Accelerated telomere length attrition has been associated with psychological stress and early adversity in adults; however, no studies have examined whether telomere length in childhood is associated ...with early experiences. The Bucharest Early Intervention Project is a unique randomized controlled trial of foster care placement compared with continued care in institutions. As a result of the study design, participants were exposed to a quantified range of time in institutional care, and represented an ideal population in which to examine the association between a specific early adversity, institutional care and telomere length. We examined the association between average relative telomere length, telomere repeat copy number to single gene copy number (T/S) ratio and exposure to institutional care quantified as the percent of time at baseline (mean age 22 months) and at 54 months of age that each child lived in the institution. A significant negative correlation between T/S ratio and percentage of time was observed. Children with greater exposure to institutional care had significantly shorter relative telomere length in middle childhood. Gender modified this main effect. The percentage of time in institutional care at baseline significantly predicted telomere length in females, whereas the percentage of institutional care at 54 months was strongly predictive of telomere length in males. This is the first study to demonstrate an association between telomere length and institutionalization, the first study to find an association between adversity and telomere length in children, and contributes to the growing literature linking telomere length and early adversity.
The authors examined the impact of cumulative neighborhood risk of psychosocial stress on allostatic load (AL) among adolescents as a mechanism through which life stress, including neighborhood ...conditions, may affect health and health inequities. They conducted multilevel analyses, weighted for sampling and propensity score-matched, among adolescents aged 12-20 years in the National Health and Nutrition Examination Survey (1999-2006). Individuals (first level, n = 11,886) were nested within families/households (second level, n = 6,696) and then census tracts (third level, n = 2,191) for examination of the contextual effect of cumulative neighborhood risk environment on AL. Approximately 35% of adolescents had 2 or more biomarkers of AL. A significant amount of variance in AL was explained at the neighborhood level. The likelihood of having a high AL was approximately 10% higher for adolescents living in medium-cumulative-risk neighborhoods (adjusted odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.08, 1.09), 28% higher for those living in high-risk neighborhoods (adjusted OR = 1.28, 95% CI: 1.27, 1.30), and 69% higher for those living in very-high-risk neighborhoods (adjusted OR = 1.69, 95% CI: 1.68, 1.70) as compared with adolescents living in low-risk areas. Effect modification was observed by both individual- and neighborhood-level sociodemographic factors. These findings offer support for the hypothesis that neighborhood risks may culminate in a range of biologically mediated negative health outcomes detectable in adolescents.
Our objective was to explore the utility of salivary telomere length (sTL) as an early indicator of neighborhood-level social environmental risk during child development. We therefore tested the ...hypothesis that sTL would be associated with markers of social stress exposure in children. Children age 4–14 from 87 neighborhoods were recruited through five urban schools in New Orleans, Louisiana, U.S. Data were collected at the level of the child, family/household, and neighborhood. DNA was obtained from saliva using commercially available kits and sTL was determined for 104 children using quantitative PCR. Analysis was performed on 99 children who had complete data including sTL, social environmental stress, and additional covariates. The mean sTL value was 7.4 T/S (telomere signal/single-copy signal) ratio units (±2.4, range = 2.5–18.0), and 4.7% of the variance in sTL was attributed to differences across neighborhoods. Children living in neighborhoods characterized by high disorder had an sTL value 3.2 units lower than children not living in high disordered environments (p < 0.05) and their odds of having low relative sTL (defined as <1 standard deviation below standardized Z-score mean) values was 3.43 times that of children not living in high disorder environments (adjusted OR = 3.43, 95% CI = 1.22, 9.62). Our findings are consistent with previous studies in adults demonstrating a strong link between psychosocial stress and sTL obtained from peripheral blood, consistent with previous studies in youth demonstrating an association between early life stress and sTL obtained from buccal cell DNA and offer increased support for the hypothesis that sTL represents a non-invasive biological indicator of psychosocial stress exposure (i.e., neighborhood disorder) able to reflect differences in stress exposure levels even in young children.
► Telomere length has been associated with health outcomes and socioeconomic status. ► In children, telomeres also associated with social deprivation and violence. ► We provide support for telomere length as an early indicator of health inequities. ► Children in high disordered neighborhoods had significantly shorter telomeres. ► Salivary telomere length may represent a biological marker of psychosocial stress.
SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered economies of countries and families ...around the world. Antiviral treatments to combat COVID-19 are currently lacking. Remdesivir, the only antiviral drug approved for the treatment of COVID-19, can affect disease severity, but better treatments are needed. SARS-CoV-2 encodes 16 non-structural proteins (nsp) that possess different enzymatic activities with important roles in viral genome replication, transcription and host immune evasion. One key aspect of host immune evasion is performed by the uridine-directed endoribonuclease activity of nsp15. Here we describe the expression and purification of nsp15 recombinant protein. We have developed biochemical assays to follow its activity, and we have found evidence for allosteric behaviour. We screened a custom chemical library of over 5000 compounds to identify nsp15 endoribonuclease inhibitors, and we identified and validated NSC95397 as an inhibitor of nsp15 endoribonuclease in vitro. Although NSC95397 did not inhibit SARS-CoV-2 growth in VERO E6 cells, further studies will be required to determine the effect of nsp15 inhibition on host immune evasion.
Many ecosystems appear subject to regime shifts--abrupt changes from one state to another after crossing a threshold or tipping point. Thresholds and their associated stability landscapes are ...determined within a coupled socioeconomic-ecological system (SES) where human choices, including those of managers, are feedback responses. Prior work has made one of two assumptions about managers: that they face no institutional constraints, in which case the SES may be managed to be fairly robust to shocks and tipping points are of little importance, or that managers are rigidly constrained with no flexibility to adapt, in which case the inferred thresholds may poorly reflect actual managerial flexibility. We model a multidimensional SES to investigate how alternative institutions affect SES stability landscapes and alter tipping points. With institutionally dependent human feedbacks, the stability landscape depends on institutional arrangements. Strong institutions that account for feedback responses create the possibility for desirable states of the world and can cause undesirable states to cease to exist. Intermediate institutions interact with ecological relationships to determine the existence and nature of tipping points. Finally, weak institutions can eliminate tipping points so that only undesirable states of the world remain.
The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal ...disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2'-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir.
African American women are more likely to experience preterm birth (<37 completed weeks gestation) compared with White women. African American women are also more likely to live in neighborhoods ...characterized as disadvantaged (i.e., exhibiting higher rates of vacant housing, poorer property conditions, and more litter and crime) and to experience racial discrimination compared with White women. These chronic stressors have been related to preterm birth (PTB) among African American women. This review focuses on potential stress-related pathways by which neighborhood disadvantage and racial discrimination increase the risk for PTB among African American women. Specifically, we propose cortisol, systemic inflammation, proteome and lipidome profiles, and telomere shortening as potential mediators linking these social determinants of health with PTB among African American women. Examination of these factors and the signaling pathways they contribute to will increase our knowledge of the effects of social determinants of health on PTB for African American women.
SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great ...pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.
Objective
Studies have shown that prenatal exome sequencing (PES) improves diagnostic yield in cases of fetal structural malformation. We have retrospectively analysed PES cases from two of the ...largest fetal medicine centres in the UK to determine the impact of results on management of a pregnancy.
Design
A retrospective review of clinical case notes.
Setting
Two tertiary fetal medicine centres.
Population
Pregnancies with fetal structural abnormalities referred to clinical genetics via a multidisciplinary team.
Methods
We retrospectively reviewed the notes of all patients who had undergone PES. DNA samples were obtained via chorionic villus sampling or amniocentesis. Variants were filtered using patient‐specific panels and interpreted using American College of Medical Genetics guidelines.
Results
A molecular diagnosis was made in 42% (18/43) ongoing pregnancies; of this group, there was a significant management implication in 44% (8/18). A positive result contributed to the decision to terminate a pregnancy in 16% (7/43) of cases. A negative result had a significant impact on management in two cases by affirming the decision to continue pregnancy.
Conclusions
We demonstrate that the results of PES can inform pregnancy management. Challenges include variant interpretation with limited phenotype information. These results emphasise the importance of the MDT and collecting phenotype and variant data. As this testing is soon to be widely available, we should look to move beyond diagnostic yield as a measure of the value of PES.
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Prenatal exome sequencing can aid decision‐making in pregnancy management; review ahead of routine implementation in NHS.
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Prenatal exome sequencing can aid decision making in pregnancy management; review ahead of routine implementation in NHS.
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