Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis

Correction: Volume13, Issue1 Article Number1122 DOI 10.1038/s41467-022-28863-y Published FEB 25 2022Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genomewide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.Peer reviewe

Protist-Type Lysozymes of the Nematode Caenorhabditis elegans Contribute to Resistance against Pathogenic Bacillus thuringiensis

Pathogens represent a universal threat to other living organisms. Most organisms express antimicrobial proteins and peptides, such as lysozymes, as a protection against these challenges. The nematode Caenorhabditis elegans harbours 15 phylogenetically diverse lysozyme genes, belonging to two distinct types, the protist- or Entamoeba-type (lys genes) and the invertebrate-type (ilys genes) lysozymes. In the present study we characterized the role of several protist-type lysozyme genes in defence against a nematocidal strain of the Gram-positive bacterium Bacillus thuringiensis. Based on microarray and subsequent qRT-PCR gene expression analysis, we identified protist-type lysozyme genes as one of the differentially transcribed gene classes after infection. A functional genetic analysis was performed for three of these genes, each belonging to a distinct evolutionary lineage within the protist-type lysozymes (lys-2, lys-5, and lys-7). Their knock-out led to decreased pathogen resistance in all three cases, while an increase in resistance was observed when two out of three tested genes were overexpressed in transgenic lines (lys-5, lys-7, but not lys-2). We conclude that the lysozyme genes lys-5, lys-7, and possibly lys-2 contribute to resistance against B. thuringiensis, thus highlighting the particular role of lysozymes in the nematode's defence against pathogens

EUNIS Habitat Classification: Expert system, characteristic species combinations and distribution maps of European habitats

Aim: The EUNIS Habitat Classification is a widely used reference framework for European habitat types (habitats), but it lacks formal definitions of individual habitats that would enable their unequivocal identification. Our goal was to develop a tool for assigning vegetation‐plot records to the habitats of the EUNIS system, use it to classify a European vegetation‐plot database, and compile statistically‐derived characteristic species combinations and distribution maps for these habitats. Location: Europe. Methods: We developed the classification expert system EUNIS‐ESy, which contains definitions of individual EUNIS habitats based on their species composition and geographic location. Each habitat was formally defined as a formula in a computer language combining algebraic and set‐theoretic concepts with formal logical operators. We applied this expert system to classify 1,261,373 vegetation plots from the European Vegetation Archive (EVA) and other databases. Then we determined diagnostic, constant and dominant species for each habitat by calculating species‐to‐habitat fidelity and constancy (occurrence frequency) in the classified data set. Finally, we mapped the plot locations for each habitat. Results: Formal definitions were developed for 199 habitats at Level 3 of the EUNIS hierarchy, including 25 coastal, 18 wetland, 55 grassland, 43 shrubland, 46 forest and 12 man‐made habitats. The expert system classified 1,125,121 vegetation plots to these habitat groups and 73,188 to other habitats, while 63,064 plots remained unclassified or were classified to more than one habitat. Data on each habitat were summarized in factsheets containing habitat description, distribution map, corresponding syntaxa and characteristic species combination. Conclusions: EUNIS habitats were characterized for the first time in terms of their species composition and distribution, based on a classification of a European database of vegetation plots using the newly developed electronic expert system EUNIS‐ESy. The data provided and the expert system have considerable potential for future use in European nature conservation planning, monitoring and assessment

X-chromosome and kidney function:evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.</p

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Population Dynamics and Management of Yellow Perch Populations in South Dakota Glacial Lakes

The relative abundance of three year classes of yellow perch Perca flavescens were monitored from the larval stage until age 1 in six glacial lakes located in eastern South Dakota in order to determine whether year-class strength could be indexed at the larval stage. Variation in annual peak larval abundance varied among years within lakes. In East 81 Slough, Sinai, and Waubay lakes, ranked peak larval abundance was significantly correlated with CPUE of age-0 yellow perch in August seine hauls; however, these measures of abundance were not correlated in Enemy Swim, Pickerel, and Madison lakes. Correlations between peak larval abundance and subsequent estimates of abundance were inconsistent both within and among lakes likely due to variation in gear effectiveness across lakes and the ineffectiveness of some gears in collecting yellow perch. Study duration prevented clear determination of when yellow perch year-class strength can be indexed. The potential effects of hatch timing and daily growth on the early development of age-0 yellow perch were assessed in the same six lakes. Hatching dates were estimated from daily ring counts made from sagittal otoliths removed from larval yellow perch collected in late May-early June with surface trawls. Larval sampling and August seine hauls suggested that only one cohort of age-0 yellow perch was produced in these lakes during each year. Over the three years of the study, yellow perch hatched between April 28 and May 16. Hatching intervals were generally short, ranging from 5 to 11 d in duration. In 2001, when larval yellow perch cohorts were produced in all six lakes, mean hatch dates significantly differed among lakes; these differences did not follow a latitudinal gradient, but appeared to be related to differences in lake area and volume. Mean daily growth rates ranged from 0.16 to 0.49 mm/d among lakes. In 8 of 10 cases, daily growth rate of larval yellow perch was significantly related to hatch timing (r = 0.36-0.77, P \u3c 0.05), with later-hatched perch tending to experience faster growth rates than those hatched earlier in the year. Daily growth rate explained 44-83% of the variation in length of larval yellow perch at time of capture. Hatching intervals for yellow perch in these lakes were much shorter than some previously reported estimates in the literature and likely made larval yellow perch populations in these lakes more susceptible to losses resulting from periods of harsh environmental conditions. Characteristics of the winter yellow perch fishery (e. g., ice fishing) were assessed for several South Dakota glacial lakes. Seasonal harvest information obtained during creel surveys on seven lakes demonstrated that the percentage of anglers targeting yellow perch and perch harvest tended to be higher during winter periods. Exploitation of yellow perch was estimated on two lakes through tag-return studies. Non-reporting rates from surrogate postcards varied between angler groups (19-52%). Exploitation on East 81 Slough, where relative stock density of 254-mm and longer yellow perch (RSD-254) was low (RSD-254 = 10), was only 7% during the winter of 2000-01 and much of the total annual mortality (48%) in the population was attributed to natural causes (40%). Conversely, exploitation rate on Pelican Lake, where size structure was dominated by larger fish (RSD-254= 92), was 61% during the winter of 2001-02. Accordingly, mean minimum TL of harvested yellow perch observed in angler creel was higher on Pelican Lake (265 mm) than on East 81 Slough (225 mm). Anglers on East 81 Slough demonstrated size-selective harvest of yellow perch, harvesting higher proportions of older, larger perch than were observed in trap-net samples. High percentages of anglers on both lakes reported preferences for catching or harvesting fewer, larger yellow perch rather than catching or harvesting more, but smaller perch. Size structure of yellow perch probably affected observed values of minimum acceptable harvest size and was likely responsible for variation in exploitation rate between lakes. Gill-net sampling precision and population dynamics were evaluated for yellow perch populations in six South Dakota lakes. Time at full recruitment to gill nets (age 2 or age 3) differed among lakes due to variation in yellow perch growth rates. Gill- net sampling precision was frequently low (CV \u3e 40%) and in most cases substantial increases in sampling effort would be required to increase confidence levels for detecting changes in mean total catch per unit effort (CPUE). Commonly-used analyses to describe growth (von Bertalanffy models) and total annual mortality (catch curves) had limited utility in describing yellow perch population dynamics in these populations due to observed trends in mean total lengths at age and CPUE data. Total annual mortality estimates for the six populations typically exceeded 45%. Populations exhibiting slow growth typically exhibited relatively consistent recruitment, low size structure, and higher observed maximum ages than fast-growing populations. With the exception of Waubay Lake, yellow perch populations in the six lakes I examined displayed relatively limited potential for production of fish \u3e 254 mm. Potential reductions in yellow perch daily creel limits were evaluated using existing creel data available for eight South Dakota lakes. Generally, reductions in daily creel limits from 25 fish per day would have limited effectiveness in reducing harvest of yellow perch unless reductions were severe (5 fish per day). A 10-fish daily creel limit on Waubay Lake was predicted to reduce harvest at levels \u3e 25% and may have utility in managing yellow perch in this lake. Beverton-Holt equilibrium yield modeling indicated that 229- and 254-mm length limits would reduce yield and harvest of yellow perch in Waubay Lake while increasing the number of perch reaching 254 mm in the population. Despite increases in the number of yellow perch reaching 254 mm, observed maximum age and growth trends resulted in minimal length- limit related improvements (\u3c 28%) in the average size of perch harvested by anglers. Based on these observations, length limits would have little utility in managing the yellow perch fishery on Waubay Lake due to the harvest-oriented nature of the fishery