into an organized hierarchy. New relationships were also discerned between astrocytic processes and other CNS microanatomy including mitochondria, tripartite synapses, and cerebrovasculature. By deploying computational resources to quantitatively understand the organizing principles and nanoarchitecture of astrocytes, this study reveals the specialized anatomical adaptations of these complex cells within the CNS.One Sentence SummaryUsing high-resolution serial electron microscopy datasets and computer vision, this study provides a systematic analysis of astrocytic nanoarchitecture from multiple samples of layer 2/3 of adult mouse neocortex, and presents quantitative evidence that astrocytes organize their morphology into purposeful, classifiable assemblies with unique structural and subcellular organelle adaptations related to their physiological functions.
The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless
Authors: Chen Rui , Deng Xiaobing , Zhu Sijun 
Published: November 2021

AbstractIntermediate neural progenitors (INPs) boost the number and diversity of neurons generated from neural stem cells (NSCs) by undergoing transient proliferation. In the developing Drosophila brains, INPs are generated from type II neuroblasts (NBs). In order to maintain type II NB identity and their capability to produce INPs, the proneural protein Asense (Ase) needs to be silenced by the Ets transcription factor pointed P1 (PntP1), a master regulator of type II NB development. However, the molecular mechanisms underlying the PntP1-mediated suppression of Ase is still unclear. In this study, we utilized genetic and molecular approaches to determine the transcriptional property of PntP1 and identify the direct downstream effector of PntP1 and the cis-DNA elements that mediate the suppression of ase. Our results demonstrate that PntP1 directly activates the expression of the transcriptional repressor, Tailless (Tll), by binding to seven Ets-binding sites, and Tll in turn suppresses the expression of Ase in type II NBs by binding to two hexameric core half-site motifs. We further show that Tll provides positive feedback to maintain the expression of PntP1 and the identity of type II NBs. Thus, our study identifies a novel direct target of PntP1 and reveals mechanistic details of the specification and maintenance of the type II NB identity by PntP1.Author summaryType II neuroblasts (NBs) are the neural stem cells (NSCs) in Drosophila central brains that produce neurons by generating intermediate neural progenitors (INPs) to boost brain complexity, as mammalian NSCs do during the development of neocortex. The key to the generation of INPs from type II NBs is the suppression of proneural protein Asense (Ase) in type II NBs by the Ets family transcription factor Pointed P1 (PntP1), but how PntP1 suppresses Ase expression remains unclear. In this study, we provided evidence to demonstrate that PntP1 directly activates the orphan nuclear receptor Tailless (Tll), which in turn suppresses Ase expression to maintain the capability of type II NBs to produce INPs. Meanwhile, Tll provides positive feedback to maintain the expression of PntP1 and type II NB identity. We further identified seven PntP1 binding sites in the tll enhancer regions and two Tll binding sites in the ase regulatory regions that mediate the activation of tll and the suppression of ase, respectively. Our work reveals detailed mechanisms of the specification and maintenance of the type II NB identity by PntP1.
Stress- and metabolic responses of Candida albicans require Tor1 kinase N-terminal HEAT repeats
Authors: Qi Wanjun , Acosta-Zaldivar Maikel , Flanagan Peter R. , Liu Ning-Ning , Jani Niketa , Fierro José F. , Andrés María T. , Moran Gary P. , Köhler Julia R. 
Published: November 2021

AbstractWhether to commit limited cellular resources toward growth and proliferation, or toward survival and stress responses, is an essential determination made by Target of Rapamycin Complex 1 (TORC1) for a eukaryotic cell in response to favorable or adverse conditions. Loss of TORC1 function is lethal. The TORC1 inhibitor rapamycin that targets the highly conserved Tor kinase domain kills fungal pathogens like Candida albicans, but is also severely toxic to human cells. The least conserved region of fungal and human Tor kinases are the N-terminal HEAT domains. We examined the role of the 8 most N-terminal HEAT repeats of C. albicans Tor1. We compared nutritional- and stress responses of cells expressing a message for N-terminally truncated Tor1 from repressible tetO, with cells expressing a wild type TOR1 allele from tetO or from the native promoter. Some but not all stress responses were significantly impaired by loss of Tor1 N-terminal HEAT repeats, including those to oxidative-, cell wall-, and heat stress; in contrast, plasma membrane stress and antifungal agents that disrupt plasma membrane function were tolerated by cells lacking this Tor1 region. Translation was inappropriately upregulated during oxidative stress in cells lacking N-terminal Tor1 HEAT repeats despite simultaneously elevated Gcn2 activity, while activation of the oxidative stress response MAP kinase Hog1 was weak. Conversely, these cells were unable to take advantage of favorable nutritional conditions by accelerating their growth. While consuming oxygen more slowly than cells containing wild type TOR1 alleles during growth in glucose, cells lacking N-terminal Tor1 HEAT repeats were capable of utilizing non-fermentable as well as fermentable carbon sources and of growth during severe acid stress, but were uniquely unable to grow on lactate. Genome-wide expression analysis showed paradoxical simultaneous activation of anabolic- and starvation responses in cells lacking Tor1 N-terminal HEAT repeats, with misregulation of carbon metabolism and of translational machinery biosynthesis. Targeting fungal-specific Tor1 N-terminal HEAT repeats with small molecules might abrogate fungal viability, especially when during infection multiple stresses are imposed by the host immune system.
Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells
Authors: Harris Rebecca , Yang Ming , Schmidt Christina , Singh Sarbjit , Natarajan Amarnath , Frezza Christian , Laman Heike 
Published: November 2021

AbstractDeregulated Fbxo7 expression is associated with many pathologies, including anaemia, male sterility, cancer, and Parkinson’s disease, demonstrating its critical role in a variety of cell types. Although Fbxo7 is an F-box protein that recruits substrates for SCF-type E3 ubiquitin ligases, it also promotes the formation of cyclin D/Cdk6/p27 complexes in an E3-ligase independent fashion. We discovered PFKP, the major gatekeeper of glycolysis, in a screen for Fbxo7 substrates. PFKP has been previously shown to be a critical substrate of Cdk6 for the viability of T-ALL cells. We investigated the molecular relationships between Fbxo7, Cdk6 and PFKP, and the functional effect Fbxo7 has on T cell metabolism, viability, and activation. Fbxo7 promotes Cdk6-independent ubiquitination and Cdk6-dependent phosphorylation of PFKP. Importantly Fbxo7-deficient cells have reduced Cdk6 activity, and haematopoietic and lymphocytic cell lines show a significant dependency on Fbxo7. Compared to WT cells, CD4+ T cells with reduced Fbxo7 expression show increased glycolysis, despite lower cell viability and activation levels. Metabolomic studies of activated CD4+ T cells confirm increased glycolytic flux in Fbxo7-deficient cells, as well as altered nucleotide biosynthesis and arginine metabolism. We show Fbxo7 expression is glucose-responsive at the mRNA and protein level, and we propose Fbxo7 inhibits PFKP and glycolysis via its activation of Cdk6.
Scalable Species Tree Inference with External Constraints
Authors: Liu Baqiao , Warnow Tandy 
Published: November 2021

AbstractSpecies tree inference under the multi-species coalescent (MSC) model is a basic step in biological discovery. Despite the developments in recent years of methods that are proven statistically consistent and that have high accuracy, large datasets create computational challenges. Although there is generally some information available about the species trees that could be used to speed up the estimation, only one method–ASTRAL-J, a recent development in the ASTRAL family of methods–is able to use this information. Here we describe two new methods, NJst-J and FASTRAL-J, that can estimate the species tree given partial knowledge of the species tree in the form of a non-binary unrooted constraint tree.. We show that both NJst-J and FASTRAL-J are much faster than ASTRAL-J and we prove that all three methods are statistically consistent under the multi-species coalescent model subject to this constraint. Our extensive simulation study shows that both FASTRAL-J and NJst-J provide advantages over ASTRAL-J: both are faster (and NJst-J is particularly fast), and FASTRAL-J is generally at least as accurate as ASTRAL-J. An analysis of the Avian Phylogenomics project dataset with 48 species and 14,446 genes presents additional evidence of the value of FASTRAL-J over ASTRAL-J (and both over ASTRAL), with dramatic reductions in running time (20 hours for default ASTRAL, and minutes or seconds for ASTRAL-J and FASTRAL-J, respectively).AvailabilityFASTRAL-J and NJst-J are available in open source form at https://github.com/RuneBlaze/FASTRAL-constrained and https://github.com/RuneBlaze/NJst-constrained. Locations of the datasets used in this study and detailed commands needed to reproduce the study are provided in the supplementary materials at http://tandy.cs.illinois.edu/baqiao-suppl.pdf.