Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis
. The ...understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited
. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2
). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
In developing countries, information on the area and spatial distribution of paddy rice fields is an essential requirement for ensuring food security and facilitating targeted actions of both ...technical assistance and restoration of degraded production areas. In this study, Sentinel 1 (S1) and Sentinel 2 (S2) imagery was used to map lowland rice crop areas in the Sédhiou region (Senegal) for the 2017, 2018, and 2019 growing seasons using the Random Forest (RF) algorithm. Ground sample datasets were annually collected (416, 455, and 400 samples) for training and testing yearly RF classification. A procedure was preliminarily applied to process S2 scenes and yield a normalized difference vegetation index (NDVI) time series less affected by clouds. A total of 93 predictors were calculated from S2 NDVI time series and S1 vertical transmit–horizontal receive (VH) and vertical transmit–vertical receive (VV) backscatters. Guided regularized random forest (GRRF) was used to deal with the arising multicollinearity and identify the most important predictors. The RF classifier was then applied to the selected predictors. The algorithm predicted the five land cover types present in the test areas, with a maximum accuracy of 87% and kappa coefficient of 0.8 in 2019. The broad land cover maps identified around 12,500 (2017), 13,800 (2018), and 12,800 (2019) ha of lowland rice crops. The study highlighted a partial difficulty of the classifier to distinguish rice from natural herbaceous vegetation (NHV) due to similar temporal patterns and high intra-class variability. Moreover, the results of this investigation indicated that S2-derived predictors provided more valuable information compared to VV and VH backscatter-derived predictors, but a combination of radar and optical imagery always outperformed a classification based on single-sensor inputs. An example is finally provided that illustrates how the maps obtained can be combined with ground observations through a ratio estimator in order to yield a statistically sound prediction of rice area all over the study region.
The use of cryopreserved peripheral blood mononuclear cells is common in biological research. It is widely accepted that primary cells are rendered unusable by several freezing cycles, although this ...practice might be very helpful when the biological material is valuable and its re-collection is impractical. To determine the extent to which primary cells undergoing repeated freezing cycles are comparable to one another and to fresh samples, we evaluated overall lymphocyte viability, their proliferation and cytokine production capabilities, as well as the levels of 27 cell subtypes in ten human peripheral blood mononuclear cells frozen for five years and repeatedly thawed. As expected, we observed a progressive increase in cell death percentages on three rounds of thawing, but the frequency of the main lymphocyte subsets was stable across the three thawings. Nevertheless, we observed a significant reduction of B cell frequency in frozen samples compared to fresh ones. On repeated thawings and subsequent conventional stimulation, lymphocyte proliferation significantly decreased, and IL-10, IL-6, GM-CSF, IFN-gamma, and IL-8 showed a trend to lower values.
The study of the gut microbiota (GM) is rapidly moving towards its functional characterization by means of shotgun meta-omics. In this context, there is still no consensus on which microbial ...functions are consistently and constitutively expressed in the human gut in physiological conditions. Here, we selected a cohort of 15 healthy subjects from a native and highly monitored Sardinian population and analyzed their GMs using shotgun metaproteomics, with the aim of investigating GM functions actually expressed in a healthy human population. In addition, shotgun metagenomics was employed to reveal GM functional potential and to compare metagenome and metaproteome profiles in a combined taxonomic and functional fashion.
Metagenomic and metaproteomic data concerning the taxonomic structure of the GM under study were globally comparable. On the contrary, a considerable divergence between genetic potential and functional activity of the human healthy GM was observed, with the metaproteome displaying a higher plasticity, compared to the lower inter-individual variability of metagenome profiles. The taxon-specific contribution to functional activities and metabolic tasks was also examined, giving insights into the peculiar role of several GM members in carbohydrate metabolism (including polysaccharide degradation, glycan transport, glycolysis, and short-chain fatty acid production). Noteworthy, Firmicutes-driven butyrogenesis (mainly due to Faecalibacterium spp.) was shown to be the metabolic activity with the highest expression rate and the lowest inter-individual variability in the study cohort, in line with the previously reported importance of the biosynthesis of this microbial product for the gut homeostasis.
Our results provide detailed and taxon-specific information regarding functions and pathways actively working in a healthy GM. The reported discrepancy between expressed functions and functional potential suggests that caution should be used before drawing functional conclusions from metagenomic data, further supporting metaproteomics as a fundamental approach to characterize the human GM metabolic functions and activities.
Aims
Previous cross-sectional observation identified arterial aging, indexed as pulse-wave velocity (PWV), as a key determinant of the simultaneous multiple organ damage (heart, carotid artery, and ...kidney). The aim of the present cohort study is to investigate trajectories of repeated measures of PWV and traditional CV risk factors in subjects who eventually presented clinical evidence of multiple organ damage in the SardiNIA study.
Methods and results
Organ damage was measured in the heart (left ventricular hypertrophy, LVH), the common carotid artery (intima–media thickness > 0.9 mm and/or plaque), and the kidney (eGFR < 60 ml/min/1.73 m
2
) of 2130 men and women of a broad age range participating the SardiNIA study. SHATS was defined as the simultaneous occurrence of all the three-organ damages. Trajectory in traditional CV risk factors and PWV was analyzed retrospectively (four observations over 9 years) according to the number of organ damage (from 0 to 3). Compared to subjects with no organ damage, after controlling for traditional CV risk factors, each 1 m/s increase in baseline PWV was accompanied by a 93% higher odds of developing SHATS; and each 1 cm/s (0.01 m/s) annual increase in PWV by a 31% greater odds of developing SHATS.
Conclusions
Arterial stiffness, a proxy of arterial aging that can be measured clinically as PWV, is an integrated predictive marker of multiple age-associated organ damage recognized as clinical diseases.
In recent years, systematic genome-wide association studies of quantitative immune cell traits, represented by circulating levels of cell subtypes established by flow cytometry, have revealed ...numerous association signals, a large fraction of which overlap perfectly with genetic signals associated with autoimmune diseases. By identifying further overlaps with association signals influencing gene expression and cell surface protein levels, it has also been possible, in several cases, to identify causal genes and infer candidate proteins affecting immune cell traits linked to autoimmune disease risk. Overall, these results provide a more detailed picture of how genetic variation affects the human immune system and autoimmune disease risk. They also highlight druggable proteins in the pathogenesis of autoimmune diseases; predict the efficacy and side effects of existing therapies; provide new indications for use for some of them; and optimize the research and development of new, more effective and safer treatments for autoimmune diseases. Here we review the genetic-driven approach that couples systematic multi-parametric flow cytometry with high-resolution genetics and transcriptomics to identify endophenotypes of autoimmune diseases for the development of new therapies.
Vaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following ...vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients.
We obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine.
MS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients.
Humoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.
Extracellular vesicles (EVs) mediate cell interactions in biological processes, such as receptor activation or molecule transfer. Estimates of variation by age and sex have been limited by small ...sample size, and no report has assessed the contribution of genetic factors to levels of EVs. Here, we evaluated blood levels of 25 EV and 3 platelet traits in 974 individuals (933 genotyped) and reported the first genome-wide association study (GWAS) on levels of these traits. EV levels all decreased with age, whereas the trend for their surface markers was more heterogeneous. Platelets and CD31dim platelet EVs significantly increased in females compared to males, although CD31 expression on both platelets and platelet EVs decreased in females. Levels of the other EV subsets were similar between sexes. GWAS revealed three statistically significant genetic signals associated with EV levels in the
and
genes and in the intergenic region between
and
. These add to a signal in the 3'UTR of
associated with CD31 expression on platelets that was previously found to be associated with other platelet traits. These findings suggest that EV formation is not a simple, constant adjunct of metabolism but is under both age-related and genetic control that can be independent of the regulation of the levels of the cells from which the EVs derive.
Physiological equivalent temperature (PET) is one of most used indices for outdoor human well-being evaluation; its determination is particularly helpful for adaptation strategies in built-up areas ...affected by the urban heat island (UHI) phenomenon. In this work, we presented a methodology to compute spatially and temporally resolved PET values during a heatwave at the city level, based on a combination of satellite products, in situ measurements and Envi-met model runs upscaled from specific test areas to the broader city. The method exploits the ECOSTRESS sensor to detect surface thermal patterns at different diurnal times by developing an hourly based index called hUHTI (hourly urban heatwave thermal index) that serves as a proxy. A case study on Prato (Italy) municipality during the 2021 summer heatwave events is presented. Based on the available satellite products, a set of six hourly diurnal PET maps at 10 m spatial resolution were derived and daytime outdoor thermal patterns and trends were investigated according to land cover. hUHTI index resulted a more suitable tool as PET proxy compared to the sole ECOSTRESS land surface temperature (LST) product, especially for morning and evening times. Hourly PET maps were summarized by the use of an average exceedance map providing public administrations and stakeholders a synthetic tool for urban regeneration purposes at city scale.
Aims
High glucose levels and Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd) have both tissue inflammatory effects. Here we determined whether G6PDd accelerates arterial aging (information ...linked stiffening) in diabetes.
Methods
Plasma glucose, interleukin 6 (IL6), and arterial stiffness (indexed as carotid-femoral Pulse Wave Velocity, PWV) and red blood cell G6PD activity were assessed in a large (4448) Sardinian population.
Results
Although high plasma glucose in diabetics
,
did not differ by G6DP status (178.2 ± 55.1 vs 169.0 ± 50.1 mg/dl) in G6DPd versus non-G6PDd subjects, respectively, IL6, and PWV (adjusted for age and glucose) were significantly increased in G6PDd vs non-G6PDd subjects (PWV, 8.0 ± 0.4 vs 7.2 ± 0.2 m/sec) and (IL6, 6.9 ± 5.0 vs 4.2 ± 3.0 pg/ml). In
non-diabetics
, neither fasting plasma glucose, nor IL6, nor PWV were impacted by G6PDd.
Conclusion
G6PDd in diabetics is associated with increased inflammatory markers and accelerated arterial aging.
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