Large‐scale modelling of deep‐diving cetacean habitats

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Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2

Human vaccinia-related kinases (VRK1 and VRK2) are atypical active Ser-Thr kinases implicated in control of cell cycle entry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK). The specific structural differences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we have determined the sensitivity of VRK1 and VRK2 to kinase inhibitors, currently used in biological assays or in preclinical studies, in order to discriminate between the two proteins as well as with respect to the vaccinia virus B1R kinase. Both VRK proteins and vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2 and DNA-PK, and most of them have no effect even at 100 µM. Despite their low sensitivity, some of these inhibitors in the low micromolar range are able to discriminate between VRK1, VRK2 and B1R. VRK1 is more sensitive to staurosporine, RO-31-8220 and TDZD8. VRK2 is more sensitive to roscovitine, RO 31–8220, Cdk1 inhibitor, AZD7762, and IC261. Vaccinia virus B1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present a different pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structural framework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1 inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorer prognosis, as is the case of VRK1 in breast cancer

Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression

This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.VRK2 is a novel Ser-Thr kinase whose VRK2A isoform is located in endoplasmic reticulum and mitochondrial membranes. We have studied the potential role that VRK2A plays on the regulation of mitochondrial-mediated apoptosis. VRK2A can regulate the intrinsic apoptotic pathway in two different ways. The VRK2A protein directly interacts with Bcl-xL, but not with Bcl-2, Bax, Bad, PUMA or Binp-3L. VRK2A does not compete with Bax for interaction with Bcl-xL, and these proteins can form a complex that reduces apoptosis. Thus high VRK2 levels confer protection against apoptosis. In addition, VRK2 knockdown results in an increased expression of BAX gene expression that is mediated by its proximal promoter, thus VRK2A behaves as a negative regulator of BAX. Low levels of VRK2A causes an increase in mitochondrial Bax protein level, leading to an increase in the release of cytochrome C and caspase activation, detected by PARP processing. VRK2A loss results in an increase in cell death that can be detected by an increase in annexinV+ cells. Low levels of VRK2A increase cell sensitivity to induction of apoptosis by chemotherapeutic drugs like camptothecin or doxorubicin. We conclude that VRK2A protein is a novel modulator of apoptosis.D.M.M., I. F. F., and M. V-C., have JAE-CSIC-Fondo Social Europeo Predoctoral fellowships. T.M. and S. B. were funded by CSIC-Banco Santander and Ministerio de Ciencia e Innovación fellowships respectively. This work was funded by grants from Ministerio de Ciencia e Innovación (SAF2010-14935 and CSD2007-0017), and Kutxa-Fundación Inbiomed.Peer reviewe

Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis

Disruption of the histone modification patterns is one of the most common features of human tumors. However, few genetic alterations in the histone modifier genes have been described in tumorigenesis. Herein we show that the histone methyltransferase SETDB1 undergoes gene amplification in non-small and small lung cancer cell lines and primary tumors. The existence of additional copies of the SETDB1 gene in these transformed cells is associated with higher levels of the corresponding mRNA and protein. From a functional standpoint, the depletion of SETDB1 expression in amplified cells reduces cancer growth in cell culture and nude mice models, whereas its overexpression increases the tumor invasiveness. The increased gene dosage of SETDB1 is also associated with enhanced sensitivity to the growth inhibitory effect mediated by the SETDB1-interfering drug mithramycin. Overall, the findings identify SETDB1 as a bona fide oncogene undergoing gene amplification-associated activation in lung cancer and suggest its potential for new therapeutic strategies.This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under Grant agreement number HEALTH-F2-2010-258677—CURELUNG project, the Institute of Health Carlos III (ISCIII)—PI10/02992, Ministerio de Educación, Ciencia e Innovación Grant SAF2010-14935, Kutxa-Fundación INBIOMED and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya).Peer Reviewe

VRK2 (vaccinia related kinase 2)

Review on VRK2 (vaccinia related kinase 2), with data on DNA, on the protein encoded, and where the gene is implicated

Vaccinia-Related Kinase-3

VRK3 is the most divergent member of the VRK family. It has no kinase activity due to several substitutions in key residues within its catalytic domain. VRK3 is mostly located within the nucleus and appears to play a scaffold role, where it downregulates MAPK signaling and reduces the level of p-ERK by recruiting the VHR phosphatasePeer Reviewe

Small cetacean distribution in North Atlantic Iberian Peninsula waters 2007-2019

34th European Cetacean Society Conference, O Grove, 16-20 April 2023Information on cetacean distribution is needed at a range of scales, such as European, national, subregional or regional level. Providing detailed information at larger scales, with the highest possible spatial resolution, is essential to adequately assess and evaluate the impacts of human activities at the population or subpopulation level, as required by several legal instruments and international agreements (e.g., OSPAR or ASCOBANS). In this study, we modelled the distribution and relative abundance of common dolphin (Delphinus delphis), bottlenose dolphin (Tursiops truncatus), and pilot whale (Globicephala melas) in continental shelf waters of the Spanish North Atlantic waters, using a time series of 13 years of sightings collected on the PELACUS multipurpose survey in spring months by means of Distance Sampling methodology. Species distribution models were fitted using geographical and biological explanatory variables. The more than 20,000 km of effort, regularly distributed over the study area throughout the time series, provided more than 400 sightings of the species of interest. The three species showed interannual variability in distribution and relative abundance. These annual differences might reflect changes in their movement patterns due to the different timing of oceanographic and biological processes between years, as shown by the models and the variables analysed. The results prove the relevance of the continental shelf in southern Galicia (the Rias Baixas) as an area of importance for these species. The maps produced have several applications, including the identification of relevant areas for these species and, when combined with other data (e.g., fishing effort, underwater noise), quantitative risk analysis to different anthropogenic activitiesN

Deep ocean drivers better explain habitat preferences of sperm whales Physeter macrocephalus than beaked whales in the Bay of Biscay

International audienceAbstract Species Distribution Models are commonly used with surface dynamic environmental variables as proxies for prey distribution to characterise marine top predator habitats. For oceanic species that spend lot of time at depth, surface variables might not be relevant to predict deep-dwelling prey distributions. We hypothesised that descriptors of deep-water layers would better predict the deep-diving cetacean distributions than surface variables. We combined static variables and dynamic variables integrated over different depth classes of the water column into Generalised Additive Models to predict the distribution of sperm whales Physeter macrocephalus and beaked whales Ziphiidae in the Bay of Biscay, eastern North Atlantic. We identified which variables best predicted their distribution. Although the highest densities of both taxa were predicted near the continental slope and canyons, the most important variables for beaked whales appeared to be static variables and surface to subsurface dynamic variables, while for sperm whales only surface and deep-water variables were selected. This could suggest differences in foraging strategies and in the prey targeted between the two taxa. Increasing the use of variables describing the deep-water layers would provide a better understanding of the oceanic species distribution and better assist in the planning of human activities in these habitats

Where, when and why: modelling the distribution and habitat of deep-diving cetaceans incorporating variables depicting the deep oceanic layers

The use of Species Distribution Models (SDMs) has increased considerably in recent decades, notably for conservation purposes. SDMs are used particularly to characterise and predict marine top predator distributions thanks to the use of surface dynamic environmental variables (easily accessible and available at various spatial and temporal scales) as proxies for prey distribution. For oceanic species that spend most of their time in depth waters like deep-diving cetaceans (here beaked whales and sperm whales), the use of surface variables may limit the ability to correctly infer their habitats through SDMs. We combine, static variables that characterise the topography of the bottom water and dynamic variables integrated over different depth classes that characterise the water column into Generalised Additive Models to model the distribution of deep-diving cetaceans in the Bay of Biscay and to identify which variables are the most important for each species. We obtained relationships with the environment that allow predicting the highest densities of beaked whales and sperm whales near the continental slope, near canyons and seamounts and in the abyssal plain of the Bay of Biscay. We also identified different responses between beaked whales, for which surface, subsurface and static variables were selected as the most important variables, and sperm whales. For the latter only surface and depth variables were selected, which could suggest differences in foraging strategies and in the prey targeted between these species. The continuous development of ocean models and the availability of depth variables, allows as we have shown, the improvement of the tools available for the planning of human activities, especially for species that would be closely linked to processes taking place in deep waters, such as top predators