bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the inter-relationships between social isolation and loneliness and their correlates among older British adults before and during the COVID-19 lockdown: evidence from four British longitudinal studies
Authors: Mansfield Rosie , Di Gessa Giorgio , Patel Kishan , McElroy Eoin , Wels Jaques , Henderson Morag , Maddock Jane , Stafford Jean , Steptoe Andrew , Richards Marcus , Patalay Praveetha 
Published: June 2023

AbstractBackground and ObjectivesUnprecedented social restrictions during the COVID-19 pandemic have provided a new lens for considering the inter-relationship between social isolation and loneliness in later life. We present these inter-relationships before and during the COVID-19 restrictions and investigate to what extent demographic, socio-economic, and health factors associated with such experiences differed during the pandemic.Research Design and MethodWe used data from four British longitudinal population-based studies (1946 MRC NSHD, 1958 NCDS, 1970 BCS, and ELSA). Rates, co-occurrences, and correlates of social isolation and loneliness are presented prior to and during the early stage of the COVID-19 pandemic and the inter-relationships between these experiences are elucidated in both periods.ResultsAcross the four studies, pre-pandemic proportions reporting social isolation ranged from 15 to 54%, with higher rates in older ages (e.g., 32% of 70-79 and 54% of those over 80). During the pandemic, the percentage of older people reporting both social isolation and loneliness and isolation only slightly increased. The inter-relationship between social isolation and loneliness did not change. Associations between socio-demographic and health characteristics and social isolation and loneliness also remained consistent, with greater burden among those with greater economic precarity (females, non-homeowners, unemployed, illness and greater financial stress).Discussion and ImplicationsThere were already large inequalities in experiences of social isolation and loneliness and the pandemic had a small impact on worsening these inequalities. The concepts of loneliness and social isolation are not transferable and clarity is needed in how they are conceptualised, operationalised, and interpreted.
p53 secures the normal behavior of H3.1 histone in the nucleus by regulating nuclear phosphatidic acid and EZH2 during the G1/S phase
Authors: Oikawa Tsukasa , Hasegawa Junya , Handa Haruka , Ohnishi Naomi , Onodera Yasuhito , Hashimoto Ari , Sasaki Junko , Sasaki Takehiko , Ueda Koji , Sabe Hisataka 
Published: June 2023

AbstractHistones are key molecules of epigenetic regulation and inheritance, and are thought to be chaperoned and transported into the nucleus appropriately prior to being integrated into nucleosomes. H3.1 histone is predominantly synthesized and enters the nucleus during the G1/S phase of the cell cycle, as a new component of duplicating nucleosomes. Here we found that p53 is necessary to secure the normal behavior and modification of H3.1 in the nucleus during the G1/S phase, in which p53 increases C-terminal domain nuclear envelope phosphatase 1 (CTDNEP1) levels and decreases enhancer of zeste homolog 2 (EZH2) levels in the H3.1 interactome. In the absence of p53, H3.1 molecules tended to be tethered at or near the nuclear envelope (NE), where they were predominantly trimethylated at lysine 27 (H3K27me3) by EZH2, without forming nucleosomes. This accumulation was likely caused by the high affinity of H3.1 towards phosphatidic acid (PA). p53 reduced nuclear PA levels by increasing levels of CTDNEP1, which activates lipin to convert PA into diacylglycerol. Induction of theTMEM255Agene by p53 linked p53 with CTDNEP1, in which TMEM255A stabilized CTDNEP1. We moreover found that the cytosolic H3 chaperone HSC70 attenuates the H3.1-PA interaction, and our molecular imaging analyses suggested that H3.1 molecules may be anchored around the NE after their nuclear entry. Our results expand our knowledge of p53 function in regulation of the nuclear behavior of H3.1 during the G1/S phase, in which p53 may primarily target nuclear PA and EZH2.
Paridiprubart inhibits TLR4-dependant NF-κB activation by multiple pathogens
Authors: Malty Ramy , Hilbe Richard , Ahn Sang , Kesselman Leah , Lam Jessica , Kasawara Karina , Costa Larissa , Rajakulendran Nishani , Gordon Blair , Brooks Michael , Mubareka Samira , Tancevski Ivan , Gray-Owen Scott D. 
Published: June 2023

AbstractRespiratory pathogens such as SARS-CoV-2 and influenza can activate an exaggerated inflammatory response (cytokine storm) in the lungs that may result in acute respiratory distress syndrome (ARDS), hospitalization, and death. Therapies that target a specific pathogen (i.e. anti-virals) must, by nature, be selected after a specific diagnosis and may become ineffective due to pathogen evolution. An alternate strategy is to counter the exaggerated innate immune response present in ARDS patients using host-directed drug therapies that are agnostic to the infectious agent to overcome both of these challenges. Originally described as the innate immune receptor for lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) is now understood to be an important mediator of inflammation caused by a variety of pathogen-associated molecular patterns (PAMPs) and host-derived damage-associated molecular patterns (DAMPs). Here we show that paridiprubart, a monoclonal antibody that prevents TLR4 dimer formation, inhibits the response to TLR4 agonists including LPS, the SARS-CoV-2 spike protein, the DAMP high mobility group box 1 (HMGB1), as well as the NF-κB response to infection by both viral and bacterial pathogens. Notable in this regard, we demonstrate that SARS-CoV-2 increases HMGB1 levels, and that paridiprubart inhibits both the SARS-CoV-2 and HMGB1-triggered NF-κB response, illustrating its potential to suppress this self-amplifying inflammatory signal. We also observed that the inhibitory effect of paridiprubart is apparent when cells are exposed to the SARS-CoV-2 spike protein, which is itself a direct TLR4 agonist. In the context of active infection, paridiprubart suppressed the NF-κB-dependent response elicited by infection with SARS-CoV-2, the seasonal coronavirus 229E, influenza A virus orHaemophilus influenzae, a gram-negative bacterial pathogen. Combined, these findings reinforce the central role played by TLR4 in the inflammatory response to infection by diverse pathogens, and demonstrates the protective potential of paridiprubart-dependent inhibition of pathogenic TLR4 responses.
50-nm gas-filled protein nanostructures to enable the access of lymphatic cells by ultrasound technologies
Authors: Shen Qionghua , Li Zongru , Meyer Matthew D. , De Guzman Marc T. , Lim Janie C. , Bouchard Richard R. , Lu George J. 
Published: June 2023

ABSTRACTUltrasound imaging and ultrasound-mediated gene and drug delivery are rapidly advancing diagnostic and therapeutic methods; however, their use is often limited by the need of microbubbles, which cannot transverse many biological barriers due to their large size. Here we introduce 50-nm gas-filled protein nanostructures derived from genetically engineered gas vesicles that we referred to as50nmGVs. These diamond-shaped nanostructures have hydrodynamic diameters smaller than commercially available 50-nm gold nanoparticles and are, to our knowledge, the smallest stable, free-floating bubbles made to date.50nmGVs can be produced in bacteria, purified through centrifugation, and remain stable for months. Interstitially injected50nmGVs can extravasate into lymphatic tissues and gain access to critical immune cell populations, and electron microscopy images of lymph node tissues reveal their subcellular location in antigen-presenting cells adjacent to lymphocytes. We anticipate that50nmGVs can substantially broaden the range of cells accessible to current ultrasound technologies and may generate applications beyond biomedicine as ultrasmall stable gas-filled nanomaterials.
Nuclear quality control of non-imported secretory proteins attenuates proteostasis decline in the cytosol
Authors: Banik Papiya , Kamps Janine , Chen Qi-Yin , Luesch Hendrik , Winklhofer Konstanze F. , Tatzelt Jörg 
Published: June 2023

ABSTRACTMistargeting of secretory proteins to the cytosol can induce formation of aggregation-prone conformers and subsequent proteostasis decline. We have identified a quality control pathway that redirects non-ER-imported prion protein (PrP) to proteasomal degradation in the nucleus to prevent formation of toxic aggregates in the cytosol. Upon aborted ER import, PrP sequentially interacted with VCP/p97 and importins, which kept PrP soluble and promoted its nuclear import. In the nucleus, RNA buffered aggregation of PrP to facilitate ubiquitin-dependent proteasomal degradation. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import were independent of ubiquitination but required the intrinsically unstructured N-terminal domain of PrP. Transient proteotoxic stress promoted the formation of self-perpetuating PrP aggregates in the cytosol, which disrupted further nuclear targeting of PrP and compromised cellular proteostasis. Our study delineates a VCP/p97-dependent nucleus-based quality control pathway of non-ER-imported secretory proteins and emphasizes the important role of the nuclear milieu for the degradation of aggregation-prone proteins.
Deep learning pipeline reveals key moments in human embryonic development predictive of live birth in IVF
Authors: Mapstone Camilla , Hunter Helen , Brison Daniel , Handl Julia , Plusa Berenika 
Published: June 2023

AbstractDemand for IVF treatment is growing, however success rates remain low partly due to difficulty in selecting the best embryo to be transferred. Current manual assessments are subjective and may not take advantage of the most informative moments in embryo development. Here, we apply convolutional neural networks (CNNs) to identify key windows in preimplantation human development that can be linked to embryo viability and are therefore suitable for the early grading of IVF embryos. We show how machine learning models trained at these developmental time-points can be used to refine overall embryo viability assessment. Exploiting the well-known capabilities of transfer learning, we illustrate the performance of CNN models for very limited data sets, paving the way for the use on a clinic-by-clinic basis, catering for local data heterogeneity.
DENetwork: Unveiling Regulatory and Signaling Networks Behind Differentially-Expressed Genes
Authors: Su Ting-Yi , Islam Quazi S. , Huang Steven K. , Baglole Carolyn J. , Ding Jun 
Published: June 2023

ABSTRACTDifferential gene expression analysis from RNA-sequencing (RNA-seq) data offers crucial insights into biological differences between sample groups. However, the conventional focus on differentially-expressed (DE) genes often omits non-DE regulators, which are an integral part of such differences. Moreover, DE genes frequently serve as passive indicators of transcriptomic variations rather than active influencers, limiting their utility as intervention targets. To address these shortcomings, we have developedDENetwork. This innovative approach deciphers the intricate regulatory and signaling networks driving transcriptomic variations between conditions with distinct phenotypes. Unique in its integration of both DE and critical non-DE genes in a graphical model,DENetworkenhances the capabilities of traditional differential gene analysis tools, such asDESeq2. Our application ofDENetworkto an array of simulated and real datasets showcases its potential to encapsulate biological differences, as demonstrated by the relevance and statistical significance of enriched gene functional terms.DENetworkoffers a robust platform for systematically characterizing the biological mechanisms that underpin phenotypic differences, thereby augmenting our understanding of biological variations and facilitating the formulation of effective intervention strategies.
Divergent hepaciviruses, chuvirus and deltaviruses in Australian marsupial carnivores (Dasyurids) identified through transcriptome mining
Authors: Harvey Erin , Mifsud Jonathon C.O. , Holmes Edward C. , Mahar Jackie E. 
Published: June 2023

ABSTRACTAlthough Australian marsupials are characterised by unique biology and geographic isolation, little is known about the viruses present in these iconic wildlife species. The Dasyuromorphia are an order of marsupial carnivores found only in Australia that include both the extinct Tasmanian tiger (Thylacine) and the highly threatened Tasmanian devil. Several other members of the order are similarly under threat of extinction due to habitat loss, hunting, disease, and competition and predation by introduced species such as feral cats. We utilised publicly available RNA-seq data from the NCBI Sequence Read Archive (SRA) database to document the viral diversity within four Dasyuromorphia species. Accordingly, we identified 15 novel virus species from five DNA virus families (Adenoviridae,Anelloviridae,Herpesviridae,PapillomaviridaeandPolyomaviridae) and three RNA virus taxa: the orderJingchuvirales,the genusHepacivirus, and the delta-like virus group. Of particular note was the identification of a marsupial specific clade of delta-like viruses that may indicate an association of deltaviruses and with marsupial species dating back to their origin some 160 million years ago. In addition, we identified a highly divergent hepacivirus in a numbat liver transcriptome that falls outside of the larger mammalian clade, as well as the first detection of theJingchuviralesin a mammalian host – a chu-like virus in Tasmanian devils – thereby expanding the host range beyond invertebrates and ectothermic vertebrates. As many of these Dasyuromorphia species are currently being used in translocation efforts to reseed populations across Australia, understanding their virome is of key importance to prevent the spread of viruses to naive populations.
Multifaceted effects oneven-skippedtranscriptional dynamics uponKrüppeldosage changes
Authors: Lin Shufan , Lim Bomyi 
Published: June 2023

AbstractAlthough fluctuations in transcription factor (TF) dosage are often well tolerated, little is known about how TF dosage modulation changes the target gene expression dynamics and results in subsequent developmental phenotypes. Using MS2/MCP-mediated quantitative live imaging in earlyDrosophilaembryos, we characterized transcriptional dynamics of the pair-rule geneeven-skipped(eve) upon changing the gap geneKrüppel(Kr) level. DecreasingKrdosage by half leads to a transient posterior expansion of theevestripe 2 and an anterior shift of stripe 5. Surprisingly, the most significant changes are observed inevestripes 3 and 4, whose enhancers do not contain Kr binding sites. For both stripes, the widths of stripes are narrowed, boundaries are located more anteriorly, and the mRNA production level is reduced inKrheterozygous embryos. We show that Kr dosage indirectly affects stripes 3 and 4 dynamics by modulating other gap gene dynamics. We quantitatively correlate moderate body segment phenotypes ofKrheterozygotes with spatiotemporal changes ineveexpression. Our results indicate that nonlinear relationships between TF dosage and phenotypes underlie direct TF-DNA and indirect TF-TF interactions.Summary statementThis study analyzed the changes in transcriptional dynamics ofeven-skippedupon halvingKrüppeldosage, and revealed how the combination of direct TF-DNA and indirect TF-TF interactions shape proper patterning.
Identification of small molecule inhibitors of G3BP-driven stress granule formation
Authors: Freibaum Brian D. , Messing James , Nakamura Haruko , Yurtsever Ugur , Wu Jinjun , Kim Hong Joo , Hixon Jeff , Lemieux Rene , Duffner Jay , Huynh Walter , Wong Kathy , White Michael , Lee Christia , Meyers Rachel , Parker Roy , Taylor J. Paul 
Published: June 2023

ABSTRACTStress granule formation is triggered by the release of mRNAs from polysomes and is promoted by the action of the paralogs G3BP1 and G3BP2. G3BP1/2 proteins bind mRNAs and thereby promote the condensation of mRNPs into stress granules. Stress granules have been implicated in several disease states, including cancer and neurodegeneration. Consequently, compounds that limit stress granule formation or promote their dissolution have potential as both experimental tools and novel therapeutics. Herein, we describe two small molecules, referred to as G3BP inhibitor a and b (G3Ia and G3Ib), designed to bind to a specific pocket in G3BP1/2 that is known to be targeted by viral inhibitors of G3BP1/2 function. In addition to disrupting co-condensation of RNA, G3BP1, and caprin 1in vitro, these compounds inhibit stress granule formation in cells treated prior to or concurrent with stress, and dissolve pre-existing stress granules when added to cells after stress granule formation. These effects are consistent across multiple cell types and a variety of initiating stressors. Thus, these compounds represent ideal tools to probe the biology of stress granules and hold promise for therapeutic interventions designed to modulate stress granule formation.
Lysine vitcylation is a novel vitamin C-derived protein modification that enhances STAT1-mediated immune response
Authors: He Xiadi , Wei Yun , Wu Jiang , Wang Qiwei , Bergholz Johann S. , Gu Hao , Zou Junjie , Lin Sheng , Wang Weihua , Xie Shaozhen , Jiang Tao , Lee James , Asara John M. , Zhang Ke , Cantley Lewis C. , Zhao Jean J. 
Published: June 2023

SUMMARYVitamin C (vitC) is a vital nutrient for health and also used as a therapeutic agent in diseases such as cancer. However, the mechanisms underlying vitC’s effects remain elusive. Here we report that vitC directly modifies lysine without enzymes to form vitcyl-lysine, termed “vitcylation”, in a dose-, pH-, and sequence-dependent manner across diverse proteins in cells. We further discover that vitC vitcylates K298 site of STAT1, which impairs its interaction with the phosphatase PTPN2, preventing STAT1 Y701 dephosphorylation and leading to increased STAT1-mediated IFN pathway activation in tumor cells. As a result, these cells have increased MHC/HLA class-I expression and activate immune cells in co-cultures. Tumors collected from vitC-treated tumor-bearing mice have enhanced vitcylation, STAT1 phosphorylation and antigen presentation. The identification of vitcylation as a novel PTM and the characterization of its effect in tumor cells opens a new avenue for understanding vitC in cellular processes, disease mechanisms, and therapeutics.
The Role of VSL#3® in the Treatment of Fatigue and Other Symptoms in Long Covid-19 Syndrome: a Randomized, Double-blind, Placebo-controlled Pilot Study (DELong#3)
Authors: Marinoni Beatrice , Rimondi Alessandro , Bottaro Federico , Ciafardini Clorinda , Amoroso Chiara , Muià Martina , Caridi Bruna , Noviello Daniele , Bandera Alessandra , Gori Andrea , Mantero Marco , Blasi Francesco , Ferrucci Roberta , Facciotti Federica , Vecchi Maurizio , Caprioli Flavio 
Published: June 2023

AbstractLong COVID, also known as Post-acute COVID-19 Syndrome (PACS), is a chronic condition affecting individuals who have recovered from acute COVID-19. It is currently estimated that around 65 million people worldwide suffer from Long COVID. It is characterized by a range of symptoms, including fatigue, exertion intolerance, neurocognitive and sensory impairment, sleep disturbance, myalgia/arthralgia, and dysautonomia. Among them fatigue has emerged as a burdensome and pervasive issue, significantly impacting the quality of life and daily functioning of Long COVID patients. Alterations in the composition of the intestinal microbiota has been reported in COVID-19 patients. Dysbiosis persists even after several months of recovery from acute SARS-CoV-2 infection.Based on this evidence, we carried out a phase 3, randomized, double-blind, placebo-controlled trial aimed at evaluating the efficacy of VSL#3®, a consortium of probiotic bacterial strains, in reducing fatigue and improving various aspects of patients’ well-being in patients with Long COVID syndrome.HighlightsPatients suffering from Long-COVID manifest a variety of persistent symptoms impacting daily functioning;Fatigue emerged as a burdensome and pervasive issue, significantly impacting the quality of life;VSL#3® treatment significantly reduced the Chalder Fatigue Scale scores as compared to placeboChalder Fatigue Scale scores remained significantly reduced in the treatment group 4 weeks post intervention.
Nuclear lamin A/C phosphorylation by loss of Androgen Receptor is a global determinant of cancer-associated fibroblast activation
Authors: Ghosh Soumitra , Isma Jovan , Mazzeo Luigi , Toniolo Annagiada , Simon Christian , Dotto G. Paolo 
Published: June 2023

ABSTRACTAlterations of nuclear structure and function, and associated impact on gene transcription, are a hallmark of cancer cells. Little is known of these alterations in Cancer-Associated Fibroblasts (CAFs), a key component of the tumor stroma. Here we show that loss of androgen receptor (AR), which triggers early steps of CAF activation in human dermal fibroblasts (HDFs), leads to nuclear membrane alterations and increased micronuclei formation, which are unlinked from induction of cellular senescence. Similar alterations occur in fully established CAFs, which are overcome by restored AR function. AR associates with nuclear lamin A/C and loss of AR results in a substantially increased lamin A/C nucleoplasmic redistribution. Mechanistically, AR functions as a bridge between lamin A/C with the protein phosphatase PPP1. In parallel with a decreased lamin-PPP1 association, AR loss results in a marked increase of lamin A/C phosphorylation at Ser 301, which is also a feature of CAFs. Phosphorylated lamin A/C at Ser 301 binds to the transcription promoter regulatory region of several CAF effector genes, which are upregulated due to the loss of AR. More directly, expression of a lamin A/C Ser301 phosphomimetic mutant alone is sufficient to convert normal fibroblasts into tumor-promoting CAFs of the myofibroblast subtype, without an impact on senescence. These findings highlight the pivotal role of the AR-lamin A/C-PPP1 axis and lamin A/C phosphorylation at Ser 301 in driving CAF activation.