Search

Recent genetic data suggest that abnormal cardiac development participates to the pathogenesis of Brugada Syndrome (BrS), a rare inherited arrhythmia responsible for sudden cardiac death in young adults. In vitro cardiac differentiation of human induced pluripotent stem cells (hiPSCs) mimics cardiac development at the cellular level up to a prenatal stage. This study aims at defining whether BrS impairs cardiac differentiation of hiPSCs. Single-cell transcriptomic data were generated at day 30 of in vitro cardiac differentiation of hiPSCs from 2 control subjects (n = 6139 cells) and 2 BrS patients (n = 13756 cells). These transcriptomic data have been annotated using public data obtained from human heart samples at 7.5 post conception weeks (PCW). In addition, bulk 3′RNA-seq data were generated in triplicate for 3 control hiPSC lines and 3 BrS-patient hiPSC lines at each day of the 30-day cardiac-directed differentiation protocol. Single-cell data revealed (1) differences in cell type distribution, with BrS-hiPSCs and control-hiPSCs cardiac-directed differentiation generating 9.8% and 32.85% cardiomyocytes and 16.6% and 2.75% smooth muscle cells, respectively, and (2) cardiomyocytes transcriptomic alterations associated with biological processes of cardiac development, morphogenesis and conduction in BrS. Based on the finding, showing that BrS is associated with alterations in cardiac differentiation, we used the bulk transcriptomic kinetic data to analyze temporal transcriptomic alterations during cardiac-directed differentiation. Differential gene expression analysis unveiled (1) gene expression signatures specific to each BrS patients and (2) expression alterations that were common to all 3 BrS-hiPSCs lines as compared with control lines. Interestingly, the misexpressed genes were associated to the cell differentiation process (GO: 0030154) and their expression kinetics were altered during the cardiac differentiation process. By generating and analyzing single-cell and bulk transcriptomic data during cardiac-directed differentiation of hiPSCs, this study strongly suggests that transcriptomic remodeling occurs as early as the cardiac development for BrS patients. [ABSTRACT FROM AUTHOR]

The nephrotoxicity of low-chronic metal exposures is unclear, especially considering several metals simultaneously. We assessed the individual and joint association of metals with longitudinal change in renal endpoints in Aragon Workers Health Study participants with available measures of essential (cobalt [Co], copper [Cu], molybdenum [Mo] and zinc [Zn]) and non-essential (As, barium [Ba], Cd, chromium [Cr], antimony [Sb], titanium [Ti], uranium [U], vanadium [V] and tungsten [W]) urine metals and albumin-to-creatinine ratio (ACR) (N = 707) and estimated glomerular filtration rate (eGFR) (N = 1493) change. Median levels were 0.24, 7.0, 18.6, 295, 3.1, 1.9, 0.28, 1.16, 9.7, 0.66, 0.22 μg/g for Co, Cu, Mo, Zn, As, Ba, Cd, Cr, Sb, Ti, V and W, respectively, and 52.5 and 27.2 ng/g for Sb and U, respectively. In single metal analysis, higher As, Cr and W concentrations were associated with increasing ACR annual change. Higher Zn, As and Cr concentrations were associated with decreasing eGFR annual change. The shape of the longitudinal dose-responses, however, was compatible with a nephrotoxic role for all metals, both in ACR and eGFR models. In joint metal analysis, both higher mixtures of Cu–Zn–As–Ba–Ti–U–V–W and Co–Cd–Cr–Sb–V–W showed associations with increasing ACR and decreasing eGFR annual change. As and Cr were main drivers of the ACR change joint metal association. For the eGFR change joint metal association, while Zn and Cr were main drivers, other metals also contributed substantially. We identified potential interactions for As, Zn and W by other metals with ACR change, but not with eGFR change. Our findings support that Zn, As, Cr and W and suggestively other metals, are nephrotoxic at relatively low exposure levels. Metal exposure reduction and mitigation interventions may improve prevention and decrease the burden of renal disease in the population. [Display omitted] • High Zn, As, Cr, and W were associated with adverse longitudinal renal endpoints. • Joint metal associations were mainly driven by As and Cr for ACR, and Zn and Cr for eGFR. • As, Zn, and W showed interactions by other metals with ACR, but not eGFR. • Metal exposure reduction and mitigation may decrease the renal disease burden. [ABSTRACT FROM AUTHOR]

• MeSA can be assayed in wines at concentrations over its olfactory detection threshold. • MeSA is extracted during alcoholic fermentation from V.vinifera grape skins and stems. • MeSA in wines can be related to grapevine alteration level by several pathogens. Methyl salicylate (MeSA) is a plant metabolite that induces plant defence resistance and an odorous volatile compound presenting green nuances. This volatile compound was shown to be present in wine samples, sometimes at concentrations above its olfactory detection threshold. MeSA is localized in grapes, particularly in the skins and stems, and is extracted during red wine vinification. It was detected at the highest concentrations in wines of several grape varieties, made from grapes affected by cryptogamic diseases, namely downy mildew caused by Plasmopara viticola , and black rot caused by Guignardia bidwellii. It has also been detected in wines from vines affected by Esca, a Grapevine Trunk Disease. MeSA can also be considered to be a chemical marker in grapes and wine indicative of the level of development of several vine cryptogamic diseases. [ABSTRACT FROM AUTHOR]

Cells activate distinctive regulatory pathways that prevent excessive initiation of DNA replication to achieve timely and accurate genome duplication. Excess DNA synthesis is constrained by protein–DNA interactions that inhibit initiation at dormant origins. In parallel, specific modifications of pre-replication complexes prohibit post-replicative origin relicensing. Replication stress ensues when the controls that prevent excess replication are missing in cancer cells, which often harbor extrachromosomal DNA that can be further amplified by recombination-mediated processes to generate chromosomal translocations. The genomic instability that accompanies excess replication origin activation can provide a promising target for therapeutic intervention. Here we review molecular pathways that modulate replication origin dormancy, prevent excess origin activation, and detect, encapsulate, and eliminate persistent excess DNA. Cells have evolved specialized mechanisms to avoid the deleterious effects of excess initiation from replication origins. During unperturbed proliferation, most potential replication origins are dormant and do not initiate replication but are prepared for activation to facilitate complete genome duplication if cells encounter replication stress. Cells prevent initiation at dormant origins by adjusting chromatin structure to constrain the assembly and activation of pre-replication complexes, targeting components of the replication machinery for degradation or modulating specific protein–DNA interactions at origins. Cancer cells often lack the controls that prevent excess activation of replication origins, resulting in the amplification of extrachromosomal DNA that can persist if they contain genes that can confer a selective growth advantage. Cells activate metabolic and inflammatory responses to sense and encapsulate and eliminate excess DNA. Because excess replication origin activation can directly or indirectly lead to genomic instability, targeting the pathways that prevent excess replication or eliminate excess DNA is a promising avenue for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Dielectric constants of Al 2 O 3 (alumina) ceramic samples have been measured with non-destructive terahertz time-domain spectroscopy. Using an effective medium approximation, we demonstrated that the relative permittivity can be used to evaluate the porous alumina samples, with porosity fractions ranging from 0% to 20% per volume. This result makes it possible to control sample porosity, a key material parameter related to mechanical strength under compression load, hardness and wear resistance, or thermal stability. We also employed terahertz time-domain spectroscopy to differentiate alumina samples fabricated with different grain sizes, or reveal a small fraction of impurities, such as 5% vol of ZrO 2 , embedded in non-porous alumina. These results demonstrated the potential of terahertz radiation for non-destructive characterization of low loss high dielectric constant ceramics. [ABSTRACT FROM AUTHOR]

The potential joint influence of metabolites on bone fragility has been rarely evaluated. We assessed the association of plasma metabolic patterns with bone fragility endpoints (primarily, incident osteoporosis-related bone fractures, and, secondarily, bone mineral density BMD) in the Hortega Study participants. Redox balance plays a key role in bone metabolism. We also assessed differential associations in participant subgroups by redox-related metal exposure levels and candidate genetic variants. In 467 participants older than 50 years from the Hortega Study, a representative sample from a region in Spain, we estimated metabolic principal components (mPC) for 54 plasma metabolites from NMR-spectrometry. Metals biomarkers were measured in plasma by AAS and in urine by HPLC-ICPMS. Redox-related SNPs (N = 341) were measured by oligo-ligation assay. The prospective association with incident bone fractures was inverse for mPC1 (non-essential and essential amino acids, including branched-chain, and bacterial co-metabolites, including isobutyrate, trimethylamines and phenylpropionate, versus fatty acids and VLDL) and mPC4 (HDL), but positive for mPC2 (essential amino acids, including aromatic, and bacterial co-metabolites, including isopropanol and methanol). Findings from BMD models were consistent. Participants with decreased selenium and increased antimony, arsenic and, suggestively, cadmium exposures showed higher mPC2-associated bone fractures risk. Genetic variants annotated to 19 genes, with the strongest evidence for NCF4, NOX4 and XDH, showed differential metabolic-related bone fractures risk. Metabolic patterns reflecting amino acids, microbiota co-metabolism and lipid metabolism were associated with bone fragility endpoints. Carriers of redox-related variants may benefit from metabolic interventions to prevent the consequences of bone fragility depending on their antimony, arsenic, selenium, and, possibly, cadmium, exposure levels. • Several metabolic patterns, so-called mPCs, were associated with bone fragility endpoints. • For mPC2, the bone fracture risk was higher with high exposure to Sb, As and, suggestively, Cd, and low Se. • Carriers of genetic variants in NCF4, NOX4 and XDH showed differential metabolic-related bone fracture risk. • Identified gene-environment statistical interactions may be relevant for metabolic bone fragility prevention. [ABSTRACT FROM AUTHOR]

Low-cost particulate matter (PM) sensors are increasingly used by researchers, public health agencies, and the public to measure spatial and temporal variations in air pollution, which can inform strategies for community air pollution reduction. While low-cost PM sensors provide a valuable measure of harmful fine particulate matter (PM 2.5), a significant portion of ambient PM 2.5 is typically the secondary product of air pollution emitted by varied sources outside of community boundaries. In contrast, concentrations of black carbon (BC), a component of PM 2.5 , are directly emitted by a few specific sources, such as diesel engines within communities. Motivated by community organizations seeking to understand persistent sources of local pollution, this study deployed a suite of custom-built BC sensors alongside a network of low-cost PM sensors for four weeks in two seasons at 50 stationary locations in the adjacent cities of Richmond, North Richmond, and San Pablo, California, east of the San Francisco Bay. Concentrations of BC varied more than PM 2.5 both temporally and spatially. Monthly network-average BC was 3 × higher in winter than late spring, while PM 2.5 was only 10% lower. In both seasons, average PM 2.5 concentrations at two-thirds of sites were within ±10% of the network average, whereas two-thirds of sites had BC levels outside of ±10% of the network-average concentration. The most and least polluted locations were more persistent across seasons for BC than PM 2.5 , and the temporal dynamics of BC at these sites were similar, signifying that they are impacted by the same emission sources. Together, these spatiotemporal trends show that BC is a better indicator of the proximity and activity of local pollution sources than PM 2.5. Thus, including BC in addition to PM 2.5 in community monitoring networks can provide additional insights about local sources of air pollution. [Display omitted] • BC and PM sensors deployed 4 weeks in 2 seasons at 50 sites in an environmental justice community. • Greater spatiotemporal heterogeneity and location persistence of BC compared to PM 2.5 • BC more informative than PM 2.5 of proximity and activity of local emission sources. • Recommend measuring PM 2.5 plus BC for insights to community air protection plans. [ABSTRACT FROM AUTHOR]

Due to its short-lived progeny, including gaseous radon isotopes that can be inhaled and its significant transfer into vegetation, radium poses a substantial concern in radiation risk assessment. Although the transfer of Ra from soil to plants has been previously documented, the distribution and speciation of radium within the plant tissues, particularly within trees, remain unclear. The temporal dimension of Ra transfer is also poorly known. Therefore, the transfer of radium and others alkaline earth cations in beech trees was investigated through the analysis of fine (<2 mm) roots and leaves corresponding to tree organs with a life cycle limited to one season. This study was conducted at the experimental Montiers (INRAE-Andra site, France) and Strengbach watershed (OHGE site, France) beech-forested site. The activity of 226Ra and the isotopic ratio (228Ra/226Ra) were measured in roots and leaves using gamma spectrometry. Additionally, the concentration of alkaline earth cations (Mg, Ca, Sr, and Ba) was measured, to better constraint the mechanism of alkaline earth cation transfer through the xylem. The retention of these cations within the trees increases with the mass of the element, following the order Mg < Ca < Sr ≈ Ba < Ra, i.e.: light alkaline earth cations are more efficiently transferred from roots to leaves than heavy one. Our results suggest that these cations maintain their hydration shell during their ascent in stems and a low pH ion-exchange process rather than a complexation process with carboxylic group occurs. The decay of the (228Ra/226Ra) isotopic ratio over time during transfer within the trees allows us to quantify the slow Ra translocation from roots to the leaves, ranging from 1 to more than 16 years. This duration increases with the age of the trees. Hence, radioactive decay of Ra provides particularly valuable timescale information that is usually difficult to assess for Ca or other alkaline earth cations. [Display omitted] • Light alkaline earth cations are more transferred to leaves than heavy one. • Alkaline earth cations keep their hydration shell during ascent in tree stems. • The 228Ra/226Ra ratio provides a means to determine AE cations transfer time in trees. • The translocation of Ra in trees is really slow. • The residence time of Ra increases with the age and/or the size of the tree. [ABSTRACT FROM AUTHOR]