The nuclear genome drives differences in immune cell populations and differentiation potentials, in part regulated by changes in metabolism. Despite this connection, the role of mitochondrial DNA ...(mtDNA) polymorphisms (SNP) in this process has not been examined. Using mitochondrial nuclear exchange (MNX) mice, we and others have shown that mtDNA strongly influences varying aspects of cell biology and disease. Based upon an established connection between mitochondria and immune cell polarization, we hypothesized that mtDNA SNP alter immune cell development, trafficking, and/or differentiation. Innate and adaptive immune cell populations were isolated and characterizated from the peritoneum and spleen. While most differences between mouse strains are regulated by nuclear DNA (nDNA), there are selective changes that are mediated by mtDNA differences (e.g., macrophage (CD11c) differentiation), These findings highlight how nuclear-mitochondrial crosstalk may alter pathology and physiology via regulation of specific components of the immune system.
•mtDNA SNP are quantitative trait loci for the immune system.•Major baseline strain differences in immune cell populations appear to be driven by nuclear encoded factors.•mtDNA regulates selective changes in immune cell populations.•Primary mtDNA-mediated effects drive immune cell differentiation/polarization.•CD11c+ expression in large peritoneal macrophages appears to exhibit strong regulation by mtDNA.
The evaluation of serological responses to COVID-19 is crucial for population-level surveillance, developing new vaccines, and evaluating the efficacy of different immunization programs. Research and ...development of point-of-care test technologies remain essential to improving immunity assessment, especially for SARS-CoV-2 variants that partially evade vaccine-induced immune responses. In this work, an impedimetric biosensor based on the immobilization of the recombinant trimeric wild-type spike protein (S protein) on zinc oxide nanorods (ZnONRs) was employed for serological evaluation. We successfully assessed its applicability using serum samples from spike-based COVID-19 vaccines: ChAdOx1-S (Oxford-AstraZeneca) and BNT162b2 (Pfizer-BioNTech). Overall, the ZnONRs/ spike-modified electrode displayed accurate results for both vaccines, showing excellent potential as a tool for assessing and monitoring seroprevalence in the population. A refined outcome of this technology was achieved when the ZnO immunosensor was functionalized with the S protein from the P.1 linage (Gamma variant). Serological responses against samples from vaccinated individuals were acquired with excellent performance. Following studies based on traditional serological tests, the ZnONRs/spike immunosensor data reveal that ChAdOx1-S vaccinated individuals present significantly less antibody-mediated immunity against the Gamma variant than the BNT162b2 vaccine, highlighting the great potential of this point-of-care technology for evaluating vaccine-induced humoral immunity against different SARS-CoV-2 strains.
The COVID-19 caused by the SARS-CoV-2 virus was declared a pandemic disease in March 2020 by the World Health Organization (WHO). Structure-Based Drug Design strategies based on docking methodologies ...have been widely used for both new drug development and drug repurposing to find effective treatments against this disease. In this work, we present the developments implemented in the DockThor-VS web server to provide a virtual screening (VS) platform with curated structures of potential therapeutic targets from SARS-CoV-2 incorporating genetic information regarding relevant non-synonymous variations. The web server facilitates repurposing VS experiments providing curated libraries of currently available drugs on the market. At present, DockThor-VS provides ready-for-docking 3D structures for wild type and selected mutations for Nsp3 (papain-like, PLpro domain), Nsp5 (Mpro, 3CLpro), Nsp12 (RdRp), Nsp15 (NendoU), N protein, and Spike. We performed VS experiments of FDA-approved drugs considering the therapeutic targets available at the web server to assess the impact of considering different structures and mutations to identify possible new treatments of SARS-CoV-2 infections. The DockThor-VS is freely available at www.dockthor.lncc.br .
Despite significant interest from health care authorities, patient organizations, and insurance companies, data on procedural outcome and quality of endoscopic retrograde cholangiopancreatography ...(ERCP) in general and academic practice are sparse. The aims of this study were to assess procedural outcome of ERCP within a large prospective registry in The Netherlands, and to evaluate associations between endoscopist-related factors and procedural outcome.
All endoscopists performing ERCP in The Netherlands were invited to register their ERCPs over a 1-year period using the Rotterdam Assessment Form for ERCP (RAF-E). The primary outcome measure was procedural success. A priori difficulty level of the procedure was classified according to Schutz. Baseline characteristics of the endoscopist (e. g. previous experience) were recorded at study entry. Regression analysis was performed to identify predictors of procedural outcome.
A total of 8575 ERCPs were registered by 171 endoscopists from 61 centers, constituting about 50 % of all ERCPs performed nationally during the study period. Overall procedural success was 85.8 %. Intact papillary anatomy was present in 5106 patients (59.5 %): procedural success in this subgroup of patients was 83.4 % vs. 89.4 % after sphincterotomy (P < 0.001). Multivariate logistic regression identified "degree of difficulty," "intact papillary anatomy," and "previous ERCP failure" to be independently associated with procedural failure. "Yearly volume of ERCPs" and "trainee involvement" were independently associated with success.
The nationwide prospective RAF-E registry proved to be a valuable tool to gain insight into procedural outcome of ERCPs.
Social networks, i.e., our in-person and online social relations, are key to lifestyle behavior and health, via mechanisms of influence and support from our relations. We assessed associations ...between various social network aspects and practicing behavior to prevent respiratory infectious diseases.
We analyzed baseline-data (2019) from the SaNAE-cohort on social networks and health, collected by an online questionnaire in Dutch community-dwelling people aged 40-99 years. Outcome was the number of preventive behaviors in past two months range 0-4. Associations between network aspects were tested using ordinal regression analyses, adjusting for confounders.
Of 5,128 participants (mean age 63; 54% male), 94% regularly washed hands with water and soap, 55% used only paper (not cloth) handkerchiefs/tissues; 19% touched their face as little as possible; 39% kept distance from people with respiratory infectious disease symptoms; median score of behaviors was 2. Mean network size was 11 (46% family; 27% friends); six network members were contacted exclusively in-person and two exclusively via phone/internet. Participants received informational, emotional, and practical support from four, six, and two network members, respectively. Independently associated with more preventive behaviors were: 'strong relationships', i.e., large share of friends and aspects related to so called 'weak relationships', a larger share of distant living network members, higher number of members with whom there was exclusively phone/internet contact, and more network members providing informational support. Club membership and a larger share of same-aged network members were inversely associated.
Friends ('strong' relationships) may play an important role in the adoption of infection-preventive behaviors. So may 'weak relationships', e.g. geographically more distant network members, who may provide informational support as via non-physical modes of contact. Further steps are to explore employment of these types of relationships when designing infectious diseases control programs aiming to promote infection-preventive behavior in middle aged-and older individuals.
Some COVID-19 survivors suffer from persistent pulmonary function impairment, but the extent and associated factors are unclear. This study aimed to characterize pulmonary function impairment three ...to five months after hospital discharge and the association with disease severity. Survivors of COVID-19 after hospitalization to the VieCuri Medical Centre between February and December 2020 were invited for follow-up, three to five months after discharge. Dynamic and static lung volumes, respiratory muscle strength and diffusion capacity were measured. The cohort comprised 257 patients after a moderate (n = 33), severe (n = 151) or critical (n = 73) COVID-19 infection with a median follow-up of 112 days (interquartile range 96-134 days). The main sequelae included reduced diffusion capacity (36%) and reduced maximal expiratory pressure (24%). Critically ill patients were more likely to have reduced diffusion capacity than moderate (OR 8.00, 95% CI 2.46-26.01) and severe cases (OR 3.74, 95% CI 1.88-7.44) and lower forced vital capacity (OR 3.29, 95% CI 1.20-9.06) compared to severe cases. Many COVID-19 survivors, especially after a critical disease course, showed pulmonary function sequelae, mainly DLCO impairments, three to five months after discharge. Monitoring is needed to investigate the persistence of these symptoms and the longer-term implications of the COVID-19 burden.
Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated ...GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor(-/-) mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15(-/-) chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15(-/-) macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein-coupled receptor kinase 2(+/-) macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.
Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spastic paresis of the lower limbs. Treatment is often focused on reducing spasticity and its ...physical consequences. To better address individual patients' needs, we investigated a broad range of experienced complaints, activity limitations, and loss of motor capacities in pure HSP. In addition, we aimed to identify patient characteristics that are associated with increased fall risk and/or reduced walking capacity.
We developed and distributed an HSP-specific online questionnaire in the Netherlands. A total of 109 out of 166 questionnaires returned by participants with pure HSP were analyzed.
Participants experienced the greatest burden from muscle stiffness and limited standing and walking activities, while 72% reported leg and/or back pain. Thirty-five and 46% reported to use walking aids (e.g. crutches) indoors and outdoors, respectively; 57% reported a fall incidence of at least twice a year ('fallers'); in 51% a fall had led to an injury at least once; and 73% reported fear of falling. Duration of spasticity and incapacity to rise from the floor were positively associated with being a 'faller', whereas non-neurological comorbidity and wheelchair use were negatively associated. Higher age, experienced gait problems, not being able to stand for 10 min, and incapacity to open a heavy door showed a negative association with being a 'walker without aids' (> 500 m).
Our results emphasize the large impact of spastic paraparesis on the lives of people with pure HSP and contribute to a better understanding of possible targets for rehabilitation.
Abstract A significant proportion of COVID-19 survivors still experience a reduced diffusion capacity three and twelve months after discharge. We aimed to compare pulmonary function trajectories ...between hospitalized COVID-19 patients with pre-existing respiratory disease (PRD) and patients without pre-existing respiratory disease (Non-PRD) at three and twelve months after hospital discharge. This single-centre retrospective cohort study included COVID-19 patients admitted to the VieCuri Medical Centre (Venlo, the Netherlands) between February and December 2020 that were invited to the outpatient clinic at three and twelve months after discharge. During this visit, pulmonary function tests were performed and impairments were based on lower limit of normal. Data of 239 patients were analysed (65% male, 66 ± 10 years, and 26% with a history of respiratory disease). Three months after discharge, 49% and 64% of the Non-PRD patients (n = 177) and PRD patients (n = 62) had a low diffusion capacity, respectively. This improved over time in Non-PRD patients ( p = 0.003), but not in PRD patients ( p = 0.250). A low diffusion capacity was still observed in 34% and 57% of the Non-PRD and PRD group, respectively, twelve months after discharge. Pulmonary function impairments, mainly a reduced diffusion capacity, are observed among hospitalized COVID-19 patients with PRD and Non-PRD, at three and twelve months follow-up. Although diffusion capacity impairments restore over time in Non-PRD patients, poor recovery was observed among PRD patients.
Pig and poultry breeding programs aim at improving crossbred (CB) performance. Selection response may be suboptimal if only purebred (PB) performance is used to compute genomic estimated breeding ...values (GEBV) because the genetic correlation between PB and CB performance (Formula: see text) is often lower than 1. Thus, it may be beneficial to use information on both PB and CB performance. In addition, the accuracy of GEBV of PB animals for CB performance may improve when the breed-of-origin of alleles (BOA) is considered in the genomic relationship matrix (GRM). Thus, our aim was to compare scenarios where GEBV are computed and validated by using (1) either CB offspring averages or individual CB records for validation, (2) either a PB or CB reference population, and (3) a GRM that either accounts for or ignores BOA in the CB individuals. For this purpose, we used data on body weight measured at around 7 (BW7) or 35 (BW35) days in PB and CB broiler chickens and evaluated the accuracy of GEBV based on the correlation GEBV with phenotypes in the validation population (validation correlation).
With validation on CB offspring averages, the validation correlation of GEBV of PB animals for CB performance was lower with a CB reference population than with a PB reference population for BW35 (Formula: see text = 0.96), and about equal for BW7 (Formula: see text = 0.80) when BOA was ignored. However, with validation on individual CB records, the validation correlation was higher with a CB reference population for both traits. The use of a GRM that took BOA into account increased the validation correlation for BW7 but reduced it for BW35.
We argue that the benefit of using a CB reference population for genomic prediction of PB animals for CB performance should be assessed either by validation on CB offspring averages, or by validation on individual CB records while using a GRM that accounts for BOA in the CB individuals. With this recommendation in mind, our results show that the accuracy of GEBV of PB animals for CB performance was equal to or higher with a CB reference population than with a PB reference population for a trait with an Formula: see text of 0.8, but lower for a trait with an Formula: see text of 0.96. In addition, taking BOA into account was beneficial for a trait with an Formula: see text of 0.8 but not for a trait with an Formula: see text of 0.96.
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