Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses

BackgroundPolygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD.Methods and findingsUsing data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation.ConclusionsOur results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.

Luanluan Sun and colleagues investigate whether adding polygenic risk scores to conventional risk factors of cardiovascular disease helps predict disease risk.     

Dll1 Marks Cells of Origin of Ras-Induced Cancer in Mouse Squamous Epithelia

The Notch signaling pathway has been implicated in homeostasis and disease, including cancer, in various tissues. Moreover, it has been involved both in stem cell maintenance and differentiation, in a context-dependent manner. Stem/progenitor cells, on the other hand, have long been suspected to be the cells of origin in various malignancies. In order to gain insight in the role of the Notch ligand Dll1 in mouse development, we generated a knock-in line expressing an inducible Cre recombinase. We have employed in vivo approaches in mice to genetically mark rare subpopulations of cells expressing Dll1 in various adult tissues. Moreover, we conditionally expressed a constitutively active Ras oncoprotein in these cells and showed that within days, mice develop squamous neoplasias in the skin, as well as in the stomach.     

Secular trends of blood isolates in patients from a rural area population hospitalized in a tertiary center in a small city in Greece

Background  

Most of the studies evaluating the secular trends of blood isolates come from tertiary hospitals in urban areas. We sought to study the trends of the antimicrobial resistance of blood isolates in patients from a rural population hospitalized in a tertiary hospital in a small city in Greece.     

Micropropagation and salt tolerance of in vitro grown Crithmum maritimum L.

Crithmum maritimum (Apiaceae), a perennial halophyte native in Greece, could be used as an alternative culture at problematic soils. It presents significant economical potentials as its essential oils are in high demand from the medicinal and cosmetic industry. The response of the species on in vitro conditions was studied. MS proved to be the most effective of the basal media tested for in vitro adventitious shoot production, resulting in significantly increased number of new microshoots/explant and higher shoots. 6-Benzyladenine (BA) at 2.5 μM increased shoot proliferation. The combination of α-Naphthaleneacetic acid (NAA) (1–2.5 μM) with BA (2.5 μM) had a positive influence at simultaneous proliferation and rooting resulting in high rooting percentage (82.5–95%) and increased number of roots. Rooting percentage reached 100% and number of roots increased significantly when 0.5 μM and 1 μM IBA was combined with ½MS and full strength MS. The in vitro response to salinity stress (0–300 mM NaCl) was also tested. Shoot proliferation was gradually reduced at higher concentrations of NaCl but shoot height was enhanced. Acclimatization procedure was successful.     

Grammar resources for modelling dialogue dynamically

This paper argues that by analysing language as a mechanism for growth of information (Cann et al. in The Dynamics of Language, Elsevier, Oxford, 2005; Kempson et al. in Dynamic Syntax, Blackwell, Oxford, 2001), not only does a unitary basis for ellipsis become possible, otherwise thought to be irredeemably heterogeneous, but also a whole range of sub-types of ellipsis, otherwise thought to be unique to dialogue, emerge as natural consequences of use of language in context. Dialogue fragment types modelled include reformulations, clarification requests, extensions, and acknowledgements. Buttressing this analysis, we show how incremental use of fragments serves to progressively narrow down the otherwise mushrooming interpretational alternatives in language use, and hence is central to fluent conversational interaction. We conclude that, by its ability to reflect dialogue dynamics as a core phenomenon of language use, a grammar with inbuilt parsing dynamics opens up the potential for analysing language as a mechanism for communicative interaction.     

Biotechnological production of the European corn borer sex pheromone in the yeast Yarrowia lipolytica

The European corn borer (ECB) Ostrinia nubilalis is a widespread pest of cereals, particularly maize. Mating disruption with the sex pheromone is a potentially attractive method for managing this pest; however, chemical synthesis of pheromones requires expensive starting materials and catalysts and generates hazardous waste. The goal of this study was to develop a biotechnological method for the production of ECB sex pheromone. Our approach was to engineer the oleaginous yeast Yarrowia lipolytica to produce (Z)-11-tetradecenol (Z11-14:OH), which can then be chemically acetylated to (Z)-11-tetradecenyl acetate (Z11-14:OAc), the main pheromone component of the Z-race of O. nubilalis. First, a C14 platform strain with increased biosynthesis of myristoyl-CoA was obtained by introducing a point mutation into the α-subunit of fatty acid synthase, replacing isoleucine 1220 with phenylalanine (Fas2p^I1220F). The intracellular accumulation of myristic acid increased 8.4-fold. Next, fatty acyl-CoA desaturases (FAD) and fatty acyl-CoA reductases (FAR) from nine different species of Lepidoptera were screened in the C14 platform strain, individually and in combinations. A titer of 29.2 ± 1.6 mg L^-1 Z11-14:OH was reached in small-scale cultivation with an optimal combination of a FAD (Lbo_PPTQ) from Lobesia botrana and FAR (HarFAR) from Helicoverpa armigera. When the second copies of FAD and FAR genes were introduced, the titer improved 2.1-fold. The native FAS1 gene's overexpression led to a further 1.5-fold titer increase, reaching 93.9 ± 11.7 mg L^-1 in small-scale cultivation. When the same engineered strain was cultivated in controlled 1 L bioreactors in fed-batch mode, 188.1 ± 13.4 mg L^-1 of Z11-14:OH was obtained. Fatty alcohols were extracted from the biomass and chemically acetylated to obtain Z11-14:OAc. Electroantennogram experiments showed that males of the Z-race of O. nubilalis were responsive to biologically-derived pheromone blend. Behavioral bioassays in a wind tunnel revealed attraction of male O. nubilalis, although full precopulatory behavior was observed less often than for the chemically synthesized pheromone blend. The study paves the way for the production of ECB pheromone by fermentation.     

The effect of spike mutations on SARS-CoV-2 neutralization

1. Download : Download high-res image (178KB)
2. Download : Download full-size image

     

Reevaluating sponge diversity and distribution in the Mediterranean Sea

The aim of this paper was (1) to update sponge diversity and distribution in the Mediterranean and (2) to re-examine faunal relationships among the Mediterranean areas on the basis of their sponge fauna. The Mediterranean demosponge faunal list was updated to 629 species by taking into consideration recent data from previously poorly studied areas. The species lists of 14 Mediterranean areas were compared on the basis of their sponge species richness, species composition, and taxonomic relatedness of species using multivariate analyses and diversity measures, such as PD, Delta+, and Lambda+. The 14 Mediterranean areas examined for their diversity and affinities were assembled into four major zoogeographic groups: the northwestern, northeastern, the central zone, and southeastern areas. Richest in species numbers were the areas belonging to the two northern groups. The species richness comparisons and similarity analyses performed at the generic level showed that it can be safely used as a surrogate for sponge species diversity in the Mediterranean. The results of this study showed that the simple traditional division of the Mediterranean Sea into a western, central, and eastern basin cannot reliably describe the distribution of sponges in the area. Thus, the W to E faunal decline previously presented for several faunal groups shifts to a general NNW-SSE pattern when one examines separately the northern and the southern parts of the traditional basins. This gradient seems to be in agreement with differences in key environmental variables, such as latitude, salinity, temperature, and water circulation, besides the typically examined distance from Gibraltar. Handling editor: T. P. Crowe