CYBORG GENESIS

We are currently living in an artificial, increasingly complex created system of discourse heavily base on socially constructed systems of language and digital technologies. How we use these technologies to advance the human condition in terms of our very existence makes us inherently cyborg in nature. With the increase in digital technologies in every aspect of day –to-day existence from your morning coffee to higher education, we have become increasingly dependent on our cyborg identities. This thesis, then, serves as a project that looks to understand how we have come to this point and to what extent our newly found cyborg identities can serve as the catalyst for progress particularly in education and the further production and transmission of human knowledge

Income inequality and its relationship with loneliness prevalence: A cross-sectional study among older adults in the US and 16 European countries

BACKGROUNDS: The prevalence of loneliness increases among older adults, varies across countries, and is related to within-country socioeconomic, psychosocial, and health factors. The 2000-2019 pooled prevalence of loneliness among adults 60 years and older went from 5.2% in Northern Europe to 24% in Eastern Europe, while in the US was 56% in 2012. The relationship between country-level factors and loneliness, however, has been underexplored. Because income inequality shapes material conditions and relative social deprivation and has been related to loneliness in 11 European countries, we expected a relationship between income inequality and loneliness in the US and 16 European countries. METHODS: We used secondary cross-sectional data for 75,891 adults age 50+ from HRS (US 2014), ELSA (England, 2014), and SHARE (15 European countries, 2013). Loneliness was measured using the R-UCLA three-item scale. We employed hierarchical logistic regressions to analyse whether income inequality (GINI coefficient) was associated with loneliness prevalence. RESULTS: The prevalence of loneliness was 25.32% in the US (HRS), 17.55% in England (ELSA) and ranged from 5.12% to 20.15% in European countries (SHARE). Older adults living in countries with higher income inequality were more likely to report loneliness, even after adjusting for the sociodemographic composition of the countries and their Gross Domestic Products per capita (OR: 1.52; 95% CI: 1.17-1.97). DISCUSSION: Greater country-level income inequality was associated with higher prevalence of loneliness over and above individual-level sociodemographics. The present study is the first attempt to explore income inequality as a predictor of loneliness prevalence among older adults in the US and 16 European countries. Addressing income distribution and the underlying experience of relative deprivation might be an opportunity to improve older adults' life expectancy and wellbeing by reducing loneliness prevalence

Genetic impacts on DNA methylation help elucidate regulatory genomic processes

BACKGROUND: Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. RESULTS: We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2358 blood samples from three UK cohorts. Methylation levels at 34.2% of CpGs are affected by SNPs, and 98% of effects are cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both SNPs and CpGs with meQTLs are overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identify 1520 co-localisations across 1325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such as USP1 and DOCK7 (total cholesterol levels), and ICOSLG (inflammatory bowel disease). Enrichment analysis of meQTLs and integration with expression QTLs give insights into mechanisms underlying cis-meQTLs (e.g. through disruption of transcription factor binding sites for CTCF and SMC3) and trans-meQTLs (e.g. through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites). CONCLUSIONS: Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. The MeQTL EPIC Database and viewer are available online at https://epicmeqtl.kcl.ac.uk

Paucity and discordance of neutralising antibody responses to SARS-CoV-2 VOCs in vaccinated immunodeficient patients and health-care workers in the UK.

As of June, 2021, the UK population is only partly vaccinated against COVID-19, with many people having received just one vaccination dose (either BNT162b2 [Pfizer–BioNTech]) or ChAdOx1 nCoV-19 [AZD1222; Oxford–AstraZeneca]). Tracking the spread of SARS-CoV-2 Variants of Concern (VOCs) remains important for understanding the levels of vaccine-induced immunity and for identifying the emergence of vaccine escape variants. The immune correlates of protection to SARS-CoV-2 and COVID-19 established in phase 3 clinical trials following two doses of vaccine was the titre of neutralising antibodies (NAbs) to SARS-CoV-2 in study groups, before the VOCs emerged.1 Vaccination programmes are leading to promising reductions in disease severity and mortality in vaccinated populations. However, the combined situation of ongoing transmission within communities, including in some vaccine recipients, alongside newly arising VOCs, continues to pose a serious threat to public health and the efficacy of these vaccines. As of Jan 11, 2021, in the UK, the interval between the first and second dose of vaccination was extended to 12 weeks. This extension achieved the aim of maximising population coverage by immunising the greatest possible number of individuals to prevent disease and hospital admissions. Encouragingly, a growing number of studies have reported a marked reduction in the number of individuals with moderate-to-severe clinical symptoms and a substantial decline in the number of hospitalised patients with COVID-19 in the UK, underscoring the success of this strategy

Beyond Undetectable: Modeling the Clinical Benefit of Improved Antiretroviral Adherence in Persons With Human Immunodeficiency Virus With Virologic Suppression

BACKGROUND: Incomplete antiretroviral therapy (ART) adherence has been linked to deleterious immunologic, inflammatory, and clinical consequences, even among virally suppressed (<50 copies/mL) persons with human immunodeficiency virus (PWH). The impact of improving adherence in the risk of severe non-AIDS events (SNAEs) and death in this population is unknown. METHODS: We estimated the reduction in the risk of SNAEs or death resulting from an increase in ART adherence by (1) applying existing data on the association between adherence with high residual inflammation/coagulopathy in virally suppressed PWH, and (2) using a Cox proportional hazards model derived from changes in plasma interleukin 6 (IL-6) and D-dimer from 3 randomized clinical trials. Comparatively, assuming 100% ART adherence in a PWH who achieves viral suppression, we estimated the number of persons in whom a decrease in adherence to <100% would need to be observed for an additional SNAE or death event to occur during 3- and 5-year follow-up. RESULTS: Increasing ART adherence to 100% in PWH who are suppressed on ART despite imperfect adherence translated into a 6%-37% reduction in the risk of SNAEs or death. Comparatively, based on an anticipated 12% increase in IL-6, 254 and 165 PWH would need to decrease their adherence from 100% to <100% for an additional event to occur over 3- and 5-year follow-up, respectively. CONCLUSIONS: Modest gains in ART adherence could have clinical benefits beyond virologic suppression. Increasing ART adherence (eg, via an intervention or switch to long-acting ART) in PWH who remain virally suppressed despite incomplete adherence should be evaluated

Hepcidin sequesters iron to sustain nucleotide metabolism and mitochondrial function in colorectal cancer epithelial cells

Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours

DNA methylation age and physical and cognitive ageing

Background DNA methylation (DNAm) age acceleration (AgeAccel) has been shown to be predictive of all-cause mortality but it is unclear what functional aspect/s of ageing it captures. We examine associations between four measures of AgeAccel in adults aged 45-87 years and physical and cognitive performance and their age-related decline. Methods AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno and AgeAccelGrim were calculated in the Medical Research Council National Survey of Health and Development (NSHD), National Child Development Study (NCDS) and TwinsUK. Three measures of physical (grip strength, chair rise speed and forced expiratory volume in one second[FEV1]) and two measures of cognitive (episodic memory and mental speed) performance were assessed. Results AgeAccelPheno and AgeAccelGrim, but not AgeAccelHannum and AgeAccelHorvath were related to performance in random effects meta-analyses (n=1388-1685). For example, a one year increase in AgeAccelPheno/AgeAccelGrim was associated with a 0.01ml[95%CI:0.01,0.02]/0.03ml[95%CI:0.01,0.05] lower mean FEV1. In NSHD, AgeAccelPheno and AgeAccelGrim at 53 years were associated with age-related decline in performance between 53 and 69 years as tested by linear mixed models (p<0.05). In a subset of NSHD participants(n=482), there was little evidence that change in any AgeAccel measure was associated with change in performance conditional on baseline performance. Conclusions We found little evidence to support associations between the first generation of DNAm-based biomarkers of ageing and age-related physical or cognitive performance in mid-life to early old age. However, there was evidence that the second generation biomarkers, AgeAccelPheno and AgeAccelGrim, could act as makers of an individual’s health-span as proposed.This work was supported by the Economic and Social Research Council/Biotechnology and Biological Sciences Research Council [ES/N000404/1] and the UK Medical Research Council (MC_UU_12015/2).The UK Medical Research Council also provides core funding for the MRC National Survey of Health and Development and support for AW, RC, DK and RH [MC_UU_12019/1, MC_UU_12019/2, MC_UU_12019/4]. JM is supported by CLOSER through the Economic and Social Research Council [547821 GA3 ESRC]. The TwinsUK study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007–2013); National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College Londo

Novel Lobophorins Inhibit Oral Cancer Cell Growth and Induce Atf4- and Chop-Dependent Cell Death in Murine Fibroblasts

As part of the International Cooperative Biodiversity Groups (ICBG) Program, we were interested in identifying biologically active unfolded protein response (UPR) inducing compounds from marine microorganisms isolated from Costa Rican biota. With this aim in mind we have now generated more than 33,000 unique prefractionated natural product extracts from marine and terrestrial organisms that have been submitted to the Center of Chemical Genomics (CCG) at the University of Michigan for high throughput screening (HTS). An effective complementary cell-based assay to identify novel modulators of UPR signaling was used for screening extracts. Active fractions were iteratively subjected to reverse-phase HPLC chromatographic analysis, and together with lobophorin A, B, E, and F (1–4), three new lobophorin congeners, designated as CR1 (5), CR2 (6), and CR3 (7) were isolated. Herein, we report that secondary assays revealed that the new lobophorins induced UPR-associated gene expression, inhibited oral squamous cell carcinoma cell growth, and led to UPR-dependent cell death in murine embryonic fibroblast (MEF) cells.International Cooperative Biodiversity Groups/[U01 TW007404]/ICBG/Estados UnidosNational Institutes of Health/[DK042394]/NIH/Estados UnidosNational Institutes of Health/[DK088227]/NIH/Estados UnidosNational Institutes of Health/[HL052173]/NIH/Estados UnidosUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigaciones en Productos Naturales (CIPRONA)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Químic

Water mass age and ageing driving chromophoric dissolved organic matter in the dark global ocean

Research articleThe omnipresence of chromophoric dissolved organic matter (CDOM) in the open ocean enables its use as a tracer for biochemical processes throughout the global overturning circulation. We made an inventory of CDOM optical properties, ideal water age (τ), and apparent oxygen utilization (AOU) along the Atlantic, Indian, and Pacific Ocean waters sampled during the Malaspina 2010 expedition. A water mass analysis was applied to obtain intrinsic, hereinafter archetypal, values of τ, AOU, oxygen utilization rate (OUR), and CDOM absorption coefficients, spectral slopes and quantum yield for each one of the 22 water types intercepted during this circumnavigation. Archetypal values of AOU and OUR have been used to trace the differential influence of water mass aging and aging rates, respectively, on CDOM variables. Whereas the absorption coefficient at 325nm (a325) and the fluorescence quantum yield at 340nm (Φ340) increased, the spectral slope over the wavelength range 275–295nm (S275–295) and the ratio of spectral slopes over the ranges 275–295nm and 350–400nm (SR) decreased significantly with water mass aging (AOU). Combination of the slope of the linear regression between archetypal AOU and a325 with the estimated global OUR allowed us to obtain a CDOM turnover time of 634 ± 120 years, which exceeds the flushing time of the dark ocean (>200 m) by 46%. This positive relationship supports the assumption of in situ production and accumulation of CDOM as a by-product of microbial metabolism as water masses turn older. Furthermore, our data evidence that global-scale CDOM quantity (a325) is more dependent on aging (AOU), whereas CDOM quality (S275–295, SR, Φ340) is more dependent on aging rate (OUR).Versión del editor4,785