Phenotypic Plasticity of Staphylococcus aureus in Liquid Medium Containing Vancomycin

Phenotypic plasticity enables individuals to develop different phenotypes in a changing environment and promotes adaptive evolution. Genome-wide association study (GWAS) facilitates the study of the genetic basis of bacterial phenotypes, and provides a new opportunity for bacterial phenotypic plasticity research. To investigate the relationship between growth plasticity and genotype in bacteria, 41 Staphylococcus aureus strains, including 29 vancomycin-intermediate S. aureus (VISA) strains, were inoculated in the absence or presence of vancomycin for 48 h. Growth curves and maximum growth rates revealed that strains with the same minimum inhibitory concentration (MIC) showed different levels of plasticity in response to vancomycin. A bivariate GWAS was performed to map single-nucleotide polymorphisms (SNPs) associated with growth plasticity. In total, 227 SNPs were identified from 14 time points, while 15 high-frequency SNPs were mapped to different annotated genes. The P-values and growth variations between the two cultures suggest that non-coding region (SNP 738836), ebh (SNP 1394043), drug transporter (SNP 264897), and pepV (SNP 1775112) play important roles in the growth plasticity of S. aureus. Our study provides an alternative strategy for dissecting the adaptive growth of S. aureus in vancomycin and highlights the feasibility of bivariate GWAS in bacterial phenotypic plasticity research

Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis

Surfactant proteins (SP) are involved in surfactant function and innate immunity in the human lung. Both lung function and innate immunity are altered in CF, and altered SP levels and genetic association are observed in Cystic Fibrosis (CF). We hypothesized that single nucleotide polymorphisms (SNPs) within the SP genes associate with CF or severity subgroups, either through single SNP or via SNP-SNP interactions between two SNPs of a given gene (intragenic) and/or between two genes (intergenic). We genotyped a total of 17 SP SNPs from 72 case-trio pedigree (SFTPA1 (5), SFTPA2 (4), SFTPB (4), SFTPC (2), and SFTPD (2)), and identified SP SNP associations by applying quantitative genetic principles. The results showed (a) Two SNPs, SFTPB rs7316 (p = 0.0083) and SFTPC rs1124 (p = 0.0154), each associated with CF. (b) Three intragenic SNP-SNP interactions, SFTPB (rs2077079, rs3024798), and SFTPA1 (rs1136451, rs1059057 and rs4253527), associated with CF. (c) A total of 34 intergenic SNP-SNP interactions among the 4 SP genes to be associated with CF. (d) No SNP-SNP interaction was observed between SFTPA1 or SFTPA2 and SFTPD. (e) Equal number of SNP-SNP interactions were observed between SFTPB and SFTPA1/SFTPA2 (n = 7) and SP-B and SFTPD (n = 7). (f) SFTPC exhibited significant SNP-SNP interactions with SFTPA1/SFTPA2 (n = 11), SFTPB (n = 4) and SFTPD (n = 3). (g) A single SFTPB SNP was associated with mild CF after Bonferroni correction, and several intergenic interactions that are associated (p < 0.01) with either mild or moderate/severe CF were observed. These collectively indicate that complex SNP-SNP interactions of the SP genes may contribute to the pulmonary disease in CF patients. We speculate that SPs may serve as modifiers for the varied progression of pulmonary disease in CF and/or its severity

The Genomic Landscape of Crossover Interference in the Desert Tree Populus euphratica

Crossover (CO) interference is a universal phenomenon by which the occurrence of one CO event inhibits the simultaneous occurrence of other COs along a chromosome. Because of its critical role in the evolution of genome structure and organization, the cytological and molecular mechanisms underlying CO interference have been extensively investigated. However, the genome-wide distribution of CO interference and its interplay with sex-, stress-, and age-induced differentiation remain poorly understood. Multi-point linkage analysis has proven to be a powerful tool for landscaping CO interference, especially within species for which CO mutants are rarely available. We implemented four-point linkage analysis to landscape a detailed picture of how CO interference is distributed through the entire genome of Populus euphratica, the only forest tree that can survive and grow in saline desert. We identified an extensive occurrence of CO interference, and found that its strength depends on the length of chromosomes and the genomic locations within the chromosome. We detected high-order CO interference, possibly suggesting a highly complex mechanism crucial for P. euphratica to grow, reproduce, and evolve in its harsh environment

A blood pressure-associated variant of the SLC39A8 gene influences cellular cadmium accumulation and toxicity.

Genome-wide association studies have revealed a relationship between inter-individual variation in blood pressure and the single nucleotide polymorphism rs13107325 in the SLC39A8 gene. This gene encodes the ZIP8 protein which co-transports divalent metal cations, including heavy metal cadmium, the accumulation of which has been associated with increased blood pressure. The polymorphism results in two variants of ZIP8 with either an alanine (Ala) or a threonine (Thr) at residue 391. We investigated the functional impact of this variant on protein conformation, cadmium transport, activation of signalling pathways and cell viability in relation to blood pressure regulation. Following incubation with cadmium, higher intracellular cadmium was detected in cultured human embryonic kidney cells (HEK293) expressing heterologous ZIP8-Ala391, compared with HEK293 cells expressing heterologous ZIP8-Thr391. This Ala391-associated cadmium accumulation also increased the phosphorylation of the signal transduction molecule ERK2, activation of the transcription factor NFκB, and reduced cell viability. Similarly, vascular endothelial cells with the Ala/Ala genotype had higher intracellular cadmium concentration and lower cell viability than their Ala/Thr counterpart following cadmium exposure. These results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure

A Drive to Driven Model of Mapping Intraspecific Interaction Networks.

Community ecology theory suggests that an individual\u27s phenotype is determined by the phenotypes of its coexisting members to the extent at which this process can shape community evolution. Here, we develop a mapping theory to identify interaction quantitative trait loci (QTL) governing inter-individual dependence. We mathematically formulate the decision-making strategy of interacting individuals. We integrate these mathematical descriptors into a statistical procedure, enabling the joint characterization of how QTL drive the strengths of ecological interactions and how the genetic architecture of QTL is driven by ecological networks. In three fish full-sib mapping experiments, we identify a set of genome-wide QTL that control a range of societal behaviors, including mutualism, altruism, aggression, and antagonism, and find that these intraspecific interactions increase the genetic variation of body mass by about 50%. We showcase how the interaction QTL can be used as editors to reconstruct and engineer new social networks for ecological communities

Quantitatively assessing ecological stress of urbanization on natural ecosystems by using a landscape-adjacency index

Urban spatial expansion poses a threat to regional ecosystems and biodiversity directly through altering the size, shape, and interconnectivity of natural landscapes. Monitoring urban spatial expansion using traditional area-based metrics from remote sensing provides a feasible way to quantify this regional ecological stress. However, variation in landscape-adjacency relationships (i.e., the adjacency between individual landscape classes) caused by urban expansion is often overlooked. In this study, a novel edge-based index (landscape-adjacency index, LAdI) was proposed based on the spatial-adjacency relationship between landscape patches to measure the regional ecological stress of urban expansion on natural landscapes. Taking the entire Yangtze River Delta Urban Agglomerations (YRD) as a study area, we applied the LAdI for individual landscape classes (Vi) and landscape level (LV) to quantitatively assess change over time in the ecological stress of YRD from 1990 to 2015 at two spatial scales: municipal scale and 5 km-grid scale. The results showed that the vulnerable zones (LV ≥ 0.6) were mainly distributed in the north of the YRD, and cultivated land was the most vulnerable natural landscape (Vi ≥ 0.6) at the 5 km-grid scale. The most vulnerable landscape at the municipal scale was cultivated land in 19 of 26 cities in each period, and that in the remaining 7 cities varied at distinct urbanization stages. We used scatter diagrams and Pearson correlation analysis to compare the edge-based LAdI with an area-based index (percent of built-up area, PB) and found that: LV and PB had a significant positive correlation at both the municipal scale and 5 km-grid scale. But there were multiple LVs with different values corresponding to one PB with the same value at the 5 km-grid scale. Both indexes could represent the degree of urban expansion; however, the edge-based metric better quantified ecological stress under different urban-sprawl patterns sharing the same percent of built-up area. As changes in land use affect both the size and edge effect among landscape patches, the area-based PB and the edge-based LAdI should be applied together when assessing the ecological stress caused by urbanization

Greenspace’s value orientations of ecosystem service and socioeconomic service in China

Background: Natural ecosystems provide necessary services for human beings, including ecosystem service values (ESVs) and socioeconomic service values (SSVs). The value orientations of ESVs and SSVs are mainly related to people’s interaction with nature. This study reclassified greenspace from a perspective of exposed and non-exposed greenspace based on the level of interaction by people and greenspace. We applied an expert questionnaire to survey the SSVs value orientations of forestland, grassland, wetland, and water bodies, and quantitatively compared the value orientations between the ESVs and SSVs of greenspace in China. Result: (1) The values of exposed greenspace were relatively far higher than non-exposed greenspace, as it had both ESVs and SSVs. (2) The forestland and grassland had relatively high ESVs and SSVs, and are the priority for both the exposed and non-exposed greenspace. (3) Wetland had relatively high ESVs but low SSVs, which was unpopular for exposed greenspace. (4) The ESVs and SSVs of water body were relatively balanced. Conclusion: Greenspace had both ESVs and SSVs when they are exposed to human. Our study provided an innovative perspective to explore the value orientations of greenspace, which provides an actionable scientific basis for greenspace planning, design and construction in human habitat.

The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle.

Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention

Coronary-Heart-Disease-Associated Genetic Variant at the COL4A1/COL4A2 Locus Affects COL4A1/COL4A2 Expression, Vascular Cell Survival, Atherosclerotic Plaque Stability and Risk of Myocardial Infarction.

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk

A Regulatory Network for miR156-SPL Module in Arabidopsis thaliana

Vegetative phase changes in plants describes the transition between juvenile and adult phases of vegetative growth before flowering. It is one of the most fundamental mechanisms for plants to sense developmental signals, presenting a complex process involving many still-unknown determinants. Several studies in annual and perennial plants have identified the conservative roles of miR156 and its targets, SBP/SPL genes, in guiding the switch of plant growth from juvenile to adult phases. Here, we review recent progress in understanding the regulation of miR156 expression and how miR156-SPLs mediated plant age affect other processes in Arabidopsis. Powerful high-throughput sequencing techniques have provided rich data to systematically study the regulatory mechanisms of miR156 regulation network. From this data, we draw an expanded miR156-regulated network that links plant developmental transition and other fundamental biological processes, gaining novel and broad insight into the molecular mechanisms of plant-age-related processes in Arabidopsis