HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis

The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability, and DNA interstrand crosslink repair in vertebrates. We identify HSF2BP, a protein previously described as testis specific and not characterized functionally, as an interactor of BRCA2 in mouse embryonic stem cells, where the 2 proteins form a constitutive complex. HSF2BP is transcribed in all cultured human cancer cell lines tested and elevated in some tumor samples. Inactivation of the mouse Hsf2bp gene results in male infertility due to a severe HR defect during spermatogenesis. The BRCA2-HSF2BP interaction is highly evolutionarily conserved and maps to armadillo repeats in HSF2BP and a 68-amino acid region between the BRC repeats and the DNA binding domain of human BRCA2 (Gly2270-Thr2337) encoded by exons 12 and 13. This region of BRCA2 does not harbor known cancer-associated missense mutations and may be involved in the reproductive rather than the tumor-suppressing function of BRCA2. BRCA2 is a key homologous recombination mediator in vertebrates. Brandsma et al. show that it directly interacts with a testis-expressed protein, HSF2BP, and that male mice deficient for HSF2BP are infertile due to a meiotic recombination defect. They also find that HSF2BP contributes to DNA repair in mouse embryonic stem cells

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

On the mean overtopping rate of rubble mound structures

Estimation of the mean overtopping discharge is a major task in the design and assessment of the crest level of rubble mound structures such as breakwaters and seawalls. The tolerable mean overtopping rates are given based on the associated risk and wave characteristics. Several empirical formulas have been developed for the prediction of mean overtopping discharge at coastal structures. These formulas can be applied to a wide variety of coastal structures, but have limited accuracy and/or do not reflect the physics of the phenomena. The main aim of this study is to overcome these issues for rubble mound structures by considering the physics of the process in the formula development. To achieve this, first, the references used in the extended CLASH database (also called the EurOtop-2018 database), were scrutinized, the reported wave characteristics were corrected (if required) and the rubble mound structure subset was extended using a recent study. Then noting that overtopping occurs when the wave runup exceeds the freeboard, the difference between the maximum wave runup and crest freeboard was considered as the governing parameter in the mean overtopping discharge formula. In the developed formula, a semi-empirical relationship between the mean overtopping and wave runup has been established. The performances of the developed formulas and existing ones were evaluated both qualitatively and quantitively. Accuracy metrics such as RMSE and BIAS indicated the superiority of the developed simple formula. Finally, a design formula to consider uncertainty and some guidelines are provided for practitioners

On the toe stability of rubble mound structures

Toe design is an important task for coastal engineers as it ensures the stability of the main armor layer and prevents scour in front of the armor slope. Several laboratory experiments have been conducted to investigate the toe stability using different testing approaches, i.e. damage due to a single test condition and cumulative damage due to a number of conditions. In addition, the methods of measuring and reporting damage to the toe are not the same as some researchers have counted only stones that were washed away from the toe; while others counted all the stones that have been displaced. Several formulas with different levels of success have been developed based on these studies. However, the scatter in the results is large and effects of some parameters are disregarded. The aims of this study are (a) to briefly review the abovementioned differences and exiting formulas, and (b) to develop a and physically sound formula for common design conditions, which considers the effect of all governing parameters. To achieve this, first a comprehensive data base from existing reliable studies was collected. Then nondimensional parameters which capture effects of governing parameters such as wave height, wave period, water depth, toe depth, toe width and foreshore slopes were deployed to develop a stability formula using physical reasoning and regression analysis. The new formula outperforms existing formulae for toe stability. The coefficient of variation of the formula was also determined to be used for probabilistic design applications. Finally, some design hints are provided for practitioners

Neural network modelling of wave overtopping at coastal structures

[EN] A method has been developed to estimate wave overtopping discharges for a wide range of coastal structures. The prediction method is based on Neural Network modelling. For this purpose use is made of a data set obtained from a large number of physical model tests (collected within the framework of the European project CLASH, see e.g. [Steendarn, G.J., Van der Meer, J.W., Verhaeghe, H., Besley, P., Franco, L. and Van Gent, MKA. (2004). The international database on wave overtopping. World Scientific, Proc. 29th ICCE, vol. 4, pp. 4301-4313, Lisbon, Portugal.]). Moreover, a method was developed to obtain confidence intervals for the overtopping predictions of the neural network.This study was co-sponsored by the Commission of the European Communities within the framework of the CLASH project (‘Crest Level Assessment of Coastal Structures by fullscale monitoring, neural network prediction and Hazard analysis on permissible wave overtopping’, contract EVK3–2001–00058).Van Gent, MRA.; Van Den Boogaard, HFP.; Pozueta, B.; Medina, JR. (2007). Neural network modelling of wave overtopping at coastal structures. Coastal Engineering. 54(8):586-593. https://doi.org/10.1016/j.coastaleng.2006.12.001S58659354