bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein interaction network analysis reveals growth conditions-specific crosstalk between chromosomal DNA replication and other cellular processes in E. coli
Authors: Morcinek-Orłowska Joanna , Walter Beata Maria , Forquet Raphaël , Cysewski Dominik , Carlier Maxime , Meyer Sam , Glinkowska Monika 
Published: December 2021

AbstractE. coli and many other bacterial species can alter their cell cycle according to nutrient availability. Under optimal conditions bacteria grow and divide very fast but they slow down the cell cycle when conditions deteriorate. This adaptability is underlined by mechanisms coordinating cell growth with duplication of genetic material and cell division. Several mechanisms regulating DNA replication process in E. coli have been described with biochemical details so far. Nevertheless we still don’t fully understand the source of remarkable precision that allows bacterial cells to coordinate their growth and chromosome replication. To shed light on regulation of E. coli DNA replication at systemic level, we used affinity purification coupled with mass spectrometry (AP-MS) to characterize protein-protein interactions (PPIs) formed by key E. coli replication proteins, under disparate bacterial growth conditions and phases. We present the resulting dynamic replication protein interaction network (PIN) and highlight links between DNA replication and several cellular processes, like outer membrane synthesis, RNA degradation and modification or starvation response.ImportanceDNA replication is a vital process, ensuring propagation of genetic material to progeny cells. Despite decades of studies we still don’t fully understand how bacteria coordinate chromosomal DNA duplication with cell growth and cell division under optimal and stressful conditions. At molecular level, regulation of processes, including DNA replication, is often executed through direct protein-protein interactions (PPIs). In this work we present PPIs formed by the key E. coli replication proteins under three different bacterial growth conditions. We show novel PPIs with confirmed impact on chromosomal DNA replication. Our results provide also alternative explanations of genetic interactions uncovered before by others for E.coli replication machinery.
Low circulating adropin levels in late-middle aged African Americans with poor cognitive performance
Authors: Aggarwal Geetika , Malmstrom Theodore K. , Morley John E. , Miller Douglas K. , Nguyen Andrew D. , Butler Andrew A. 
Published: December 2021

ABSTRACTWe recently reported accelerated cognitive decline in Europeans aged >70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations also associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR=0.775, P<0.05; age range 45-65y, n=352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Advanced age suppresses adropin expression in all cell-types, with no effect of dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin amd transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Suppression of astrocyte adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline.
Nanoscale architecture and coordination of actin cores within the sealing zone of human osteoclasts
Authors: Portes Marion , Mangeat Thomas , Escallier Natacha , Raynaud-Messina Brigitte , Thibault Christophe , Maridonneau-Parini Isabelle , Vérollet Christel , Poincloux Renaud 
Published: December 2021

AbstractOsteoclasts are unique in their capacity to degrade bone tissue. To achieve this process, osteoclasts form a specific structure called the sealing zone, which creates a close contact with bone and confines the release of protons and hydrolases for bone degradation. The sealing zone is composed of actin structures called podosomes nested in a dense actin network. The organization of these actin structures inside the sealing zone at the nano scale is still unknown. Here, we combine cutting-edge microscopy methods to reveal the nanoscale architecture and dynamics of the sealing zone formed by human osteoclasts on bone surface. Random illumination microscopy allowed the identification and live imaging of densely packed actin cores within the sealing zone. A cross-correlation analysis of the fluctuations of actin content at these cores indicates that they are locally synchronized. Further examination shows that the sealing zone is composed of groups of synchronized cores linked by α-actinin1 positive filaments, and encircled by adhesion complexes. Thus, we propose that the confinement of bone degradation mediators is achieved through the coordination of islets of actin cores and not by the global coordination of all podosomal subunits forming the sealing zone.
Boron Supply Restores Aluminum-Blocked Auxin Transport by Modulation PIN2 Trafficking in the Arabidopsis Roots
Authors: Tao Lin , Feng Yingming , Li Yalin , Li Xuewen , Meng Xiaodong , Li Meng , Pirayesh Niloufar , Mahmud Sakil , Shabala Sergey , Baluška František , Shi Lei , Yu Min 
Published: December 2021

AbstractThis study tested a hypothesis that boron (B) supply alleviates aluminum (Al) toxicity by modifying auxin distribution in functionally different root zones. Auxin distribution and transport at various Al and B ratios were analyzed using the range of molecular and imaging techniques. Al stress resulted in increased auxin accumulation in root apical meristem (MZ) and transition zones (TZ) while reducing its content in elongation zone (EZ). This phenomenon was explained by reduction in basipetal auxin transport caused by Al blockage of PIN2 endocytosis, regulated at posttranscriptional level. This inhibition of PIN2 endocytosis was dependent on actin filaments and microtubules. B supply facilitated the endocytosis and exocytosis of PIN2 carriers via recycling endosomes conjugated with IAA to modify Al-induced auxin depletion in the EZ. However, disruption of auxin signaling with auxinole did not alleviate Al-induced inhibition of root growth. B supply alleviates Al-induced inhibition of root growth via restoring the endocytic recycling of PIN2 proteins involved in the basipetal (shootward) auxin transport, restoring Al-induced auxin depletion in the elongation zone.Short summaryAluminum-intensified PIN2 abundance, nontranscriptional, via repressing PIN2 endocytosis to block polar auxin transport, and this adverse effect could be alleviated by boron supply.
Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda
Authors: Lengeler Christian , Burri Christian , Awor Phyllis , Athieno Prosciova , Kimera Joseph , Tumukunde Gloria , Angiro Irene , Tshefu Antoinette , Okitawutshu Jean , Kalenga Jean-Claude , Omoluabi Elizabeth , Akano Babatunde , Ayodeji Kazeem , Okon Charles , Yusuf Ocheche , Brunner Nina C , Delvento Giulia , Lee Tristan , Lambiris Mark , Visser Theodoor , Napier Harriet G , Cohen Justin M , Buj Valentina , Signorell Aita , Hetzel Manuel W ,   the CARAMAL Consortium
Published: December 2021

AbstractThe key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s. RAS allows the rapid initiation of life-saving antimalarial treatment, before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed to-date: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact.From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in Nigeria, Uganda and the Democratic Republic of the Congo (DRC). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. In order to achieve this, a number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed to track cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS.Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and cost-effectiveness of the RAS intervention.
Adverse event reviews in healthcare: What matters to patients and their family? A qualitative study exploring the perspective of patients and family
Authors: McQueen Jean , Gibson Kyle , Manson Moira , Francis Morag 
Published: December 2021

AbstractObjectivesExplore what ‘good’ patient and family involvement in healthcare adverse event reviews may involve.DesignData was collected using semi-structured telephone interviews. Interview transcripts were analysed using an inductive thematic approach.SettingNHS Scotland.Participants19 interviews were conducted with patients who had experienced an adverse event during the provision of their healthcare, or their family member.ResultsFour key themes were derived from these interviews: trauma, communication, learning and litigation.ConclusionsFindings suggest there are many advantages of actively involving patients and their families in adverse event reviews. An open, collaborative, person-centred approach which listens to, and involves, patients and their families is perceived to lead to improved outcomes for all. For the patient and their family, it can help with reconciliation following a traumatic event and help restore their faith in the healthcare system. For the health service, listening and involving people will likely enhance learning with subsequent improvements in healthcare provision with reduction in risk of similar events occurring for other patients. Communicating in a compassionate manner could also decrease litigation claims following an adverse event. Overall, having personalised conversations and a streamlined review process, with open engagement to enhance learning, was important to most participants in this study.
COVID-19 vaccine effectiveness against laboratory confirmed symptomatic SARS-CoV-2 infection, COVID-19 related hospitalizations and deaths, among individuals aged 65 years or more in Portugal: a cohort study based on data-linkage of national registries February-September 2021
Authors: Machado Ausenda , Kislaya Irina , Rodrigues Ana Paula , Sequeira Duarte , Lima João , Cruz Camila , Leite Pedro Pinto , Matias-Dias Carlos , Nunes Baltazar 
Published: December 2021

AbstractBackgroundUsing data from electronic health registries, this study intended to estimate the COVID-19 vaccine effectiveness in the population aged 65 years and more, against symptomatic infection, COVID-19 related hospitalizations and deaths, overall and by time since complete vaccination.MethodsWe stablished a cohort of individuals aged 65 and more years old, resident in Portugal mainland, using the National Health Service unique identifier User number to link eight electronic health registries. Outcomes included were symptomatic SARS-CoV-2 infections, COVID-19 related hospitalizations or deaths. The exposures of interest were the mRNA vaccines (Cominarty or Spikevax) and the viral vector Vaxzevria vaccine. Complete scheme vaccine effectiveness (VE) was estimated as one minus the confounder adjusted hazard ratio, for each outcome, estimated by time-dependent Cox regression with time dependent vaccine exposure.ResultsFor the cohort of individuals aged 65-79 years, complete scheme VE against symptomatic infection varied between 43% (Vaxzevria) and 65% (mRNA vaccines). This estimate was slightly lower in the ≥80 year cohort (53% for mRNA vaccines. VE against COVID-19 hospitalization varied between 89% (95%CI: 52-94) for Vaxzevria and 95% (95%CI: 93-97) for mRNA vaccines for the cohort aged 65-79 years and was 76% (95%CI: 67-83) for mRNA vaccines in the ≥80 year cohort. High VE against COVID-19 related deaths were estimated, for both vaccine types, 95% and 81% for the 65-79 years and the ≥80 year cohort, respectively.We observed a significant waning of VE against symptomatic infection, with VE estimates reaching approximately 34% for both vaccine types and cohorts. Significant waning was observed for the COVID-19 hospitalizations in the ≥80 year cohort (decay from 83% 14-41 days to 63% 124 days after mRNA second dose). No significant waning effect was observed for COVID-19 related deaths in the period of follow-up of either cohorts.ConclusionsIn a population with a high risk of SARS-CoV-2 complications, we observed higher overall VE estimates against more severe outcomes for both age cohorts when compared to symptomatic infections. Considering the analysis of VE according to time since complete vaccination, the results showed a waning effect for both age cohorts in symptomatic infection and COVID-19 hospitalization for the 80 and more yo cohort.
SMER28 attenuates PI3K/mTOR signaling by direct inhibition of PI3K p110 delta
Authors: Kirchenwitz Marco , Stahnke Stephanie , Prettin Silvia , Borowiak Malgorzata , Birchmeier Carmen , Rottner Klemens , Stradal Theresia E.B. , Steffen Anika 
Published: December 2021

AbstractSMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and consequently growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction of phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by interference of SMER28 with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor typrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited.
Sex-dependent effects ofSetd1ahaploinsufficiency on development and adult behaviour
Authors: Bosworth Matthew L. , Isles Anthony R. , Wilkinson Lawrence S. , Humby Trevor 
Published: December 2021

ABSTRACTLoss of function (LoF) mutations affecting the histone methyl transferaseSETD1Aare implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model ofSetd1ahaploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, maleSetd1a+/-mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young maleSetd1a+/-mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes inSetd1a+/samples. In adulthood, we found enhanced acoustic startle responding in maleSetd1a+/-mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and femaleSetd1a+/-mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety,Setd1ahaplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use ofSetd1ahaploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.
A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues
Authors: Saul Dominik , Kosinsky Robyn Laura , Atkinson Elizabeth J , Doolittle Madison L. , Zhang Xu , LeBrasseur Nathan K. , Pignolo Robert J. , Robbins Paul D. , Niedernhofer Laura J. , Ikeno Yuji , Jurk Diana , Passos João F. , Hickson LaTonya J. , Xue Ailing , Monroe David G. , Tchkonia Tamara , Kirkland James L. , Farr Joshua N. , Khosla Sundeep 
Published: December 2021

AbstractAlthough cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.
SARS-CoV2 variant-specific replicating RNA vaccines protect from disease and pathology and reduce viral shedding following challenge with heterologous SARS-CoV2 variants of concern
Authors: Hawman David W. , Meade-White Kimberly , Archer Jacob , Leventhal Shanna , Wilson Drew , Shaia Carl , Randall Samantha , Khandhar Amit P. , Hsiang Tien-Ying , Gale Michael , Berglund Peter , Fuller Deborah Heydenburg , Feldmann Heinz , Erasmus Jesse H. 
Published: December 2021

AbstractDespite mass public health efforts, the SARS-CoV2 pandemic continues as of late-2021 with resurgent case numbers in many parts of the world. The emergence of SARS-CoV2 variants of concern (VoC) and evidence that existing vaccines that were designed to protect from the original strains of SARS-CoV-2 may have reduced potency for protection from infection against these VoC is driving continued development of second generation vaccines that can protect against multiple VoC. In this report, we evaluated an alphavirus-based replicating RNA vaccine expressing Spike proteins from the original SARS-CoV-2 Alpha strain and recent VoCs delivered in vivo via a lipid inorganic nanoparticle. Vaccination of both mice and Syrian Golden hamsters showed that vaccination induced potent neutralizing titers against each homologous VoC but reduced neutralization against heterologous challenges. Vaccinated hamsters challenged with homologous SARS-CoV2 variants exhibited complete protection from infection. In addition, vaccinated hamsters challenged with heterologous SARS-CoV-2 variants exhibited significantly reduced shedding of infectious virus. Our data demonstrate that this vaccine platform elicits significant protective immunity against SARS-CoV2 variants and supports continued development of this platform.
Active neural coordination of motor behaviors with internal states
Authors: Zhang Yisi S. , Takahashi Daniel Y. , El Hady Ahmed , Liao Diana A. , Ghazanfar Asif A. 
Published: December 2021

AbstractThe brain continuously coordinates skeletomuscular movements with internal physiological states like arousal, but how is this coordination achieved? One possibility is that brain simply reacts to changes in external and/or internal signals. Another possibility is that it is actively coordinating both external and internal activities. We used functional ultrasound imaging to capture a large medial section of the brain, including multiple cortical and subcortical areas, in marmoset monkeys while monitoring their spontaneous movements and cardiac activity. By analyzing the causal ordering of these different time-series, we found that information flowing from the brain to movements and heart rate fluctuations were significantly greater than in the opposite direction. The brain areas involved in this external versus internal coordination were spatially distinct but also extensively interconnected. Temporally, the brain alternated between network states for this regulation. These findings suggest that the brain’s dynamics actively and efficiently coordinate motor behavior with internal physiology.