Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described

LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

Premature ovarian failure and female infertility are frequent side effects of anticancer therapies, owing to the extreme sensitivity of the ovarian reserve oocytes to the damaging effects of irradiation and chemotherapy on DNA. We report here a robust protective effect of luteinizing hormone (LH) on the primordial follicle pool of prepubertal ovaries against the cisplatin (Cs)-induced apoptosis. In vitro LH treatment of prepubertal ovarian fragments generated anti-apoptotic signals by a subset of ovarian somatic cells expressing LH receptor (LHR) through cAMP/PKA and Akt pathways. Such signals, reducing the oocyte level of pro-apoptotic TAp63 protein and favoring the repair of the Cs-damaged DNA in the oocytes, prevented their apoptosis. Noteworthy, in vivo administration to prepubertal female mice of a single dose of LH together with Cs inhibited the depletion of the primordial follicle reserve caused by the drug and preserved their fertility in reproductive age, preventing significant alteration in the number of pregnancy and of delivered pups. In conclusion, these findings establish a novel ovoprotective role for LH and further support the very attracting prospective to use physiological 'fertoprotective' approaches for preventing premature infertility and risks linked to precocious menopause in young patients who survived cancer after chemotherapy

An example of secondary fault activity along the North Anatolian Fault on the NE Marmara Sea Shelf, NW Turkey

Seismic data on the NE Marmara Sea Shelf indicate that a NNE-SSW-oriented buried basin and ridge system exist on the sub-marine extension of the Paleozoic Rocks delimited by the northern segment of the North Anatolian Fault (NS-NAF), while seismic and multi-beam bathymetric data imply that four NW-SE-oriented strike-slip faults also exist on the shelf area. Seismic data indicate that NW-SE-oriented strike-slip faults are the youngest structures that dissect the basin-ridge system. One of the NW-SE-oriented faults (F1) is aligned with a rupture of the North Anatolian Fault (NAF) cutting the northern slope of the Cinarcik Basin. This observation indicates that these faults have similar characteristics with the NS-NAF along the Marmara Sea. Therefore, they may have a secondary relation to the NAF since the principle deformation zone of the NAF follows the Marmara Trough in that region. The seismic energy recorded on these secondary faults is much less than that on the NAF in the Marmara Sea. These faults may, however, produce a large earthquake in the long term

Evaluating susceptibility of karst dolines (sinkholes) for collapse in Sango, Tennessee, USA

Dolines or sinkholes are earth depressions that develop in soluble rocks complexes such as limestone, dolomite, gypsum, anhydrite, and halite; dolines appear in a variety of shapes from nearly circular to complex structures with highly curved perimeters. The occurrence of dolines in the studied karst area is not random; they are the results of geomorphic, hydrologic and chemical processes that have caused partial subsidence, even total collapse of the land surface, when voids and caves are present in the bedrock and the regolith arch overbridging these voids is unstable. In the study area, the majority of collapses occur in the regolith (bedrock cover) that bridges voids in the bedrock. Because these collapsing dolines can damage property and cause even the loss of lives, there is a need to develop methods for evaluating karst hazards; such methods can be used by planners and practitioners for urban and economic development, especially in regions with a growing population. The purpose of this project is threefold: 1) to develop a karst feature database, 2) to investigate critical indicators associated with doline collapse, and 3) to design a doline susceptibility model for potential doline collapse based on external morphometric data. The study revealed the presence of short range spatial dependence in the distribution of the dolines’ morphometric parameters such as circularity, geographic orientation of the main doline axes and the length-to-width doline ratios; therefore, geostatistics can be used to spatially evaluate the susceptibility of the karst area for doline collapse using the probability of occurrence of these critical parameters. The partial susceptibility estimates were combined into final spatial probabilities enabling the identification of areas where undetected dolines may cause significant hazards

The behaviour of natural shear waves under different loading conditions

Background Shear wave imaging (SWI) is a novel ultrasound technique based on the detection of transverse waves traveling through the myocardium using high frame rate echocardiography. These waves can be naturally induced e.g. by mitral valve closure (MVC). Their propagation velocity is dependent on the stiffness of the myocardium. Previous studies have shown the potential of SWI for the non-invasive assessment of myocardial stiffness. So far, the influence of loading on shear wave propagation velocities has not been extensively investigated. Purpose The aim of this study was to explore how loading changes affect shear wave propagation velocities after MVC. Methods Until now, 5 pigs (weight: 33.5±6.9 kg) were included. Echocardiographic images and left ventricular pressure recordings were simultaneously acquired during acute loading alterations: 1) preload was reduced by balloon occlusion of the vena cava inferior, 2) afterload was increased by balloon occlusion of the descending aorta and 3) preload was increased by intra-venous administration of 500 ml of saline. Left ventricular parasternal long-axis views were acquired with an experimental high frame rate ultrasound scanner (average frame rate: 1247±179 Hz). Shear waves were visualized on tissue acceleration maps by drawing an M-mode line along the interventricular septum. Shear wave propagation velocities after MVC were calculated by measuring the slope of the wave front on the acceleration maps (Figure A). Results The changes in left ventricular end-diastolic pressures (LV EDP) between baseline and each intervention are shown in Figure B. Preload reduction resulted in significantly reduced LV EDP (p<0.01). The shear wave propagation velocities after MVC dropped with preload reduction and increased significantly by increasing afterload as well as preload (both p<0.05) (Figure C). There was a good positive correlation between the change in LV EDP and the change in shear wave velocities (r=0.83; p<0.001) (Figure D). Conclusion The shear wave propagation velocity after MVC was significantly influenced by alterations in left ventricular loading conditions and changes in these velocities were related to changes in LV EDP. These results indicate that shear wave measurements at MVC might be a potential novel parameter for the estimation of left ventricular filling pressures. More pigs will be included in the future to further confirm these findings. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Fonds Wetenschappelijk Onderzoek - Vlaandere