Gender Differences in Homicide of Neonates,Infants, and Children under 5 y in South Africa: Results from the Cross-Sectional 2009 National Child Homicide Study

BackgroundHomicide of children is a global problem. The under-5-y age group is the second largest homicide age group after 15–19 y olds, but has received little research attention. Understanding age and gender patterns is important for assisting with developing prevention interventions. Here we present an age and gender analysis of homicides among children under 5 y in South Africa from a national study that included a focus on neonaticide and infanticide.ConclusionsHomicide of children is an extreme form or consequence of violence against children. This national study provides one of the first analyses of neonaticide and infanticide by age and gender and shows the failure of reproductive and mental health and social services to identify and help vulnerable mothers. Multi-sectoral prevention strategies are needed.     

Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R2 > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.     

THE BIOLOGY OF SPECIATION

Since Darwin published the “Origin,” great progress has been made in our understanding of speciation mechanisms. The early investigations by Mayr and Dobzhansky linked Darwin's view of speciation by adaptive divergence to the evolution of reproductive isolation, and thus provided a framework for studying the origin of species. However, major controversies and questions remain, including: When is speciation nonecological? Under what conditions does geographic isolation constitute a reproductive isolating barrier? and How do we estimate the “importance” of different isolating barriers? Here, we address these questions, providing historical background and offering some new perspectives. A topic of great recent interest is the role of ecology in speciation. “Ecological speciation” is defined as the case in which divergent selection leads to reproductive isolation, with speciation under uniform selection, polyploid speciation, and speciation by genetic drift defined as “nonecological.” We review these proposed cases of nonecological speciation and conclude that speciation by uniform selection and polyploidy normally involve ecological processes. Furthermore, because selection can impart reproductive isolation both directly through traits under selection and indirectly through pleiotropy and linkage, it is much more effective in producing isolation than genetic drift. We thus argue that natural selection is a ubiquitous part of speciation, and given the many ways in which stochastic and deterministic factors may interact during divergence, we question whether the ecological speciation concept is useful. We also suggest that geographic isolation caused by adaptation to different habitats plays a major, and largely neglected, role in speciation. We thus provide a framework for incorporating geographic isolation into the biological species concept (BSC) by separating ecological from historical processes that govern species distributions, allowing for an estimate of geographic isolation based upon genetic differences between taxa. Finally, we suggest that the individual and relative contributions of all potential barriers be estimated for species pairs that have recently achieved species status under the criteria of the BSC. Only in this way will it be possible to distinguish those barriers that have actually contributed to speciation from those that have accumulated after speciation is complete. We conclude that ecological adaptation is the major driver of reproductive isolation, and that the term “biology of speciation,” as proposed by Mayr, remains an accurate and useful characterization of the diversity of speciation mechanisms.     

Effect of Soy Protein Subunit Composition on the Rheological Properties of Soymilk during Acidification

The effect of soy protein subunit composition on the acid-induced aggregation of soymilk was investigated by preparing soymilk from different soybean lines lacking specific glycinin and β-conglycinin subunits. Acid gelation was induced by glucono-δ-lactone (GDL) and analysis was done using diffusing wave spectroscopy and rheology. Aggregation occurred near pH 5.8 and the increase in radius corresponded to an increase in the elastic modulus measured by small deformation rheology. Diffusing wave spectroscopy was also employed to follow acid gelation, and data indicated that particle interactions start to occur at a higher pH than the pH of onset of gelation (corresponding to the start of the rapid increase in elastic modulus). The protein subunit composition significantly affected the development of structure during acidification. The onset of aggregation occurred at a higher pH for soymilk samples containing group IIb (the acidic subunit A₃) of glycinin, than for samples prepared from Harovinton (a commercial variety containing all subunits) or from genotypes null in glycinin. The gels made from lines containing group I (A₁, A₂) and group IIb (A₃) of glycinin resulted in stiffer acid gels compared to the lines containing only β-conglycinin. These results confirmed that the ratio of glycinin/β-conglycinin has a significant effect on gel structure, with an increase in glycinin causing an increase in gel stiffness. The type of glycinin subunits also affected the aggregation behavior of soymilk.     

Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR)?=?1.03, 95% CI 1.00-1.06, p?=?0.023). There was evidence for heterogeneity in the ORs among studies (I(2)?=?49.3%; p?=?<0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR?=?0.89, 95%CI 0.80-1.00, p?=?0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.     

Sex,gender, and pharmaceutical politics: From drug development to marketing

Background: Biological sex differences and sociocultural gender norms affect the provision of health care products and services, but there has been little explicit analysis of the impact of sex differences and gender norms on the regulation of pharmaceutical development and marketing.Objectives: This article provides an overview of the regulation of pharmaceuticals and examines the ways that regulatory agencies account for sex and gender in their review of scientific data and marketing materials.Methods: The primary focus is on the US context, but information is also included about regulatory models in Europe, Canada, and Japan for comparative purposes. Specific examples show how sex differences and gender norms influence scientific and policy decisions about pharmaceuticals.Results: The United States and Canada were found to be the only countries that have explicit requirements to include women in clinical trials and to perform sex-based subgroup analysis on study results. The potential influence of politics on regulatory decisions may have led to an uneven application of standards, as seen through the examples of mifepristone (for abortion) and sildenafil citrate (for erectile dysfunction). Three detailed case studies illustrate the importance of considering sex and gender in pharmaceutical development and marketing: Phase I clinical trials; human papillomavirus quadrivalent vaccine; and tegaserod, a drug for irritable bowel syndrome.Conclusions: Sex and gender play important roles in pharmaceutical regulation, from the design of clinical trials and the approval of new drugs to advertising and postmarketing surveillance. However, regulatory agencies pay insufficient attention to both biological sex differences and sociocultural gender norms. This disregard perpetuates inequalities by ignoring drug safety problems that predominate in women and by allowing misleading drug marketing that reinforces gender stereotypes. Recommendations have been made to improve the regulation of pharmaceuticals in regard to sex and gender.     

Binding of Extracellular Maspin to ��1 Integrins Inhibits Vascular Smooth Muscle Cell Migration

Maspin is a serpin that has multiple effects on cell behavior, including inhibition of migration. How maspin mediates these diverse effects remains unclear, as it is devoid of protease inhibitory activity. We have previously shown that maspin rapidly inhibits the migration of vascular smooth muscle cells (VSMC), suggesting the involvement of direct interactions with cell surface proteins. Here, using immunofluorescence microscopy, we demonstrate that maspin binds specifically to the surface of VSMC in the dedifferentiated, but not the differentiated, phenotype. Ligand blotting of VSMC lysates revealed the presence of several maspin-binding proteins, with a protein of 150 kDa differentially expressed between the two VSMC phenotypes. Western blotting suggested that this protein was the β1 integrin subunit, and subsequently both α3β1 and α5β1, but not αvβ3, were shown to associate with maspin by coimmunoprecipitation. Specific binding of these integrins was also observed using maspin-affinity chromatography, using HT1080 cell lysates. Direct binding of maspin to α5β1 was confirmed using a recombinant α5β1-Fc fusion protein. Using conformation-dependent anti-β1 antibodies, maspin binding to VSMC was found to lead to a decrease in the activation status of the integrin. The functional involvement of α5β1 in mediating the effect of maspin was established by the inhibition of migration of CHO cells overexpressing human α5 integrin, but not those lacking α5 expression. Our observations suggest that maspin engages in specific interactions with a limited number of integrins on VSMC, leading to their inactivation, and that these interactions are responsible for the effects of maspin in the pericellular environment.Maspin is a member of the serpin family of serine protease inhibitors (SERPINB5).² It was originally identified as a gene down-regulated in invasive breast cancer and proposed as a class II tumor suppressor (1), and has since been shown to have many effects on cellular behavior that are consistent with this activity. It has been shown to decrease the proliferation, migration, and metastasis of tumor cells in vivo (1, 2) and their invasion in vitro (3, 4), and to increase apoptosis of endothelial cells (5) and inhibit angiogenesis (6). However, the cellular effects of maspin are not restricted to tumor cells, and we have demonstrated that maspin can inhibit the migration of vascular smooth muscle cells (7).VSMC migration is a key event in the development of atherosclerosis (8), and contributes significantly to restenosis after angioplasty (9) and transplant arteriosclerosis (10). VSMC are not terminally differentiated and acquire migratory capacity as part of a phenotypic switch from a contractile, quiescent state to a dedifferentiated phenotype, characterized by proliferation and increased extracellular matrix synthesis, in addition to motility (11). This allows VSMC to respond to environmental cues following vascular injury. The phenotypic plasticity of VSMC is regulated by an array of signals, among which integrin-mediated association with surrounding extracellular matrix and changes in the expression of matrix-degrading proteases are prominent (12–14).How maspin mediates its various cellular effects is unclear. Maspin has been reported to be an inhibitor of plasminogen activation (3, 15, 16), but we have shown that maspin is unable to inhibit either uPA- or tPA-catalyzed plasminogen activation under conditions in which the serpin PAI-1 was completely inhibitory (7). The anti-proteolytic inhibitory mechanism of serpins is dependent on characteristics of the reactive center loop (RCL) allowing it to adopt the necessary canonical conformation and rearrangements subsequent to protease binding (17). The RCL of maspin does not have the required characteristics (7, 18), and the conclusion that maspin is a non-inhibitory serpin is fully supported by its crystal structure (19, 20).Another confounding factor in understanding the mechanisms underlying the cellular effects of maspin is that, in common with the serpin PAI-2, it lacks an authentic secretion signal sequence. Nevertheless it has been shown to enter secretory vesicles (21) and is found extracellularly, in the cytoplasm and also in the nucleus (21, 22). Cytoplasmic and nuclear binding proteins for maspin have been identified (23–25), and may be responsible for its effects on proliferation and apoptosis. How secreted, extracellular maspin exerts its effects is unclear, but a function as a cell signaling ligand has been proposed (26–28). However, the characteristics of the maspin inhibitory effect on VSMC migration point to a more direct effect of maspin.To determine the mechanism of the maspin effect on VSMC migration, we have now attempted to identify maspin-binding proteins on the surface of these cells. In this report we provide biochemical, cellular, and functional evidence that the effect of maspin on cell migration is mediated by specific binding to cell adhesion receptors of the integrin family. We find that maspin binds specifically to β1 integrins on the surface of dedifferentiated VSMC, which leads to a reduction in the activation status of the integrin, and that the binding of maspin to α5β1 is sufficient for its inhibitory effects on cell migration and may represent a more general mechanism underlying its diverse biological effects.     

Quantification of mesocosm fish and amphibian species diversity via environmental DNA metabarcoding

Freshwater fauna are particularly sensitive to environmental change and disturbance. Management agencies frequently use fish and amphibian biodiversity as indicators of ecosystem health and a way to prioritize and assess management strategies. Traditional aquatic bioassessment that relies on capture of organisms via nets, traps and electrofishing gear typically has low detection probabilities for rare species and can injure individuals of protected species. Our objective was to determine whether environmental DNA (eDNA) sampling and metabarcoding analysis can be used to accurately measure species diversity in aquatic assemblages with differing structures. We manipulated the density and relative abundance of eight fish and one amphibian species in replicated 206‐L mesocosms. Environmental DNA was filtered from water samples, and six mitochondrial gene fragments were Illumina‐sequenced to measure species diversity in each mesocosm. Metabarcoding detected all nine species in all treatment replicates. Additionally, we found a modest, but positive relationship between species abundance and sequencing read abundance. Our results illustrate the potential for eDNA sampling and metabarcoding approaches to improve quantification of aquatic species diversity in natural environments and point the way towards using eDNA metabarcoding as an index of macrofaunal species abundance.     

Commensal bacteria augment Staphylococcus aureus infection by inactivation of phagocyte-derived reactive oxygen species

Staphylococcus aureus is a human commensal organism and opportunist pathogen, causing potentially fatal disease. The presence of non-pathogenic microflora or their components, at the point of infection, dramatically increases S. aureus pathogenicity, a process termed augmentation. Augmentation is associated with macrophage interaction but by a hitherto unknown mechanism. Here, we demonstrate a breadth of cross-kingdom microorganisms can augment S. aureus disease and that pathogenesis of Enterococcus faecalis can also be augmented. Co-administration of augmenting material also forms an efficacious vaccine model for S. aureus. In vitro, augmenting material protects S. aureus directly from reactive oxygen species (ROS), which correlates with in vivo studies where augmentation restores full virulence to the ROS-susceptible, attenuated mutant katA ahpC. At the cellular level, augmentation increases bacterial survival within macrophages via amelioration of ROS, leading to proliferation and escape. We have defined the molecular basis for augmentation that represents an important aspect of the initiation of infection.