bluuebunny/crossref_metadata_2025_split huggingface dataset:
Syndecan-1 is overexpressed in human thoracic aneurysm but is dispensable for the disease progression in vivo
Authors: Zalghout Sara , Vo Sophie , Arocas Véronique , Jadoui Soumaya , Hamade Eva , Badran Bassam , Oudar Olivier , Charnaux Nathalie , Boulaftali Yacine , Bouton Marie-Christine , Richard Benjamin 
Published: December 2021

ABSTRACTGlycosaminoglycans (GAGs) pooling has been considered since long as one of the histopathological characteristics defining thoracic aortic aneurysm (TAA) together with smooth muscle cells (SMCs) apoptosis and elastin fibers degradation. However, few information is provided about GAGs composition or potential implication in TAA pathology. Syndecan-1 (Sdc-1) is a heparan sulfate proteoglycan that is implicated in extracellular matrix (ECM) interaction and assembly, regulation of SMCs phenotype and various aspects of inflammation in the vascular wall. In the current work, the regulation of Sdc-1 protein was examined in human TAA by ELISA and immunohistochemistry. In addition, the role of Sdc-1 was evaluated in descending TAA in vivo using a mouse model combining both aortic wall weakening and hypertension. Our results showed that Sdc-1 protein is over expressed in human TAA aortas compared to healthy counterparts and that SMCs are the major cell type expressing Sdc-1. Similarly, in the mouse model used, Sdc-1 expression was increased in TAA aortas compared to healthy samples. Although its protective role against abdominal aneurysm has been reported, we observed that Sdc-1 was dispensable for TAA prevalence or rupture. In addition, Sdc-1 deficiency did not alter the extent of aortic wall dilatation, elastin degradation, collagen deposition, or leukocyte recruitment in our TAA model. These findings suggest that Sdc-1 could be a biomarker revealing TAA pathology. Future investigations could uncover the underlying mechanisms leading to Sdc-1 expression alteration in TAA.
The effects of locomotion on sensory-evoked haemodynamic responses in the cortex of awake mice
Authors: Eyre Beth , Shaw Kira , Sharp Paul , Boorman Luke , Lee Llywelyn , Shabir Osman , Berwick Jason , Howarth Clare 
Published: December 2021

AbstractInvestigating neurovascular coupling in awake rodents is becoming ever more popular due, in part, to our increasing knowledge of the profound impacts that anaesthesia can have upon brain physiology. Although awake imaging brings with it many advantages, we still do not fully understand how voluntary locomotion during imaging affects sensory-evoked haemodynamic responses. In this study we investigated how evoked haemodynamic responses can be affected by the amount and timing of locomotion. Using an awake imaging set up, we used 2D-Optical Imaging Spectroscopy (2D-OIS) to measure changes in cerebral haemodynamics within the sensory cortex of the brain during either 2s whisker stimulation or spontaneous (no whisker stimulation) experiments, whilst animals could walk on a spherical treadmill. We show that locomotion alters haemodynamic responses. The amount and timing of locomotion relative to whisker stimulation is important, and can significantly impact sensory-evoked haemodynamic responses. If locomotion occurred before or during whisker stimulation, the amplitude of the stimulus-evoked haemodynamic response was significantly altered. Therefore, monitoring of locomotion during awake imaging is necessary to ensure that conclusions based on comparisons of evoked haemodynamic responses (e.g., between control and disease groups) are not confounded by the effects of locomotion.
Different armpits under my new nose: olfactory sex but not gender affects implicit measures of embodiment
Authors: Roel Lesur Marte , Stussi Yoann , Bertrand Philippe , Delplanque Sylvain , Lenggenhager Bigna 
Published: December 2021

AbstractResearch has shown that conflicting multisensory signals may alter embodiment to the point of self-identifying with a foreign body, but the role of olfaction in this process has been overlooked. Here, we study in healthy participants how sex (male and female sweat odors) and gender (male and female cosmetic scents) olfactory stimuli contribute to embodiment. Participants saw from the perspective of a sex mismatching person in virtual reality and received synchronous visuo-tactile stimulation to elicit illusory embodiment of the seen body while smelling either sex- or gender-congruent stimuli. We assessed implicit (skin conductance responses to visual threats) and explicit (questionnaire) measures of embodiment. Stronger responses to threat were found when participants smelled the sex-congruent compared to the sex-incongruent odor, while no such differences were found for the cosmetic scents. According to the questionnaire, embodiment did not differ between conditions. Post-experimental assessment of the presented cues, suggest that while both sweat odors were considered generally male, cosmetic scents were not. The presented scents were generally not associated to the embodied body. Our results suggest that sex-related body odors influence implicit but not explicit aspects of embodiment and are in line with unique characteristics of olfaction in other aspects of cognition.
Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior
Authors: Kelly Kevin P. , Alassaf Mroj , Sullivan Camille E. , Brent Ava E. , Goldberg Zachary H. , Poling Michelle E. , Dubrulle Julien , Rajan Akhila 
Published: December 2021

AbstractDiet-induced obesity (DIO) leads to dysfunctional feeding behavior. However, the precise molecular nodes underlying diet-induced dysregulation of satiety sensing and feeding motivation are poorly understood. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high sugar regime in Drosophila, we sought to address how lipid alteration in fat cells alters feeding behavior. We find that prolonged exposure to HSD degrades the hunger-driven feeding (HDF) response. Lipidomics analysis reveals that longitudinal exposure to HSD significantly alters whole body phospholipid profiles. By performing a systematic screen for phospholipid enzymes, we identify Pect as a critical regulator of hunger-driven feeding. Pect is a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2. We show that disrupting Pect only in the fat body causes insulin-resistant phenotypes and a loss of hunger-driven feeding. Excitingly, we find that overexpression of Pect restores HSD-induced loss of hunger-driven feeding response. Strikingly human studies have noted a correlation between PCYT2/Pect levels and clinical obesity. Now, our unbiased studies in Drosophila provide specific genetic evidence for Pect in maintaining nutrient sensing during DIO. Our study provides novel insights into the role of phospholipids in interorgan communication of nutrient status.
Replication origins drive genetic and phenotypic variation in humans
Authors: Murat Pierre , Guilbaud Guillaume , Sale Julian E. 
Published: December 2021

ABSTRACTDNA replication starts with the activation of the replicative helicases, polymerases and associated factors at thousands of origins per S-phase 1. Due to local torsional constraints generated during licensing 2 and the switch between polymerases of distinct fidelity and proofreading ability following firing 3,4, origin activation has the potential to induce DNA damage and mutagenesis. However, whether sites of replication initiation exhibit a specific mutational footprint has not yet been established. Here we demonstrate that mutagenesis is increased at early and highly efficient origins. The elevated mutation rate observed at these sites is caused by two distinct mutational processes consistent with formation of DNA breaks at the origin itself and local error-prone DNA synthesis in the immediate vicinity of the origin. We demonstrate that these replication-dependent mutational processes create the skew in base composition observed at human replication origins. Further, we show that mutagenesis associated with replication initiation exerts an influence on phenotypic diversity in human populations disproportionate to the origins’ genomic footprint: by increasing mutational loads at gene promoters and splice junctions the presence of an origin influences both gene expression and mRNA isoform usage. These findings have important implications for our understanding of the mutational processes that sculpt the human genome.
Human TLR4 and noncanonical inflammasome differ in their ability to respond to distinct lipid A variants
Authors: Alexander-Floyd Jasmine , Bass Antonia R. , Harberts Erin M. , Grubaugh Daniel , Buxbaum Joseph D. , Brodsky Igor E. , Ernst Robert K. , Shin Sunny 
Published: December 2021

AbstractDetection of Gram-negative bacterial lipid A by the extracellular sensor, MD-2/TLR4 or the intracellular inflammasome sensors, CASP4 and CASP5, induces robust inflammatory responses. The chemical structure of lipid A, specifically the phosphorylation and acylation state, varies across and within bacterial species, potentially allowing pathogens to evade or suppress host immunity. Currently, it is not clear how distinct alterations in the phosphorylation or acylation state of lipid A affect both human TLR4 and CASP4/5 activation. Using a panel of engineered lipooligosaccharides (LOS) derived fromYersinia pestiswith defined lipid A structures that vary in their acylation or phosphorylation state, we identified that differences in phosphorylation state did not affect TLR4 or CASP4/5 activation. However, the acylation state differentially impacted TLR4 and CASP4/5 activation. Specifically, all of the examined tetra-, penta-, and hexa-acylated LOS variants activated CASP4/5-dependent responses, whereas TLR4 responded to penta- and hexa-acylated LOS but did not respond to tetra-acylated LOS or pentaacylated LOS lacking the secondary acyl chain at the 3’ position. As expected, lipid A alone was sufficient for TLR4 activation; however, human macrophages required both lipid A and the core oligosaccharide to mount a robust CASP4/5 inflammasome response. Our findings show that human TLR4 and CASP4/5 detect both shared and non-overlapping LOS/lipid A structures, which enables the innate immune system to recognize a wider range of bacterial LOS/lipid A, thereby constraining the ability of pathogens to evade innate immune detection.
The costs and benefits of dispersal in small populations
Authors: Polechová Jitka 
Published: December 2021

AbstractDispersal has three major effects on adaptation. First, gene flow mixes alleles adapted to different environments, potentially hindering (swamping) adaptation. Second, it brings in other variants and inflates genetic variance: this aids adaptation to spatially (and temporally) varying environments but if selection is hard, it lowers the mean fitness of the population. Third, neighbourhood size, which determines how weak genetic drift is, increases with dispersal – when genetic drift is strong, increase of the neighbourhood size with dispersal aids adaptation. In this note I focus on the role of dispersal in environments which change gradually across space, and when local populations are quite small such that genetic drift has a significant effect. Using individual-based simulations, I show that in small populations, even leptokurtic dispersal benefits adaptation, by reducing the power of genetic drift. This has implications for management of fragmented or marginal populations: the beneficial effect of increased dispersal into small populations is stronger than swamping of adaption under a broad range of conditions, including a mixture of local and long-distance dispersal. However, when environmental gradient is steep, heavily fat-tailed dispersal will swamp continuous adaptation so that only patches of locally adapted subpopulations remain.
Treatment with IgM-enriched intravenous immunoglobulins (IgM-IVIg) enhances clearance of stroke-associated bacterial lung infection
Authors: McCulloch Laura , Harris Alison J. , Malbon Alexandra , Daniels Michael J. D. , Younas Mehwish , Grainger John R. , Allan Stuart M. , Smith Craig J. , McColl Barry W. 
Published: December 2021

ABSTRACTPost-stroke infection is a common complication of stroke that is associated with increased mortality and morbidity. We previously found that experimental stroke induces an ablation of multiple sub-populations of B cells and reduced levels of IgM antibody that coincide with the development of spontaneous bacterial pneumonia. Reduced circulating IgM concentrations were also observed in acute stroke patients. The loss of IgM antibody after stroke could be an important determinant of infection susceptibility and highlights this pathway as an important target for intervention.We treated mice with a low (replacement), dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after experimental stroke induced by middle cerebral artery occlusion (MCAO) or sham surgery, then recovered mice for 2 d or 5 d. The effect of treatment on lung bacterial burden, lung pathology, brain infarct volume, antibody levels and both lung and systemic cellular and cytokine immune profiles was determined. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved pathology but did not impact infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO, and treatment also reduced concentrations of pro-inflammatory cytokines in the lung. The effects of MCAO and IgM-IVIg treatment on the immune system were tissue specific as no impact on B cells or mouse immunoglobulins were found within the lung. However, the presence of human immunoglobulins from the IgM-IVIg treatment led to increased total lung immunoglobulin concentration. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced their capability to phagocytose Staphylococcus aureus bioparticles in vitro by increasing opsonisation.Low dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance phagocytic activity. Immunomodulatory effects of IgM-IVIg treatment, including reduced pro-inflammatory cytokine production, may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.GRAPHICAL ABSTRACT
The dynamic range of voltage-dependent gap junction signaling is maintained by Ih-induced membrane potential depolarization
Authors: Stein Wolfgang , DeMaegd Margaret L. , Braun Lena Yolanda , Vidal-Gadea Andrés , Harris Allison L. , Städele Carola 
Published: December 2021

AbstractLike their chemical counterparts, electrical synapses show complex dynamics such as rectification and voltage dependence that interact with other electrical processes in neurons. The consequences arising from these interactions for the electrical behavior of the synapse, and the dynamics they create, remain largely unexplored. Using a voltage-dependent electrical synapse between a descending modulatory projection neuron (MCN1) and a motor neuron (LG) in the crustacean stomatogastric ganglion, we find that the influence of the hyperpolarization-activated inward current (Ih) is critical to the function of the electrical synapse. When we blocked Ih with CsCl, the apparent voltage dependence of the electrical synapse shifted by 18.7 mV to more hyperpolarized voltages, placing the dynamic range of the electrical synapse outside of the range of voltages used by the LG motor neuron (−60.2 mV – −44.9 mV). With dual electrode current- and voltage-clamp recordings, we demonstrate that this voltage shift is not due to a change in the properties of the gap junction itself, but is a result of a sustained effect of Ih on the presynaptic MCN1 axon terminal membrane potential. Ih-induced depolarization of the axon terminal membrane potential increased the electrical postsynaptic potentials and currents. With Ih present, the axon terminal resting membrane potential depolarized, shifting the dynamic range of the electrical synapse towards the functional range of the motor neuron. We thus demonstrate that the function of an electrical synapse is critically influenced by a voltage-dependent ionic current (Ih).New & NoteworthyElectrical synapses and voltage-gated ionic currents are often studied independently from one another, despite mounting evidence that their interactions can alter synaptic behavior. We show that the hyperpolarization-activated inward ionic current shifts the voltage dependence of an electrical synaptic transmission through its depolarizing effect on the membrane potential, enabling it to lie within the functional membrane potential range of a motor neuron. Thus, the electrical synapse’s function critically depends on the voltage-gated ionic current.
Structure of the hepatitis C virus E1E2 glycoprotein complex
Authors: de la Peña Alba Torrents , Sliepen Kwinten , Eshun-Wilson Lisa , Newby Maddy , Allen Joel D. , Koekkoek Sylvie , Zon Ian , Chumbe Ana , Crispin Max , Schinkel Janke , Lander Gabriel C. , Sanders Rogier W. , Ward Andrew B. 
Published: December 2021

AbstractHepatitis C virus (HCV) infection is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma in humans, and afflicts more than 58 million people worldwide. The HCV envelope E1 and E2 glycoproteins are essential for viral entry and infection, and comprise the primary antigenic target for neutralizing antibody responses. The molecular mechanisms of E1E2 assembly, as well as how the E1E2 heterodimer binds broadly neutralizing antibodies, remains elusive. We present the cryo-electron microscopy (cryoEM) structure of the membrane-extracted full-length E1E2 heterodimer in complex with broadly neutralizing antibodies (bNAbs) AR4A, AT12009 and IGH505 at ∼3.5 Å resolution. We resolve the long sought-after interface between the E1 and E2 ectodomains and reveal how it is stabilized by hydrophobic interactions and glycans. This structure deepens our understanding of the HCV fusion glycoprotein and delivers a blueprint for the rational design of novel vaccine immunogens and anti-viral drugs.
Persistence of immune response in health care workers after two doses BNT162b2 in a longitudinal observational study
Authors: Herzberg Jonas , Fischer Bastian , Lindenkamp Christopher , Becher Heiko , Becker Ann-Kristin , Honarpisheh Human , Guraya Salman Yousuf , Strate Tim , Knabbe Cornelius 
Published: December 2021

AbstractBackgroundThe mRNA-based vaccine BNT162b2 of BioNTech/Pfizer has shown high efficacy against SARS-CoV-2 infection and a severe course of the COVID-19 disease. However, little is known about the long-term durability of the induced immune response resulting from the vaccination.MethodsIn a longitudinal observational study in employees at a German hospital we compared the humoral and cellular immune response in 184 participants after two doses of the BioNTech/Pfizer vaccine (BNT162b2) with a mid-term follow-up after 9 months. Anti-SARS-CoV-2 binding antibodies were determined using both a quantitative and a semi-quantitative assay. For a qualitative assessment of the humoral immune response, we additionally measured neutralizing antibodies. Cellular immune response was evaluated by measuring Interferon-gamma release after stimulating blood-cells with SARS-CoV-2 specific peptides using a commercial assay.ResultsIn the first analysis, a 100% humoral response rate was described after two doses of BNT162b2 vaccine with a mean antibody ratio of 8.01 ± 1.00. 9 months after the second dose of BNT162b2, serological testing showed a significant decreased mean antibody ratio of 3.84 ± 1.69 (p < 0.001). Neutralizing antibodies were still detectable in 96% of all participants, showing an average binding inhibition value of 68.20% ± 18.87%. Older age, (p < 0.001) and obesity (p = 0.01) had a negative effect on the antibody persistence. SARS-CoV-2 specific cellular immune response was proven in 75% of individuals (mean IFN-gamma release: 579.68 mlU/ml ± 705.56 mlU/ml).ConclusionOur data shows a declining immune response 9 months after the second dose of BNT162b2, supporting the potentially beneficial effect of booster vaccinations, the negative effect of obesity and age stresses the need of booster doses especially in these groups.
Predictors of uncertainty and unwillingness to receive the COVID-19 booster vaccine: an observational study of 22,139 fully vaccinated adults in the UK
Authors: Paul Elise , Fancourt Daisy 
Published: December 2021

SummaryBackgroundThe continued success of the COVID-19 vaccination programme in the UK will depend on widespread uptake of booster vaccines. However, there is evidence of hesitancy and unwillingness to receive the booster vaccine, even in fully vaccinated adults. Identifying factors associated with COVID-19 booster vaccine intentions specifically in this population is therefore critical.MethodsWe used data from 22,139 fully vaccinated adults who took part in the UCL COVID-19 Social Study. Multinomial logistic regression examined predictors of uncertainty and unwillingness (versus willingness) to receive a COVID-19 booster vaccine (measured 22 November 2021 to 6 December 2021), including (i) socio-demographic factors, (ii) COVID-19 related factors (e.g., having been infected with COVID-19), and (iii) initial intent to receive a COVID-19 vaccine in the four months following the announcement in the UK that the vaccines had been approved (2 December 2020 to 31 March 2021).Findings4% of the sample reported that they were uncertain about receiving a COVID-19 booster vaccine, and a further 4% unwilling. Initial uncertainty and unwillingness to accept the first COVID-19 vaccine in 2020-21 were each associated with over five times the risk of being uncertain about and unwilling to accept a booster vaccine. Healthy adults (those without a pre-existing physical health condition) were also more likely to be uncertain or unwilling to receive a booster vaccine. In addition, low levels of current stress about catching or becoming seriously ill from COVID-19, consistently low compliance with COVID-19 government guidelines during periods of strict restrictions (e.g., lockdowns), lower levels of educational qualification, lower socio-economic position, and age below 45 years were all associated with uncertainty and unwillingness.InterpretationOur findings highlight that there are a range of factors that predict booster intentions, with the strongest predictor being previous uncertainty and unwillingness. Two other concerning patterns also emerged from our results. First, administration of booster vaccinations may increase social inequalities in experiences of COVID-19 as adults from lower socio-economic backgrounds are also most likely to be uncertain or unwilling to accept a booster vaccine as well as most likely to be seriously affected by the virus. Second, some of those most likely to spread COVID-19 (i.e., those with poor compliance with guidelines) are most likely to be uncertain and unwilling. Public health messaging should be tailored specifically to these groups.FundingThe Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].