Deletion mapping of wildtype and mutant alleles at the B incompatibility factor of Schizophyllum

Summary Strains of Schizophyllum commune carrying mutations at the B incompatibility locus were crossed to strains with wildtype B alleles to determine the recombinational spectra of the mutations. An excellent correlation between recombining ability and mating behavior supports the hypothesis that many wildtype and mutant alleles are associated with deletions and that the degree of impairment of recombination and mating interaction reflects the size of the deletion.This study was supported by a grant from the United States-Israel Binational Science Foundation     

Identification of a locus for nongoitrous congenital hypothyroidism on chromosome 15q25.3-26.1

Permanent congenital hypothyroidism is the most prevalent inborn endocrine disorder, and principally due to developmental defects leading to absent, ectopic or hypoplastic thyroid gland. Although commonly regarded as sporadic disease, nonsyndromic thyroid hypoplasia has, in rare cases, been attributed to inherited defects in PAX8 and the TSHR gene. The shared clinical picture caused by these defects is a variable degree of thyrotropin resistance (RTSH [MIM 275200]), accompanied in its severe form by thyroid gland hypoplasia. We recently identified six extended kindreds with autosomal dominant RTSH, only one of which was linked to a mutation in the PAX8 candidate gene. Genome wide scans conducted in two of the remaining five families revealed independently significant linkage to chromosome 15q25.3–26.1, with maximum multipoint LOD scores of 8.51 and 4.31. Linkage to this novel locus was replicated (P<0.01) in each of the three remaining kindreds. Fine mapping of key recombinants in the largest family localized the causative gene within a 3 cM/2.9 Mb interval. Thus, we report the first locus for congenital nongoitrous hypothyroidism identified by a genome wide screening approach.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.Helmut Grasberger Martine Vaxillaire have contributed equally to this work.     

Extreme Polygyny: Multi-seasonal “Hypergynous” Nesting in the Introduced Paper Wasp <Emphasis Type="Italic">Polistes dominulus</Emphasis>

In temperate climates, female paper wasps typically initiate new colonies in the spring. Several nest-founding tactics have been documented in Polistes species, including solitary nest initiation, joining a cooperative association, usurping an existing nest, or adopting an abandoned nest. Occasionally, exceptionally large groups of females have also been found reusing nests from the previous season. Here we report this phenomenon in introduced populations of the Eurasian species Polistes dominulus. We describe in detail the demographic and genetic characteristics of one such spring colony from Los Angeles, California, USA, which was collected with 84 associated adults and all stages of developing brood in its 613 cells. Genetic and morphological data indicate the presence of multiple reproductively active females of varying relatedness, as well as many nonbreeding females, including probable early-produced offspring. Despite some evidence of chaotic social conditions, the colony appeared to have been highly productive. Additional observations of similar colonies are needed to determine how control is maintained within such a large breeding aggregation.     

Scaling Up Family Planning to Reduce Maternal and Child Mortality: The Potential Costs and Benefits of Modern Contraceptive Use in South Africa

Introduction

Family planning contributes significantly to the prevention of maternal and child mortality. However, many women still do not use modern contraception and the numbers of unintended pregnancies, abortions and subsequent deaths are high. In this paper, we estimate the service delivery costs of scaling up modern contraception, and the potential impact on maternal, newborn and child survival in South Africa.

Methods

The Family Planning model in Spectrum was used to project the impact of modern contraception on pregnancies, abortions and births in South Africa (2015-2030). The contraceptive prevalence rate (CPR) was increased annually by 0.68 percentage points. The Lives Saved Tool was used to estimate maternal and child deaths, with coverage of essential maternal and child health interventions increasing by 5% annually. A scenario analysis was done to test impacts when: the change in CPR was 0.1% annually; and intervention coverage increased linearly to 99% in 2030.

Results

If CPR increased by 0.68% annually, the number of pregnancies would reduce from 1.3 million in 2014 to one million in 2030. Unintended pregnancies, abortions and births decrease by approximately 20%. Family planning can avert approximately 7,000 newborn and child and 600 maternal deaths. The total annual costs of providing modern contraception in 2030 are estimated to be US$33 million and the cost per user of modern contraception is US$7 per year. The incremental cost per life year gained is US$40 for children and US$1,000 for mothers.

Conclusion

Maternal and child mortality remain high in South Africa, and scaling up family planning together with optimal maternal, newborn and child care is crucial. A huge impact can be made on maternal and child mortality, with a minimal investment per user of modern contraception.     

Bone age advancement in prepubertal children with obesity and premature adrenarche: possible potentiating factors

Obesity and premature adrenarche (PA) are both associated with bone age (BA) advancement of unclear etiology, which may lead to earlier puberty, suboptimal final height and obesity in adulthood. Our objective was to understand the hormonal and anthropometric characteristics of BA advancement in a spectrum of prepubertal children with and without obesity and PA. In this cross-sectional study of 66 prepubertal children (35 PA, 31 control, 5-9 years), BMI z-score, hormonal values and response to an oral glucose tolerance test were the main outcome measures. Subjects were divided into tertiles by BA divided by chronological age (BA/CA), an index of BA advancement. Subjects in the top tertile for BA/CA had the highest dehydroepiandrosterone sulfate (DHEAS), free testosterone (%), hemoglobin A(1C), BMI z-score, and weight (P < 0.05). BMI z-score (r = 0.47), weight (r = 0.40), free testosterone (%) (r = 0.34), and DHEAS (r = 0.30) correlated with BA/CA (P < 0.02). Regression analysis showed greater BA/CA in PA compared to controls after controlling for weight (0.21 ± 0.56, P < 0.004). An exploratory stepwise regression model showed that weight, estradiol, and DHEAS were the strongest predictors of BA/CA accounting for 24% of its variance. Obesity was highly associated with BA advancement in this study of prepubertal children. In addition, children with PA had greater BA/CA at any given weight when compared to controls. These findings suggest a possible hormonal factor, which potentiates the effect of obesity on BA advancement in children with obesity and/or PA.     

Val-BoroPro Accelerates T Cell Priming via Modulation of Dendritic Cell Trafficking Resulting in Complete Regression of Established Murine Tumors

Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.     

Front Cover

Maternal investment in mammals may take many forms, including spatial relocation of offspring. Litter relocation behavior, in which a female moves her litter to a new location, has been reported for several species of carnivores and rodents but has received little study. We describe litter relocations during long-term studies of two species of ground-dwelling squirrels, yellow-bellied marmots (YBM, Marmota flaviventer) and golden-mantled ground squirrels (GMGS, Callospermophilus lateralis), to determine the distance and frequency of litter relocations and to explore possible explanations for litter relocation behavior. We observed 19 litters relocated by YBM mothers and 32 by GMGS mothers. Although YBM are much larger than GMGS, relocation distances for YBM (median = 46 m and range = 15–324 m) were not greater than those for GMGS (median = 79 m and range = 16–252 m), possibly because YBM home ranges in our study area were exceptionally small. Frequency of litter relocation was greater for GMGS (21% of litters produced) than for YBM (10%), perhaps because GMGS experience fewer social constraints or greater predation risk. We identified several possible costs (energy expenditure and vulnerability to predators while transporting young) and benefits (reduced exposure to predation risk, increased habitat quality, and social benefits) of litter relocation. Future studies should continue to explore litter relocations to better understand the ecological causes and consequences of this behavior.     

Localized egg-cell expression of effector proteins for targeted modification of the Arabidopsis genome

Targeted modification of the genome is an important genetic tool, which can be achieved via homologous, non-homologous or site-specific recombination. Although numerous efforts have been made, such a tool does not exist for routine applications in plants. This work describes a simple and useful method for targeted mutagenesis or gene targeting, tailored to floral-dip transformation in Arabidopsis, by means of specific protein expression in the egg cell. Proteins stably or transiently expressed under the egg apparatus-specific enhancer (EASE) were successfully localized to the area of the egg cell. Moreover, a zinc-finger nuclease expressed under EASE induced targeted mutagenesis. Mutations obtained under EASE control corresponded to genetically independent events that took place specifically in the germline. In addition, RAD54 expression under EASE led to an approximately 10-fold increase in gene targeting efficiency, when compared with wild-type plants. EASE-controlled gene expression provides a method for the precise engineering of the Arabidopsis genome through temporally and spatially controlled protein expression. This system can be implemented as a useful method for basic research in Arabidopsis, as well as in the optimization of tools for targeted genetic modifications in crop plants.