Free markets and dead mothers: the social ecology of maternal mortality in post-socialist Mongolia

Beginning in 1990, Mongolia, a former client state of what was then the Soviet Union, undertook liberal economic reforms. These came as a great shock to Mongolia and Mongolians, and resulted in food shortages, reports of famine, widespread unemployment, and a collapse of public health and health care. Although economic conditions have stabilized in recent years, unemployment and poverty are still at disturbingly high levels. One important consequence of the transition has been the transformation of the rural, primarily pastoral, economy. With de-collectivization, herding households have been thrown into a highly insecure subsistence mode of production, and, as a consequence, have become vulnerable to local fluctuations in rainfall and availability and quality of forage, and many now lack access to traded staples and essential commodities. Household food insecurity, malnutrition, and migration of impoverished households to provincial centers and the capital of Ulaanbaatar are one result. Reductions to investments in the health sector have also eroded the quality of services in rural areas, and restricted access to those services still functioning. Evidence suggests that women are particularly vulnerable to these political-ecological changes, and that this vulnerability is manifested in increasing rates of poor reproductive health and maternal mortality. Drawing on case-study ethnographic and epidemiological data, this article explores the links between neoliberal economic reform and maternal mortality in Mongolia.     

The Role of the Transmembrane and of the Intraviral Domain of Glycoproteins in Membrane Fusion of Enveloped Viruses

Fusion of enveloped viruses with their target membrane is mediated by viral integral glycoproteins. A conformational change of their ectodomain triggers membrane fusion. Several studies suggest that an extended, triple-stranded rod-shaped -helical coiled coil resembles a common structural and functional motif of the ectodomain of fusion proteins. From that, it is believed that essential features of the fusion process are conserved among the various enveloped viruses. However, this has not been established so far for the highly conserved transmembrane and intraviral sequences of fusion proteins. The article will focus on the role of both sequences in the fusion process. Recent studies from various enveloped viruses strongly imply that a transmembrane domain with a minimum length is required for later steps of membrane fusion, i.e., the formation and enlargement of the aqueous fusion pore. Although no specific sequence of the TM is necessary for pore formation, distinct properties and motifs of the domain may be obligatory to ascertain full fusion activity. However, with some exceptions, the intraviral domain seems to be not required for fusion activity of viral fusion proteins.     

Non-additive genetic variation in growth,carcass and fertility traits of beef cattle

Background

A better understanding of non-additive variance could lead to increased knowledge on the genetic control and physiology of quantitative traits, and to improved prediction of the genetic value and phenotype of individuals. Genome-wide panels of single nucleotide polymorphisms (SNPs) have been mainly used to map additive effects for quantitative traits, but they can also be used to investigate non-additive effects. We estimated dominance and epistatic effects of SNPs on various traits in beef cattle and the variance explained by dominance, and quantified the increase in accuracy of phenotype prediction by including dominance deviations in its estimation.

Methods

Genotype data (729 068 real or imputed SNPs) and phenotypes on up to 16 traits of 10 191 individuals from Bos taurus, Bos indicus and composite breeds were used. A genome-wide association study was performed by fitting the additive and dominance effects of single SNPs. The dominance variance was estimated by fitting a dominance relationship matrix constructed from the 729 068 SNPs. The accuracy of predicted phenotypic values was evaluated by best linear unbiased prediction using the additive and dominance relationship matrices. Epistatic interactions (additive × additive) were tested between each of the 28 SNPs that are known to have additive effects on multiple traits, and each of the other remaining 729 067 SNPs.

Results

The number of significant dominance effects was greater than expected by chance and most of them were in the direction that is presumed to increase fitness and in the opposite direction to inbreeding depression. Estimates of dominance variance explained by SNPs varied widely between traits, but had large standard errors. The median dominance variance across the 16 traits was equal to 5% of the phenotypic variance. Including a dominance deviation in the prediction did not significantly increase its accuracy for any of the phenotypes. The number of additive × additive epistatic effects that were statistically significant was greater than expected by chance.

Conclusions

Significant dominance and epistatic effects occur for growth, carcass and fertility traits in beef cattle but they are difficult to estimate precisely and including them in phenotype prediction does not increase its accuracy.     

Design of a low‐density SNP chip for the main Australian sheep breeds and its effect on imputation and genomic prediction accuracy

Genotyping sheep for genome‐wide SNPs at lower density and imputing to a higher density would enable cost‐effective implementation of genomic selection, provided imputation was accurate enough. Here, we describe the design of a low‐density (12k) SNP chip and evaluate the accuracy of imputation from the 12k SNP genotypes to 50k SNP genotypes in the major Australian sheep breeds. In addition, the impact of imperfect imputation on genomic predictions was evaluated by comparing the accuracy of genomic predictions for 15 novel meat traits including carcass and meat quality and omega fatty acid traits in sheep, from 12k SNP genotypes, imputed 50k SNP genotypes and real 50k SNP genotypes. The 12k chip design included 12 223 SNPs with a high minor allele frequency that were selected with intermarker spacing of 50–475 kb. SNPs for parentage and horned or polled tests also were represented. Chromosome ends were enriched with SNPs to reduce edge effects on imputation. The imputation performance of the 12k SNP chip was evaluated using 50k SNP genotypes of 4642 animals from six breeds in three different scenarios: (1) within breed, (2) single breed from multibreed reference and (3) multibreed from a single‐breed reference. The highest imputation accuracies were found with scenario 2, whereas scenario 3 was the worst, as expected. Using scenario 2, the average imputation accuracy in Border Leicester, Polled Dorset, Merino, White Suffolk and crosses was 0.95, 0.95, 0.92, 0.91 and 0.93 respectively. Imputation scenario 2 was used to impute 50k genotypes for 10 396 animals with novel meat trait phenotypes to compare genomic prediction accuracy using genomic best linear unbiased prediction (GBLUP) with real and imputed 50k genotypes. The weighted mean imputation accuracy achieved was 0.92. The average accuracy of genomic estimated breeding values (GEBVs) based on only 12k data was 0.08 across traits and breeds, but accuracies varied widely. The mean GBLUP accuracies with imputed 50k data more than doubled to 0.21. Accuracies of genomic prediction were very similar for imputed and real 50k genotypes. There was no apparent impact on accuracy of GEBVs as a result of using imputed rather than real 50k genotypes, provided imputation accuracy was >90%.     

Detection of quantitative trait loci in Bos indicus and Bos taurus cattle using genome-wide association studies

Background

The apparent effect of a single nucleotide polymorphism (SNP) on phenotype depends on the linkage disequilibrium (LD) between the SNP and a quantitative trait locus (QTL). However, the phase of LD between a SNP and a QTL may differ between Bos indicus and Bos taurus because they diverged at least one hundred thousand years ago. Here, we test the hypothesis that the apparent effect of a SNP on a quantitative trait depends on whether the SNP allele is inherited from a Bos taurus or Bos indicus ancestor.

Methods

Phenotype data on one or more traits and SNP genotype data for 10 181 cattle from Bos taurus, Bos indicus and composite breeds were used. All animals had genotypes for 729 068 SNPs (real or imputed). Chromosome segments were classified as originating from B. indicus or B. taurus on the basis of the haplotype of SNP alleles they contained. Consequently, SNP alleles were classified according to their sub-species origin. Three models were used for the association study: (1) conventional GWAS (genome-wide association study), fitting a single SNP effect regardless of subspecies origin, (2) interaction GWAS, fitting an interaction between SNP and subspecies-origin, and (3) best variable GWAS, fitting the most significant combination of SNP and sub-species origin.

Results

Fitting an interaction between SNP and subspecies origin resulted in more significant SNPs (i.e. more power) than a conventional GWAS. Thus, the effect of a SNP depends on the subspecies that the allele originates from. Also, most QTL segregated in only one subspecies, suggesting that many mutations that affect the traits studied occurred after divergence of the subspecies or the mutation became fixed or was lost in one of the subspecies.

Conclusions

The results imply that GWAS and genomic selection could gain power by distinguishing SNP alleles based on their subspecies origin, and that only few QTL segregate in both B. indicus and B. taurus cattle. Thus, the QTL that segregate in current populations likely resulted from mutations that occurred in one of the subspecies and can have both positive and negative effects on the traits. There was no evidence that selection has increased the frequency of alleles that increase body weight.     

Functional Consequences of Wnt-induced Dishevelled 2 Phosphorylation in Canonical and Noncanonical Wnt Signaling

Dishevelled (Dvl) proteins are intracellular effectors of Wnt signaling that have essential roles in both canonical and noncanonical Wnt pathways. It has long been known that Wnts stimulate Dvl phosphorylation, but relatively little is known about its functional significance. We have previously reported that both Wnt3a and Wnt5a induce Dvl2 phosphorylation that is associated with an electrophoretic mobility shift and loss of recognition by monoclonal antibody 10B5. In the present study, we mapped the 10B5 epitope to a 16-amino acid segment of human Dvl2 (residues 594–609) that contains four Ser/Thr residues. Alanine substitution of these residues (P4m) eliminated the mobility shift induced by either Wnt3a or Wnt5a. The Dvl2 P4m mutant showed a modest increase in canonical Wnt/β-catenin signaling activity relative to wild type. Consistent with this finding, Dvl2 4Pm preferentially localized to cytoplasmic puncta. In contrast to wild-type Dvl2, however, the P4m mutant was unable to rescue Wnt3a-dependent neurite outgrowth in TC-32 cells following suppression of endogenous Dvl2/3. Earlier work has implicated casein kinase 1δ/ϵ as responsible for the Dvl mobility shift, and a CK1δ in vitro kinase assay confirmed that Ser⁵⁹⁴, Thr⁵⁹⁵, and Ser⁵⁹⁷ of Dvl2 are CK1 targets. Alanine substitution of these three residues was sufficient to abrogate the Wnt-dependent mobility shift. Thus, we have identified a cluster of Ser/Thr residues in the C-terminal domain of Dvl2 that are Wnt-induced phosphorylation (WIP) sites. Our results indicate that phosphorylation at the WIP sites reduces Dvl accumulation in puncta and attenuates β-catenin signaling, whereas it enables noncanonical signaling that is required for neurite outgrowth.     

Grazing effects on intraspecific trait variability vary with changing precipitation patterns in Mongolian rangelands

Functional traits are proxies for plant physiology and performance, which do not only differ between species but also within species. In this work, we hypothesized that (a) with increasing precipitation, the percentage of focal species which significantly respond to changes in grazing intensity increases, while under dry conditions, climate‐induced stress is so high that plant species hardly respond to any changes in grazing intensity and that (b) the magnitude with which species change their trait values in response to grazing, reflected by coefficients of variation (CVs), increases with increasing precipitation. Chosen plant traits were canopy height, plant width, specific leaf area (SLA), chlorophyll fluorescence, performance index, stomatal pore area index (SPI), and individual aboveground biomass of 15 species along a precipitation gradient with different grazing intensities in Mongolian rangelands. We used linear models for each trait to assess whether the percentage of species that respond to grazing changes along the precipitation gradient. To test the second hypothesis, we assessed the magnitude of intraspecific trait variability (ITV) response to grazing, per species, trait, and precipitation level by calculating CVs across the different grazing intensities. ITV was most prominent for SLA and SPI under highest precipitation, confirming our first hypothesis. Accordingly, CVs of canopy height, SPI, and SLA increased with increasing precipitation, partly confirming our second hypothesis. CVs of the species over all traits increased with increasing precipitation only for three species. This study shows that it remains challenging to predict how plant performance will shift under changing environmental conditions based on their traits alone. In this context, the implications for the use of community‐weighted mean trait values are discussed, as not only species abundances change in response to changing environmental conditions, but also values of traits considerably change. Including this aspect in further studies will improve our understanding of processes acting within and among communities.     

Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells

Rspo2 was identified as a novel common integration site (CIS) for the mouse mammary tumor virus (MMTV) in viral induced mouse mammary tumors. Here we show that Rspo2 modulates Wnt signaling in mouse mammary epithelial cells. Co‐expression of both genes resulted in an intermediate growth phenotype on plastic and had minor effects on the growth‐promoting properties of Wnt1 in soft agar. However, individual Rspo2 and Wnt1 HC11 transfectants as well as the double transfectant were tumorigenic in athymic nude mice, with tumors from each line having distinctive histological characteristics. Rspo2 and Rspo2/Wnt1 tumors contained many spindle cells, consistent with an epithelial–mesenchymal transformation (EMT) phenotype. When Rspo2 and Rspo2/Wnt1 tumor cells were transferred into naïve mice, they exhibited greater metastatic activity than cells derived from Wnt1 tumors. For comparison, C57MG/Wnt1/Rspo2 co‐transfectants exhibited invasive properties in three‐dimensional (3D) Matrigel cultures that were not seen with cells transfected only with Wnt1 or Rspo2. Use of Dickkopf‐1, a specific antagonist of the Wnt/β‐catenin pathway, or short hairpin RNA targeting β‐catenin expression demonstrated that the invasive activity was not mediated by β‐catenin. Our results indicate that Rspo2 and Wnt1 have mutually distinct effects on mammary epithelial cell growth and these effects are context‐dependent. While Rspo2 and Wnt1 act synergistically in the β‐catenin pathway, other mechanisms are responsible for the invasive properties of stable double transfectants observed in 3D Matrigel cultures. J. Cell. Physiol. 227: 1960–1971, 2012. © 2011 Wiley Periodicals, Inc.     

Unmet need for hypercholesterolemia care in 35 low- and middle-income countries: A cross-sectional study of nationally representative surveys

BackgroundAs the prevalence of hypercholesterolemia is increasing in low- and middle-income countries (LMICs), detailed evidence is urgently needed to guide the response of health systems to this epidemic. This study sought to quantify unmet need for hypercholesterolemia care among adults in 35 LMICs.Methods and findingsWe pooled individual-level data from 129,040 respondents aged 15 years and older from 35 nationally representative surveys conducted between 2009 and 2018. Hypercholesterolemia care was quantified using cascade of care analyses in the pooled sample and by region, country income group, and country. Hypercholesterolemia was defined as (i) total cholesterol (TC) ≥240 mg/dL or self-reported lipid-lowering medication use and, alternatively, as (ii) low-density lipoprotein cholesterol (LDL-C) ≥160 mg/dL or self-reported lipid-lowering medication use. Stages of the care cascade for hypercholesterolemia were defined as follows: screened (prior to the survey), aware of diagnosis, treated (lifestyle advice and/or medication), and controlled (TC <200 mg/dL or LDL-C <130 mg/dL). We further estimated how age, sex, education, body mass index (BMI), current smoking, having diabetes, and having hypertension are associated with cascade progression using modified Poisson regression models with survey fixed effects.High TC prevalence was 7.1% (95% CI: 6.8% to 7.4%), and high LDL-C prevalence was 7.5% (95% CI: 7.1% to 7.9%). The cascade analysis showed that 43% (95% CI: 40% to 45%) of study participants with high TC and 47% (95% CI: 44% to 50%) with high LDL-C ever had their cholesterol measured prior to the survey. About 31% (95% CI: 29% to 33%) and 36% (95% CI: 33% to 38%) were aware of their diagnosis; 29% (95% CI: 28% to 31%) and 33% (95% CI: 31% to 36%) were treated; 7% (95% CI: 6% to 9%) and 19% (95% CI: 18% to 21%) were controlled. We found substantial heterogeneity in cascade performance across countries and higher performances in upper-middle-income countries and the Eastern Mediterranean, Europe, and Americas. Lipid screening was significantly associated with older age, female sex, higher education, higher BMI, comorbid diagnosis of diabetes, and comorbid diagnosis of hypertension. Awareness of diagnosis was significantly associated with older age, higher BMI, comorbid diagnosis of diabetes, and comorbid diagnosis of hypertension. Lastly, treatment of hypercholesterolemia was significantly associated with comorbid hypertension and diabetes, and control of lipid measures with comorbid diabetes. The main limitations of this study are a potential recall bias in self-reported information on received health services as well as diminished comparability due to varying survey years and varying lipid guideline application across country and clinical settings.ConclusionsCascade performance was poor across all stages, indicating large unmet need for hypercholesterolemia care in this sample of LMICs—calling for greater policy and research attention toward this cardiovascular disease (CVD) risk factor and highlighting opportunities for improved prevention of CVD.

Maja Marcus and colleagues use nationally-representative surveys conducted between 2009 and 2018 to investigate the unmet need for hypercholesterolemia care in 35 low- and middle-income countries.