Protectors or Traitors: The Roles of PON2 and PON3 in Atherosclerosis and Cancer

Cancer and atherosclerosis are major causes of death in western societies. Deregulated cell death is common to both diseases, with significant contribution of inflammatory processes and oxidative stress. These two form a vicious cycle and regulate cell death pathways in either direction. This raises interest in antioxidative systems. The human enzymes paraoxonase-2 (PON2) and PON3 are intracellular enzymes with established antioxidative effects and protective functions against atherosclerosis. Underlying molecular mechanisms, however, remained elusive until recently. Novel findings revealed that both enzymes locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress. As a result, ROS-triggered mitochondrial apoptosis and cell death are reduced. From a cardiovascular standpoint, this is beneficial given that enhanced loss of vascular cells and macrophage death forms the basis for atherosclerotic plaque development. However, the same function has now been shown to raise chemotherapeutic resistance in several cancer cells. Intriguingly, PON2 as well as PON3 are frequently found upregulated in tumor samples. Here we review studies reporting PON2/PON3 deregulations in cancer, summarize most recent findings on their anti-oxidative and antiapoptotic mechanisms, and discuss how this could be used in putative future therapies to target atherosclerosis and cancer

Cannabidiol modulates phosphorylated rpS6 signalling in a zebrafish model of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare disease caused by mutations in the TSC1 or TSC2 genes and is characterized by widespread tumour growth, intractable epilepsy, cognitive deficits and autistic behaviour. CBD has been reported to decrease seizures and inhibit tumour cell progression, therefore we sought to determine the influence of CBD on TSC pathology in zebrafish carrying a nonsense mutation in the tsc2 gene. CBD treatment from 6 to 7 days post-fertilization (dpf) induced significant anxiolytic actions without causing sedation. Furthermore, CBD treatment from 3 dpf had no impact on tsc2-/- larvae motility nor their survival. CBD treatment did, however, reduce the number of phosphorylated rpS6 positive cells, and their cross-sectional cell size. This suggests a CBD mediated suppression of mechanistic target of rapamycin (mTOR) activity in the tsc2-/- larval brain. Taken together, these data suggest that CBD selectively modulates levels of phosphorylated rpS6 in the brain and additionally provides an anxiolytic effect. This is pertinent given the alterations in mTOR signalling in experimental models of TSC. Additional work is necessary to identify upstream signal modulation and to further justify the use of CBD as a possible therapeutic strategy to manage TSC

Job Insecurity and Future Labour Market Outcomes

This paper uses longitudinal survey data to test the degree to which measures of job insecurity are correlated with changes in labour market status. Three major findings are reported. First, the perceived probability of job loss is only weakly related to both exogenous job separations and subsequent transitions to unemployment and inactivity. Second, while fears of job loss tend to persist across time and job spells, they do so at a highly diminishing rate, suggesting that the impacts on other outcomes (such as psychological well-being) may be quite limited. Third, quit intentions are strongly correlated with both voluntary separations and transitions to alternative employment. The desire to quit, however, does not appear to diminish greatly across successive employment spells

Natural Selection Affects Multiple Aspects of Genetic Variation at Putatively Neutral Sites across the Human Genome

A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations

The high-resolution map of Oxia Planum, Mars; the landing site of the ExoMars Rosalind Franklin rover mission

This 1:30,000 scale geological map describes Oxia Planum, Mars, the landing site for the ExoMars Rosalind Franklin rover mission. The map represents our current understanding of bedrock units and their relationships prior to Rosalind Franklin’s exploration of this location. The map details 15 bedrock units organised into 6 groups and 7 textural and surficial units. The bedrock units were identified using visible and near-infrared remote sensing datasets. The objectives of this map are (i) to identify where the most astrobiologically relevant rocks are likely to be found, (ii) to show where hypotheses about their geological context (within Oxia Planum and in the wider geological history of Mars) can be tested, (iii) to inform both the long-term (hundreds of metres to ∼1 km) and the short-term (tens of metres) activity planning for rover exploration, and (iv) to allow the samples analysed by the rover to be interpreted within their regional geological context.The ExoMars Rosalind Franklin Mission is a partnership between ESA and NASA. The Rosalind Franklin Rover has eight instruments in its ‘Pasteur’ Payload, with Principal Investigators from seven countries all of whom we would like to thank for there support of this project. We would like to acknowledge the following funding bodies, people and institutions supporting the lead authors of this work. We thank the UK Space Agency (UK SA) for funding P. Fawdon, on grants; ST/W002736/1, ST/L00643X/1 and ST/R001413/1, MRB on grants; ST/T002913/1, ST/V001965/1, ST/R001383/1, ST/R001413/1, P. Grindrod on grants; ST/L006456/1, ST/R002355/1, ST/V002678/1 and J. Davis on grants ST/K502388/1, ST/R002355/1, ST/V002678/1 through the ongoing Aurora space exploration programme. C. Orgel was supported by the ESA Research Fellowship Program. Alessandro Frigeri: was funded by the Italian Space Agency (ASI) grant ASI-INAF number 2017-412-H.0 (ExoMars/Ma_MISS) and D. Loizeau was funded by the H2020-COMPET-2015 programme (grant 687302), C. Quantin-Nataf was supported by the French space agency CNES, I. Torres was supported by an ESA Young Graduate Traineeship, A. Nass was supported by Helmholtz Metadata Projects (#ZT-I-PF-3-008). We thank NASA and the HiRISE camera team for data collection support throughout the ExoMars landing site selection and charectorisation process. The USGS for the HiRISE DTM data and maintaining the ISIS and SOCET SET DEM workflows. The authors wish to thank the CaSSIS spacecraft and instrument engineering teams. CaSSIS is a project of the University of Bern and funded through the Swiss Space Office via ESA's PRODEX programme. The instrument hardware development was also supported by the Italian Space Agency (ASI) (ASI-INAF agreement no. I/2020-17-HH.0), INAF/Astronomical Observatory of Padova, and the Space Research Center (CBK) in Warsaw. Support from SGF (Budapest), the University of Arizona (Lunar and Planetary Lab.) and NASA are also gratefully acknowledged. Operations support from the UK Space Agency under grant ST/R003025/1 is also acknowledged. This research has made use of the USGS Integrated Software for Imagers and Spectrometers (ISIS) Technical support for setup of the Multi-Mission Geographic Information System for concurrent team mapping was provided by F. Calef (III) and T. Soliman at NASA JPL and S. de Witte at ESA-ESTEC.This work was supported by Agencia Estatal de Investigación [grant number ID2019-107442RB-C32, MDM-2017-0737]; Agenzia Spaziale Italiana [grant number 2017-412-H.0]; Bundesministerium für Wirtschaft und Technologie [grant number 50 QX 2002]; Centre National de la Recherche Scientifique; Centre National d’Etudes Spatiales; Euskal Herriko Unibertsitatea [grant number PES21/88]; Istituto Nazionale di Astrofisica [grant number I/ 060/10/0]; Ministerio de Economía y Competitividad [grant number PID2019-104205GB-C21]; Ministry of Science and Higher Education of the Russian Federation [grant number AAAA-A18-118012290370-6]; National Aeronautics and Space Administration [grant number NNX15AH46G]; Norges Forskningsråd [grant number 223272]; European Union's Horizon 2020 (H2020-COMPET-2015) [grant number 687302 (PTAL)]; Sofja Kovalevskaja Award of the Alexander von Humboldt Foundation; MINECO [grant number PID2019-107442RB-C32]; The Open University [grant number Space Strategic Research Area]; European Union's Horizon 2020 research and innovation programme [grant number 776276]; H2020-COMPET-2015 [grant number 687302]; The Research Council of Norway, Centres of Excellence funding scheme [grant number 223272]; Helmholtz Metadata Projects [grant number ZT-I-PF-3-008]; The Research Council of Norway [grant number 223272]; Swiss Space Office via ESA's PRODEX programme; Ines Torres was supported by an ESA Young Graduate Traineeship; Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung [grant number 200021_197293]; Science and Technology Facilities Council [grant number 1967420]; UK Space Agency [grant number ST/K502388/1, ST/R002355/1, ST/V002678/1]. The ExoMars Rosalind Franklin Mission is a partnership between ESA and NASA. The Rosalind Franklin Rover has eight instruments in its ‘Pasteur’ Payload, with Principal Investigators from seven countries all of whom we would like to thank for there support of this project. We would like to acknowledge the following funding bodies, people and institutions supporting the lead authors of this work. We thank the UK Space Agency (UK SA) for funding P. Fawdon, on grants; ST/W002736/1, ST/L00643X/1 and ST/R001413/1, MRB on grants; ST/T002913/1, ST/V001965/1, ST/R001383/1, ST/R001413/1, P. Grindrod on grants; ST/L006456/1, ST/R002355/1, ST/V002678/1 and J. Davis on grants ST/K502388/1, ST/R002355/1, ST/V002678/1 through the ongoing Aurora space exploration programme. C. Orgel was supported by the ESA Research Fellowship Program. Alessandro Frigeri: was funded by the Italian Space Agency (ASI) grant ASI-INAF number 2017-412-H.0 (ExoMars/Ma_MISS) and D. Loizeau was funded by the H2020-COMPET-2015 programme (grant 687302), C. Quantin-Nataf was supported by the French space agency CNES, I. Torres was supported by an ESA Young Graduate Traineeship, A. Nass was supported by Helmholtz Metadata Projects (#ZT-I-PF-3-008). We thank NASA and the HiRISE camera team for data collection support throughout the ExoMars landing site selection and charectorisation process. The USGS for the HiRISE DTM data and maintaining the ISIS and SOCET SET DEM workflows. The authors wish to thank the CaSSIS spacecraft and instrument engineering teams. CaSSIS is a project of the University of Bern and funded through the Swiss Space Office via ESA's PRODEX programme. The instrument hardware development was also supported by the Italian Space Agency (ASI) (ASI-INAF agreement no. I/2020-17-HH.0), INAF/Astronomical Observatory of Padova, and the Space Research Center (CBK) in Warsaw. Support from SGF (Budapest), the University of Arizona (Lunar and Planetary Lab.) and NASA are also gratefully acknowledged. Operations support from the UK Space Agency under grant ST/R003025/1 is also acknowledged. This research has made use of the USGS Integrated Software for Imagers and Spectrometers (ISIS) Technical support for setup of the Multi-Mission Geographic Information System for concurrent team mapping was provided by F. Calef (III) and T. Soliman at NASA JPL and S. de Witte at ESA-ESTEC.Peer reviewe

The high-resolution map of Oxia Planum, Mars; the landing site of the ExoMars Rosalind Franklin rover mission

This 1:30,000 scale geological map describes Oxia Planum, Mars, the landing site for the ExoMars Rosalind Franklin rover mission. The map represents our current understanding of bedrock units and their relationships prior to Rosalind Franklin’s exploration of this location. The map details 15 bedrock units organised into 6 groups and 7 textural and surficial units. The bedrock units were identified using visible and near-infrared remote sensing datasets. The objectives of this map are (i) to identify where the most astrobiologically relevant rocks are likely to be found, (ii) to show where hypotheses about their geological context (within Oxia Planum and in the wider geological history of Mars) can be tested, (iii) to inform both the long-term (hundreds of metres to ∼1 km) and the short-term (tens of metres) activity planning for rover exploration, and (iv) to allow the samples analysed by the rover to be interpreted within their regional geological context

Enhancing Participation in Probability-Based Online Panels: Two Incentive Experiments and Their Effects on Response and Panel Recruitment

This article investigates how mail-based online panel recruitment can be facilitated through incentives. The analysis relies on two incentive experiments and their effects on panel recruitment, and the intermediate participation in the recruitment survey. The experiments were implemented in the context of the German Emigration and Remigration Panel Study and encompass two samples of randomly sampled persons. Tested incentives include a conditional lottery, conditional monetary incentives, and the combination of unconditional money-in-hand with conditional monetary incentives. For an encompassing evaluation of the link between incentives and panel recruitment, the article further assesses the incentives’ implications for demographic composition and panel recruitment unit costs. Multivariate analysis indicates that low combined incentives (€5/€5) or, where unconditional disbursement is unfeasible, high conditional incentives (€20) are most effective in enhancing panel participation. In terms of demographic bias, low combined incentives (€5/€5) and €10 conditional incentives are the favored options. The budget options from the perspective of panel recruitment include the lottery and the €10 conditional incentive which break-even at net sample sizes of 1000

A bacterial secreted translocator hijacks riboregulators to control type III secretion in response to host cell contact.

Numerous Gram-negative pathogens use a Type III Secretion System (T3SS) to promote virulence by injecting effector proteins into targeted host cells, which subvert host cell processes. Expression of T3SS and the effectors is triggered upon host cell contact, but the underlying mechanism is poorly understood. Here, we report a novel strategy of Yersinia pseudotuberculosis in which this pathogen uses a secreted T3SS translocator protein (YopD) to control global RNA regulators. Secretion of the YopD translocator upon host cell contact increases the ratio of post-transcriptional regulator CsrA to its antagonistic small RNAs CsrB and CsrC and reduces the degradosome components PNPase and RNase E levels. This substantially elevates the amount of the common transcriptional activator (LcrF) of T3SS/Yop effector genes and triggers the synthesis of associated virulence-relevant traits. The observed hijacking of global riboregulators allows the pathogen to coordinate virulence factor expression and also readjusts its physiological response upon host cell contact

Glutamic acid in withdrawal and weaning in patients classified according to Cloninger's and Lesch's typologies

Aims: Though glutamic acid is well known as a working excitatory in the CNS, its impact on the modulation of alcohol withdrawal symptoms and withdrawal fits are not yet clear. The study has been undertaken to examine the levels of glutamic acid in chronic alcohol-dependent patients at different stages of alcohol withdrawal and weaning and to examine any existence of any differences according to Cloninger's and Lesch's typologies. Patients and methods: One hundred and fifty-nine alcohol-dependent patients were assessed according to Cloninger's and Lesch's typologies and related to abstinence duration, age, and gender. Blood samples were taken for mean corpuscular volume (MCV), gamma-glutamyltransferase (GGT) and glutamic acid, in order to find primarily any differences in glutamic acid according to the typologies, age, abstinence duration, and liver damage. Results: There was no significant association between Cloninger's and Lesch's typologies. Cloninger's types 1 and 2 had an equal distribution of GGT and duration of abstinence, while Lesch's type I had more patients with high GGT, and more patients who were sober for a maximum of 2 days. Unlike in Lesch's types, glutamic acid levels did not differ according to Cloninger's types, as significantly higher glutamic acid values were found in Lesch's types I and IV. Glutamic acid values did not differ significantly in different age groups. Conclusions: Our study findings of varying glutamic acid levels seen in Lesch's typology, higher in types I and IV than in types II and III, are of significant clinical value and can be interpreted differently, as in type I high levels of glutamic acid is seen as a kindling phenomenon, while in type IV elevated levels might be related to either compulsivity of frequent repetition of drinking or withdrawal