Computing covariant vectors, Lyapunov vectors, Oseledets vectors, and dichotomy projectors: a comparative numerical study

Covariant vectors, Lyapunov vectors, or Oseledets vectors are increasingly being used for a variety of model analyses in areas such as partial differential equations, nonautonomous differentiable dynamical systems, and random dynamical systems. These vectors identify spatially varying directions of specific asymptotic growth rates and obey equivariance principles. In recent years new computational methods for approximating Oseledets vectors have been developed, motivated by increasing model complexity and greater demands for accuracy. In this numerical study we introduce two new approaches based on singular value decomposition and exponential dichotomies and comparatively review and improve two recent popular approaches of Ginelli et al. (2007) and Wolfe and Samelson (2007). We compare the performance of the four approaches via three case studies with very different dynamics in terms of symmetry, spectral separation, and dimension. We also investigate which methods perform well with limited data

MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells

Mammalian cells release different types of vesicles, collectively termed extracellular vesicles (EVs). EVs contain cellular microRNAs (miRNAs) with an apparent potential to deliver their miRNA cargo to recipient cells to affect the stability of individual mRNAs and the cells’ transcriptome. The extent to which miRNAs are exported via the EV route and whether they contribute to cell-cell communication are controversial. To address these issues, we defined multiple properties of EVs and analyzed their capacity to deliver packaged miRNAs into target cells to exert biological functions. We applied well-defined approaches to produce and characterize purified EVs with or without specific viral miRNAs. We found that only a small fraction of EVs carried miRNAs. EVs readily bound to different target cell types, but EVs did not fuse detectably with cellular membranes to deliver their cargo. We engineered EVs to be fusogenic and document their capacity to deliver functional messenger RNAs. Engineered fusogenic EVs, however, did not detectably alter the functionality of cells exposed to miRNA-carrying EVs. These results suggest that EV-borne miRNAs do not act as effectors of cell-to-cell communication. Author summary: The majority of metazoan cells release vesicles of different types and origins, such as exosomes and microvesicles, now collectively termed extracellular vesicles (EVs). EVs have gained much attention because they contain microRNAs (miRNAs) and thus could regulate their specific mRNA targets in recipient or acceptor cells that take up EVs. Using a novel fusion assay with superior sensitivity and specificity, we revisited this claim but found no convincing evidence for an efficient functional uptake of EVs in many different cell lines and primary human blood cells. Even EVs engineered to fuse and deliver their miRNA cargo to recipient cells had no measurable effect on target mRNAs in very carefully controlled, quantitative experiments. Our negative results clearly indicate that EVs do not act as vehicles for miRNA-based cell-to-cell communication

Covid-19 in children with down syndrome: Data from the trisomy 21 research society survey

Adults with Down Syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19) than the general population, but evidence is required to understand the risks for children with DS, which is necessary to inform COVID-19 shielding advice and vaccination priorities. We aimed to determine the epidemiological and clinical characteristics of COVID-19 in children with DS. Using data from an international survey obtained from a range of countries and control data from the United States, we compared the prevalence of symptoms and medical complications and risk factors for severe outcomes between DS and non-DS paediatric populations with COVID-19. Hospitalised COVID-19 patients <18 years with DS had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than control patients without DS <18 years. Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS, and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), contrasting with previous findings in adults with DS (who exhibit higher mortality than those without DS). Children with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure the comprehensive and early detection of COVID-19 in this population and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Our results emphasize the importance of vaccinating children with DS as soon as they become eligible

Medical vulnerability of individuals with Down syndrome to severe COVID-19–data from the Trisomy 21 Research Society and the UK ISARIC4C survey

Background: Health conditions, immune dysfunction, and premature aging associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID-19. / Methods: The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers on patients with COVID-19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. / Findings: The mean age of COVID-19 patients with DS in the T21RS survey was 29 years (SD = 18). Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p < 0.01), whereas altered consciousness/confusion were more frequent (p < 0.01). Risk factors for hospitalization and mortality were similar to the general population with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher in patients with DS (T21RS DS versus non-DS patients: risk ratio (RR) = 3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus non-DS patients: RR = 2.9 (95%-CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. / Interpretation: Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of medical complications and mortality, especially from age 40. / Funding: Down Syndrome Affiliates in Action, DSMIG-USA, GiGi's Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, NDSS, National Task Group on Intellectual Disabilities and Dementia Practices

Opioid medication use and blood DNA methylation:epigenome-wide association meta-analysis

Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate \u3c0.05) was observed at six CpGs annotated to the following genes: KIAA0226, CPLX2, TDRP, RNF38, TTC23 and GPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain. Conclusion: This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use

The Index Bundle and Multiparameter Bifurcation for Discrete Dynamical Systems

We develop a K-theoretic approach to multiparameter bifurcation theory of homoclinic solutions of discrete non-autonomous dynamical systems from a branch of stationary solutions. As a byproduct we obtain a family index theorem for asymptotically hyperbolic linear dynamical systems which is of independent interest. In the special case of a single parameter, our bifurcation theorem weakens the assumptions in previous work by Pejsachowicz and the first author

Opioid medication use and blood DNA methylation: epigenome-wide association meta-analysis.

This is the final version. Available from Future Medicine via the DOI in this record. Data sharing statement: Complete meta-analysis results can be found at Zenodo 10.5281/zenodo.7545108.Aim: To identify differential methylation related to prescribed opioid use. Methods: This study examined whether blood DNA methylation, measured using Illumina arrays, differs by recent opioid medication use in four population-based cohorts. We meta-analyzed results (282 users; 10,560 nonusers) using inverse-variance weighting. Results: Differential methylation (false discovery rate <0.05) was observed at six CpGs annotated to the following genes: KIAA0226, CPLX2, TDRP, RNF38, TTC23 and GPR179. Integrative epigenomic analyses linked implicated loci to regulatory elements in blood and/or brain. Additionally, 74 CpGs were differentially methylated in males or females. Methylation at significant CpGs correlated with gene expression in blood and/or brain. Conclusion: This study identified DNA methylation related to opioid medication use in general populations. The results could inform the development of blood methylation biomarkers of opioid use.National Institute of Healt

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: Blood samples and raw genetic data of neonatal subjects from each cohort are governed by their respective institutions and/or government agencies, and mostly could not be shared publicly without specific approvals. For example, for data from first author cohort, California Childhood Leukemia Study (CCLS), we respectfully are unable to share raw, individual genetic data freely with other investigators. Should we be contacted by other investigators who would like to use the data; we will direct them to the California Department of Public Health Institutional Review Board to establish their own approved protocol to utilize the data, which can then be shared peer-to-peer.Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.National Institute of Environmental Health SciencesNational Cancer InstituteUS Environmental Protection Agenc

Southward displacement of the North Atlantic Subtropical Gyre circulation system during North Atlantic cold spells

Key Points: - Rapid subsurface oceanographic change in the tropical W Atlantic reflect shifting Subtropical Gyre - Subsurface warming responds to deglacial AMOC perturbations (Heinrich Stadials 2, 1, and the Younger Dryas) - Southward propagation of Salinity Maximum Water during Northern Hemisphere cold spells shift the mixing zone of tropical and subtropical waters During times of deglacial Atlantic Meridional Overturning Circulation (AMOC) perturbations, the tropical Atlantic experienced considerable warming at subsurface levels. Coupled ocean‐atmosphere simulations corroborate the tight teleconnection between the tropical Atlantic and climate change at high northern latitudes, but still underestimate the relevance of the subsurface N Atlantic Subtropical Gyre (STG) for heat and salt storage and its sensitivity to rapid climatic change. We here reconstruct vertical and lateral temperature and salinity gradients in the tropical W Atlantic and the Caribbean over the last 30 kyrs, based on planktic deep and shallow dwelling foraminiferal Mg/Ca and δ18O‐records. The rapid and large amplitude subsurface changes illustrate a dynamic STG associated with abrupt shifts of North Atlantic hydrographic and atmospheric regimes. During full glacial conditions, the STG has been shifted southward while intensified Ekman‐downwelling associated to strengthened trade winds fostered the formation of warm and saline Salinity Maximum Water (SMW). The southward propagation of SMW was facilitated by the glacially eastward deflected North Brazil Current. During periods of significant AMOC perturbations (Heinrich Stadials 1, and the Younger Dryas), extreme subsurface warming by ~6°C led to diminished lateral subsurface temperature gradients. Coevally, a deep thermocline suggests that SMW fully occupied the subsurface tropical W Atlantic and that the STG reached its southernmost position. During the Holocene, modern‐like conditions gradually developed with the northward retreat of SMW and the development of a strong thermocline ridge between the Subtropical Gyre and the tropical W Atlantic