bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides
Authors: Stankov Sylvia , Vitali Cecilia , Park Joseph , Nguyen David , Mayne Leland , Englander S. Walter ,   Regeneron Genetics Center, Levin Michael G. , Vujkovic Marijana , Hand Nicholas J. , Phillips Michael C. , Rader Daniel J. 
Published: February 2023

AbstractBackgroundPlasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, geneAPOA5) is a liver-secreted protein that is carried on triglyceride-rich lipoproteins and promotes the enzymatic activity of lipoprotein lipase (LPL), thereby reducing TG levels. Little is known about apoA-V structure-function; naturally occurring humanAPOA5variants can provide novel insights.MethodsWe used hydrogen-deuterium exchange mass spectrometry to determine the secondary structure of human apoA-V in lipid-free and lipid-associated conditions and identified a C-terminal hydrophobic face. Then, we used genomic data in the Penn Medicine Biobank to identify a rare variant, Q252X, predicted to specifically eliminate this region. We interrogated the function of apoA-V Q252X using recombinant proteinin vitroandin vivoinapoa5knockout mice.ResultsHuman apoA-V Q252X carriers exhibited elevated plasma TG levels consistent with loss of function.Apoa5knockout mice injected with AAV vectors expressing wildtype and variantAPOA5-AAV recapitulated this phenotype. Part of the loss of function is due to reduced mRNA expression. Functionally, recombinant apoA-V Q252X was more readily soluble in aqueous solutions and more exchangeable with lipoproteins than WT apoA-V. Despite lacking the C- terminal hydrophobic region (a putative lipid binding domain) this protein also decreased plasma TGin vivo.ConclusionsDeletion of apoA-V’s C-terminus leads to reduced apoA-V bioavailabilityin vivoand higher TG levels. However, the C-terminus is not required for lipoprotein binding or enhancement of intravascular lipolytic activity. WT apoA-V is highly prone to aggregation, and this property is markedly reduced in recombinant apoA-V lacking the C-terminus.
Differential age-specific effects of LDL cholesterol and body mass index on the risk of coronary heart disease
Authors: Xiao Jun , Chen Liangwan , Ye Weimin , Huang Wuqing 
Published: February 2023

AbstractBackgroundLow-density lipoprotein cholesterol (LDLc) and body mass index (BMI) are not always correlated and their relationship is probably dependent on age, indicating differential age-specific effects of these two factors on health outcomes. We thus aimed to discriminate the effects of LDLc and BMI on the risk of coronary heart disease (CHD) across different age groups.MethodsThis is a prospective cohort study of 368,274 participants aged 38-73 years and free of CHD at baseline. LDLc and BMI were measured at baseline, and incident CHD was the main outcome. Cox proportional hazards model and restricted cubic spline (RCS) regression were used to estimate hazard ratio (HR) and 95% confidence interval (CI) of exposure on CHD.ResultsSimilar relationships of LDLc and BMI with CHD risk were observed in overall population but in differential age-specific patterns. Across the age groups of <50, 50-54, 55-59, 60-64 and >=65 years, the LDLc-CHD association diminished with the adjusted HRs decreasing from 1.35, 1.26, 1.19, 1.11 to 1.08; while no declining trend was found in BMI-CHD relationship with the adjusted HRs of 1.15, 1.11, 1.12, 1.13 and 1.15, respectively. The interaction and mediation between LDLc and BMI on CHD risk were only present at young-age groups. And the LDLc-CHD but not BMI-CHD association was dependent on sex, metabolic syndrome and lipid-lowering drugs use.ConclusionThere were differential age-specific effects of LDLc and BMI on the risk of developing CHD, calling for future efforts to discriminate the age-different benefits from lipids management or weight control on the primary prevention for CHD.Clinical PerspectiveWhat Is New?This study shows, for the first time, that there were differential age-specific effects of LDLc and BMI on the risk of developing coronary heart disease (CHD), in which the LDLc-CHD association diminished with increasing age while no declining trend was found in BMI-CHD relationship.The interaction and mediation between LDLc and BMI on the risk of coronary heart disease were only present in young adults.What Are the Clinical Implications?Future efforts are called to discriminate the age-different benefits from lipids management or weight control on the primary prevention for CHD.Findings from this study highlighted that lipids management at young age was expected to have a much more favorable benefit in CHD prevention; and weight control shouldn’t be overlooked, especially for elderly adults, as lipid-lowering therapy might not contribute to the reduction of obesity-related CHD.
Educational attainment in hemorrhagic stroke severity and functional outcome
Authors: Yechoor Nirupama , Rist Pamela , Ganbold Alena , Kourkoulis Christina , Mora Samantha , Mayerhofer Ernst , Parodi Livia , Anderson Christopher D. , Rosand Jonathan 
Published: February 2023

AbstractIntroductionWhile stroke education is a hallmark of clinical care in primary stroke centers, the educational attainment of patients is rarely considered. The objective of this study is to determine whether educational attainment, in addition to traditional risk factors, is associated with intracerebral hemorrhage (ICH) severity and functional outcomes.MethodsSubjects were enrolled in a prospectively ascertained cohort of patients with primary ICH from 1994 until 2020 at the Massachusetts General Hospital Neurosciences Intensive Care Unit. Data on social determinants of health (SDOH), past medical history for ICH risk factors, and ICH severity were obtained on admission. The primary outcome was stroke severity, calculated using the ICH score. The secondary outcome was 12-month modified Rankin Score (mRS).ResultsOf 2,539 patients eligible for analyses, 1,744 (69%) presented with mild ICH (ICH Score < 3) and 795 (31%) presented with severe ICH (ICH score ≥3). In a multivariable logistic regression analysis controlling for age, income, and a pre-stroke diagnosis of coronary artery disease, only educational attainment was associated with stroke severity, with patients with high school-only education more likely to present with a severe ICH compared to college diplomates (odds ratio 2.37, 95% CI 1.77, 3.19).Additionally, those with high school-only education were less likely to recover to a good functional outcome (mRS<4) after ICH when compared to college diplomates (odds ratio 0.43, 95% CI 0.19, 0.93) when controlling for stroke severity, and pre-stroke diagnoses of hypertension and dementia.DiscussionPre-stroke educational attainment is an independent predictor of ICH severity and subsequent functional outcomes at 12-month post-stroke. Given the association with recovery, tailoring inpatient stroke education to level of educational attainment may serve to reduce the disparity in outcomes after hemorrhagic stroke. Educational attainment may act as both a social and a biological determinant, and could represent a modifiable risk factor for ICH survivors.
Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis
Authors: Kayvanjoo Amir Hossein , Splichalova Iva , Bejarano David Alejandro , Huang Hao , Mauel Katharina , Makdissi Nikola , Heider David , Balzer Nora Reka , Osei-Sarpong Collins , Baßler Kevin , Schultze Joachim L. , Uderhardt Stefan , Kiermaier Eva , Beyer Marc , Schlitzer Andreas , Mass Elvira 
Published: February 2023

AbstractDuring embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
SARS-CoV2 mRNA-vaccination-induced Immunological Memory in Human Non-Lymphoid and Lymphoid Tissues
Authors: Proß Vanessa , Sattler Arne , Lukassen Sören , Tóth Laura , Laura Thole Linda Marie , Siegle Janine , Stahl Carolin , He An , Damm Georg , Seehofer Daniel , Götz Christina , Bayerl Christian , Jäger Pia , Macke Alexander , Eggeling Stephan , Kirzinger Bernadette , Mayr Thomas , Herbst Hermann , Beyer Katharina , Laue Dominik , Krönke Jan , Braune Jan , Rosseck Friederike , Friedersdorff Frank , Hubatsch Mandy , Weinberger Sarah , Lachmann Nils , Hofmann Veit Maria , Schrezenmeier Eva , Ludwig Carolin , Schrezenmeier Hubert , Jechow Katharina , Conrad Christian , Kotsch Katja 
Published: February 2023

AbstractTissue-resident lymphocytes provide organ-adapted protection against invading pathogens. Whereas their biology has been examined in great detail in various infection models, their generation and functionality in response to vaccination has not been comprehensively analyzed in humans. We therefore studied SARS-CoV2 mRNA-vaccine-specific T cells in surgery specimens of kidney, liver, lung, bone marrow and spleen in comparison to paired blood samples from largely virus-naïve individuals. As opposed to lymphoid tissues, non-lymphoid organs harbored significantly elevated frequencies of Spike-specific CD4+T cells compared to paired peripheral blood showing hallmarks of tissue residency and an expanded memory pool. Organ-derived, vaccine-specific T helper (Th) cells were characterized by increased portions of multifunctional cells over those detected in blood. Single-cell RNA sequencing revealed functional rather than organ-specific clusters of Spike-reactive Th cells, indicating similar diversification programs across tissues. T cell receptor (TCR) repertoire analysis indicated that the TCR sequence is a major determinant of transcriptomic state in tissue-resident, vaccine-specific CD4+T cells. In summary, our data demonstrate that SARS-CoV2 vaccination entails acquisition of tissue memory and residency features in organs distant from the inoculation site, thereby contributing to our understanding of how local tissue protection might be accomplished.One sentence summarySARS-CoV2 mRNA vaccination-induced CD4+Th cells reside in both human lymphoid and non-lymphoid organs showing distinct adaptations in tissues with respect to memory differentiation, retention and function.
Assessing the feasibility of Phase 3 vaccine trials against Marburg Virus Disease: a modelling study
Authors: Qian George Y , Jombart Thibaut , Edmunds W John 
Published: February 2023

AbstractBackgroundOutbreaks of Marburg virus disease (MVD) are rare and small in size, with only 16 recorded outbreaks since 1967, only two of which involved more than 100 cases. It has been proposed, therefore, that Phase 3 trials for MVD vaccines should be held open over multiple outbreaks until sufficient end points accrue to enable vaccine efficacy (VE) to be calculated. Here we estimate how many outbreaks might be needed for VE to be estimated.MethodsWe adapt a mathematical model of MVD transmission to simulate a Phase 3 individually randomised placebo controlled vaccine trial. We assume in the base case that vaccine efficacy is 70% and that 50% of individuals in affected areas are enrolled into the trial (1:1 randomisation). We further assume that the vaccine trial starts two weeks after public health interventions are put in place and that cases occurring within 10 days of vaccination are not included in VE calculations.ResultsThe median size of simulated outbreaks was 2 cases. Only 0.3% of simulated outbreaks were predicted to have more than 100 MVD cases. 95% of simulated outbreaks terminated before cases accrued in the placebo and vaccine arms. Therefore the number of outbreaks required to estimate VE was large: after 100 outbreaks, the estimated VE was 69% but with considerable uncertainty (95% CIs: 0% - 100%) while the estimated VE after 200 outbreaks was 67% (95% CIs: 42% - 85%). Altering base-case assumptions made little difference to the findings.ConclusionsIt is unlikely that the efficacy of any candidate vaccine can be calculated before more MVD outbreaks have occurred than have been recorded to date. This is because MVD outbreaks tend to be small, public health interventions have been historically effective at reducing transmission, and vaccine trials are only likely to start after these interventions are already in place. Hence, it is expected that outbreaks will terminate before, or shortly after, cases start to accrue in the vaccine and placebo arms. Manufacturers may want to consider alternative routes to licensure than Phase 3 trials for MVD vaccines.
Examining the governance arrangements for healthcare worker COVID-19 protection in Kenya: A Scoping Review
Authors: Kazungu Jacob , Kagwanja Nancy N , Wang Huihui , Chuma Jane , Munge Kenneth 
Published: February 2023

AbstractHealthcare workers (HCWs) face a high risk of infection during pandemics or public health emergencies as demonstrated in the ongoing COVID-19 pandemic. Understanding how governments respond can inform public health control measures and support health system functioning. An economic impact analysis examining HCW COVID-19 infections in Kenya and three other countries estimated that the total economic costs related to HCW COVID-19 infections costs and deaths in Kenya were US$113.2 million (range US$35.8-US$246.1). We examined the governance arrangements for HCW protection during the COVID-19 pandemic in Kenya between March 2020 and March 2021.Governance arrangements were examined following a scoping review of 44 policy and legislative documents and reports of HCW protection and 22 media articles. We adopted the transparency, accountability, participation, integrity and capacity (TAPIC) governance framework to analyse and summarize our findings into policy gaps and implementation challenges.Policy design gaps included inadequate provisions for emerging threats, inconsistencies with the devolved context and inadequate structures to monitor, inform and respond to HCW COVID-19 infections. Implementation challenges were attributed to inadequate quantity and quality of PPE, difficulty in accessing medical care for HCWs, delays in HCW remuneration, insufficient infection prevention and control measures, the top-down application of plans, difficulties in working in a decentralized context, and pre-existing public finance management (PFM) bottlenecks.Implementation of HCW protection during the COVID-19 pandemic and beyond could leverage the revamping of current legislation on labour relations to reflect devolved governance and develop a broader and long-term approach to occupational health and safety implementation that considers all HCWs. Improvements in PFM arrangements coupled with increased investment in the health sector and attention to efficient use of resources will also impact positively on HCW protection.
Association of newly diagnosed atrial fibrillation with remote intracerebral hemorrhage after intravenous thrombolysis: Results from a multicenter study in China
Authors: Pan Xiaoling , Pei Yingjian , Zhang Meixia , Zhong Wansi , Hu Jin , Wang Zhimin , Xu Dongjuan , Lou Min , Chen HongFang , Chen Zhicai 
Published: February 2023

ObjectiveTo investigate the association of atrial fibrillation (AF), especially newly diagnosed AF, with remote intracerebral hemorrhage (rICH) in patients with ischemic stroke treated by intravenous thrombolysis.MethodsThis is an observational study of patients with ischemic stroke who were treated with intravenous thrombolysis with recombinant tissue-type plasminogen activator whose data were taken from a multicenter prospective registry of a Chinese population. RICH was defined as any extraischemic hemorrhage detected by imaging examination ≤ 24 hours after intravenous thrombolysis. We collected the demographic data and clinical characteristics of all the patients. We compared patients with rICH and those without any type of hemorrhagic transformation. The association of AF and rICH was analyzed by univariate analysis and binary logistic regression.ResultsWe evaluated 20697 patients, 1566 (7.6%) of whom developed intracerebral hemorrhage (ICH), 586 (2.8%) of whom experienced rICH, and 19131 (92.4%) of whom did not experience any type of hemorrhagic transformation. Univariate analysis showed that there were significant differences in age, prethrombolysis systolic blood pressure, baseline NIHSS score, known AF, newly diagnosed AF, coronary heart disease, congestive heart failure, hyperhomocysteinemia and history of thrombolysis between the rICH and control groups (P < 0.05). Further multivariate logistic regression analysis showed that total AF [OR 1.821, (95%CI, 1.082-3.065), P < 0.05], known AF [OR 1.470, (95%CI, 1.170-1.847)] and newly diagnosed AF [OR 1.920, (95%CI, 1.304-2.825)] were all independently associated with rICH.ConclusionsThis study suggests that AF (regardless of the newly diagnosed or known AF) may be associated with the occurrence of rICH after intravenous thrombolysis. Interestingly, newly diagnosed AF may have a greater impact on rICH than known AF, but that finding needs to be confirmed by a larger prospective sample.
Hydraulic adjustments of Scots pine colonizing a harsh environment on volcano slopes
Authors: Barigah Têtè Sévérien , Santos Farnese Fernanda Dos , De Menezes Silva Paulo , Humbert Paul , Ennajeh Mustapha , Ngao Jérôme , Badel Eric , Cochard Hervé , Herbette Stephane 
Published: February 2023

AbstractThe ability of trees to survive and naturally regenerate in increasing drought conditions will depend on their capacity to vary key hydraulic and morphological traits that increase drought tolerance. Despite many studies investigating variability in these drought-tolerant traits, there has been limited investigation into this variability under recurrent severe drought conditions since the establishment phase.We investigated the long-term hydraulic and leaf trait adjustments of Scots pine trees settled in an abandoned slag quarry by comparing them across three different topographic positions inducing contrasted effects on growth and development. We measured xylem and foliar traits to compare the water status of trees according to tree location and to evaluate the respective risk for xylem hydraulic failure using the soil-plant hydraulic modelSurEau.Compared to upslope and downslope trees, slope trees exhibited lower growth, vulnerability to embolism, specific hydraulic conductivity and photosynthetic pigment contents, as well as higher water potential at turgor loss point and midday water potentials. The hydraulic adjustments of trees settled on slag slopes reduced the risk for hydraulic failure and thus prevented an increase in embolism compared to downslope and upslope trees. These results suggest a prioritization of hydraulic safety over growth in Scots pine developed in a harsh environment, resulting in a dwarf phenotype.
A human cortical adaptive mutual inhibition circuit underlying competition for perceptual decision and repetition suppression reversal
Authors: Sousa Teresa , Sayal Alexandre , Duarte João V. , Costa Gabriel N. , Castelo-Branco Miguel 
Published: February 2023

AbstractA model based on inhibitory coupling has been proposed to explain perceptual oscillations. This ‘adapting reciprocal inhibition’ model postulates that it is the strength of inhibitory coupling that determines the fate of competition between percepts. Here, we used an fMRI-based adaptation technique to reveal the influence of neighboring neuronal populations, such as reciprocal inhibition, in motion-selective hMT+/V5. If reciprocal inhibition exists in this region, the following predictions should hold: 1. stimulus-driven response would not simply decrease, as predicted by simple repetition-suppression of neuronal populations, but instead increase due to the activity from adjacent populations; 2. perceptual decision involving competing representations, should reflect decreased reciprocal inhibition by adaptation; 3. neural activity for the competing percept should also later on increase upon adaptation. Our results confirm these three predictions, showing that a model of perceptual decision based on adapting reciprocal inhibition holds true. Finally, they also show that the well-known repetition suppression phenomenon can be reversed by this mechanism.Significance StatementfMRI-based adaptation has been developed as a tool to identify functional selectivity in the human brain. This is based on the notion that stimulus-selective adaptation leads to direct response suppression. In this study, we go a step further by showing that adaptation can also reveal the influence of neighboring neuronal populations. Our data reveals neural evidence for a disinhibition effect as a result of the adaptation of adjacent populations, which is in line with the adapting reciprocal inhibition model. Reciprocal inhibition can, thus, be tracked in the human brain using fMRI, adding to the understanding of human multistable perception and the neural coding of visual information. Moreover, our results also provide a mechanism for reversal of repetition suppression.
Ventral premotor cortex influences spinal cord activation during force generation
Authors: Braaß Hanna , Feldheim Jan , Chu Ying , Tinnermann Alexandra , Finsterbusch Jürgen , Büchel Christian , Schulz Robert , Gerloff Christian 
Published: February 2023

AbstractForce generation is a crucial element of dexterity and a highly relevant skill of the human motor system. How cerebral and spinal components interact and how spinal activation is influenced by cerebral primary motor and premotor areas is poorly understood. Here we conducted combined cortico-spinal functional MRI during a simple visually guided isometric force generation task in a group of 20 healthy young subjects. Activation was localized in the ipsilateral cervical spinal cord and contralateral primary motor and premotor areas. The main finding is that spinal activation was influenced by ventral premotor cortex activation. Spinal activation was furthermore significantly correlated with primary motor cortex activation while increasing target forces led to an increase in the amount of activation. These data indicate that human premotor areas such as the ventral premotor cortex might be functionally connected to the lower cervical spinal cord contributing to distal upper limb functions, a finding which extends our understanding about human motor function beyond the animal literature.