The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the ...long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.
The aim of this study was to determine the effects of advanced chronic kidney disease (CKD) on early and late outcomes after transcatheter aortic valve implantation (TAVI), and to evaluate the ...predictive factors of poorer outcomes in such patients.
This was a multicentre study including a total of 2075 consecutive patients who had undergone TAVI. Patients were grouped according the estimated glomerular filtration rate as follows: CKD stage 1-2 (≥60 mL/min/1.73 m(2); n = 950), stage 3 (30-59 mL/min/1.73 m(2); n = 924), stage 4 (15-29 mL/min/1.73 m(2); n = 134) and stage 5 (<15 mL/min/1.73 m² or dialysis; n = 67). Clinical outcomes were evaluated at 30-days and at follow-up (median of 15 6-29 months) and defined according to the VARC criteria. Advanced CKD (stage 4-5) was an independent predictor of 30-day major/life-threatening bleeding (P = 0.001) and mortality (P = 0.027), and late overall, cardiovascular and non-cardiovascular mortality (P < 0.01 for all). Pre-existing atrial fibrillation (HR: 2.29, 95% CI: 1.47-3.58, P = 0.001) and dialysis therapy (HR: 1.86, 95% CI: 1.17-2.97, P = 0.009) were the predictors of mortality in advanced CKD patients, with a mortality rate as high as 71% at 1-year follow-up in those patients with these 2 factors. Advanced CKD patients who had survived at 1-year follow-up exhibited both a significant improvement in NYHA class (P < 0.001) and no deterioration in valve hemodynamics (P = NS for changes in mean gradient and valve area over time).
Advanced CKD was associated with a higher rate of early and late mortality and bleeding events following TAVI, with AF and dialysis therapy determining a higher risk in these patients. The mortality rate of patients with both factors was unacceptably high and this should be taken into account in the clinical decision-making process in this challenging group of patients.
GATA binding protein 2 (GATA2) deficiency is a rare disorder of hematopoiesis, lymphatics, and immunity caused by spontaneous or autosomal dominant mutations in the
gene. Clinical manifestations ...range from neutropenia, lymphedema, deafness, to severe viral and mycobacterial infections, bone marrow failure, and acute myeloid leukemia. Patients also present with monocytopenia, dendritic cell, B- and natural killer (NK)-cell deficiency. We studied the T-cell and NK-cell compartments of four GATA2-deficient patients to assess if changes in these lymphocyte populations could be correlated with clinical phenotype. Patients with more severe clinical complications demonstrated a senescent T-cell phenotype whereas patients with lower clinical score had undetectable changes relative to controls. In contrast, patients' NK-cells demonstrated an immature/activated phenotype that did not correlate with clinical score, suggesting an intrinsic NK-cell defect. These studies will help us to determine the contribution of T- and NK-cell dysregulation to the clinical phenotype of GATA2 patients, and may help to establish the most accurate therapeutic options for these patients. Asymptomatic patients may be taken into consideration for hematopoietic stem cell transplantation when dysregulation of T-cell and NK-cell compartment is present.
Angiogenesis is the process through which new blood vessels are formed from preexisting ones and plays a critical role in several conditions including embryonic development, tissue repair and ...disease. Moreover, enhanced therapeutic angiogenesis is a major goal in the field of regenerative medicine and efficient vascularization of artificial tissues and organs is one of the main hindrances in the implementation of tissue engineering approaches, while, on the other hand, inhibition of angiogenesis is a key therapeutic target to inhibit for instance tumor growth. During the last decades, the understanding of cellular and molecular mechanisms involved in this process has been matter of intense research. In this regard, several in vitro and in vivo models have been established to visualize and study migration of endothelial progenitor cells, formation of endothelial tubules and the generation of new vascular networks, while assessing the conditions and treatments that either promote or inhibit such processes. In this review, we address and compare the most commonly used experimental models to study angiogenesis in vitro and in vivo. In particular, we focus on the implementation of the zebrafish (Danio rerio) as a model to study angiogenesis and discuss the advantages and not yet explored possibilities of its use as model organism.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of
,
, or
in five unrelated children with ...MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPβ1, a surface receptor that triggers ...amyloid-β(Aβ) phagocytosis via TYROBP.
To analyze the impact of this copy-number variant in SIRPβ1 expression and how it affects AD molecular etiology.
Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPβ1 isoform-specific phagocytosis assays were performed in HEK393T cells.
The insertion alters the SIRPβ1 protein isoform landscape compromising its ability to bind oligomeric Aβ and its affinity for TYROBP. SIRPβ1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aβ ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPβ1 duplication allele correlates with higher TREM2 expression and an increased microglial activation.
The SIRPβ1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aβ. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPβ1 structural variant might be considered as a potential modulator of this causative pathway.
Background
Mosaic loss of chromosome Y (mLOY) is a highly common somatic variant among men, and has been associated to higher risk in overall mortality and several types of disease, including ...Alzheimer’s disease (Dumanski et al. 2016). In the present study, we aimed to replicate these findings in both a cross‐sectional and longitudinal setup by determining mLOY phenotype and its associated polygenic risk score (PRS).
Method
MADloy R package (González et al. 2020) was used to determine mLOY in germline blood DNA from males in the GR@ACE cohort, composed of AD patients recruited in Fundació ACE (Barcelona, Spain) and population‐based controls recruited from several Spanish centres. Additional MCI patients recruited in Fundació ACE were used to study disease progression. PRS was calculated by additive multiplication of the beta values of 114 genome‐wide significant variants reported in the most relevant mLOY GWAS published to date (Thompson et al. 2019) and their genotypes in our dataset. To ease interpretation of results, PRS per SD units were used. Only individuals with ages 65‐85 were kept for the case‐control and PRS analyses (see Table 1). Statistical analysis was performed by fitting logistic regressions and Cox proportional‐hazards models adjusted by age, APOE and PCs (when needed).
Result
mLOY phenotype did not show a significant association with AD in the case‐control setup and showed suggestive results for higher risk of conversion to AD (HR=1.45; p=0.09). However, the mLOY PRS yielded borderline significance in the case‐control dataset (OR=1.08; p=0.09), and statistical significance in MCI to AD conversion (HR=1.22; p=0.01). Importantly, PRS was independent of age, and effects were only observed in male samples, with no effect in conversion to AD or case‐control in the female subset, supporting the validity of our approach.
Conclusion
The age‐dependent nature of mLOY and lack of age at sampling information for most controls limited our power to study mLOY phenotype’s effect on AD. The mLOY PRS allowed us to overcome these limitations, acting as a male‐specific AD risk factor and providing further evidence of mLOY’s impact on AD.
Efficient natural resources management, including continental water at watershed level, requires understanding the arrangement of landscape attributes in a region. The geographical analysis of ...landscape attributes is a useful approach to delineate relatively homogeneous watersheds or regions. This research was carried out in order to evaluate the effect of land cover through time on regionalisation modelling in the poorly-gauged Cuitzeo Lake Watershed, and to develop models to create two hydrogeographical regionalisations for the years 1975 and 2000. The inputs required by the regionalisation methodology were integrated in a GIS and validated before carrying out statistical regionalisation procedures (cluster analysis and PCA). GIS operations were done in Arc View 3.2 and statistical analyses in PC-ORD. Median Euclidean distances with mean distance linkage methods were used. A 75% of similarity was chosen as the threshold to generate regions. Importance rankings of regions were obtained using multicriteria evaluation methods. Based on the analysis, 38 of the 52 subwatersheds belonging to the Cuitzeo Lake Watershed were clustered; eight groups were defined in 1975 and nine in 2000. According to PCA, the strongest positive variables are associated to morphometric, geologic, land cover and soil attributes. Fourteen subwatersheds were never clustered. Four subwatersheds changed of cluster between 1975 and 2000. This change is explained because of rainfed agricultural parcel abandonment, and subsequent shrubland growth. This means that the hydrogeographical regionalisation is sensitive to land cover change processes. The methodological approach applied in this research is a low-cost and fast alternative for evaluating the impact of land cover and land use change on hydrogeographical regionalisation; in consequence, data and information generated during the analysis were made available to local authorities so that they can improve both water resources planning and their informational baseline for decision making and for development of environmental policies in the Cuitzeo Lake Watershed.
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