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The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity
(2017)
Hohmann, Stephan ; Angioni, Carlo ; Tunaru, Sorin ; Lee, Seungkyu ; Woolf, Clifford J. ; Offermanns, Stefan ; Geisslinger, Gerd ; Scholich, Klaus ; Sisignano, Marco
Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.
Identification of unique cardiolipin and monolysocardiolipin species in Acinetobacter baumannii
(2017)
Acidic glycerophospholipids play an important role in determining the resistance of Gram-negative bacteria to stress conditions and antibiotics. Acinetobacter baumannii, an opportunistic human pathogen which is responsible for an increasing number of nosocomial infections, exhibits broad antibiotic resistances. Here lipids of A. baumannii have been analyzed by combined MALDI-TOF/MS and TLC analyses; in addition GC-MS analyses of fatty acid methyl esters released by methanolysis of membrane phospholipids have been performed. The main glycerophospholipids are phosphatidylethanolamine, phosphatidylglycerol, acyl-phosphatidylglycerol and cardiolipin together with monolysocardiolipin, a lysophospholipid only rarely detected in bacterial membranes. The major acyl chains in the phospholipids are C16:0 and C18:1, plus minor amounts of short chain fatty acids. The structures of the cardiolipin and monolysocardiolipin have been elucidated by post source decay mass spectrometry analysis. A large variety of cardiolipin and monolysocardiolipin species were found in A. baumannii. Similar lysocardiolipin levels were found in the two clinical strains A. baumannii ATCC19606T and AYE whereas in the nonpathogenic strain Acinetobacter baylyi ADP1 lysocardiolipin levels were highly reduced.
Different insurance activities exhibit different levels of persistence of shocks and volatility. For example, life insurance is typically more persistent but less volatile than non-life insurance. We examine how diversification among life, non-life insurance, and active reinsurance business affects an insurer's contribution and exposure to the risk of other companies. Our model shows that a counterparty's credit risk exposure to an insurance group substantially depends on the relative proportion of the insurance group's life and non-life business. The empirical analysis confirms this finding with respect to several measures for spillover risk. The optimal proportion of life business that minimizes spillover risk decreases with leverage of the insurance group, and increases with active reinsurance business.
Pérez-Palma, Eduardo ; Helbig, Ingo ; Klein, Karl Martin ; Anttila, Verneri ; Horn, Heiko ; Maria Reinthaler, Eva ; Gormley, Padhraig ; Ganna, Andrea ; Byrnes, Andrea ; Pernhorst, Katharina ; Toliat, Mohammad Reza ; Saarentaus, Elmo ; Howrigan, Daniel P. ; Hoffman, Per ; Miquel, Juan Francisco ; De Ferrari, Giancarlo ; Nürnberg, Peter ; Lerche, Holger ; Zimprich, Fritz ; Neubauer, Bern A. ; Becker, Albert J. ; Rosenow, Felix ; Perucca, Emilio ; Zara, Federico ; Weber, Yvonne G. ; Lal, Dennis
Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement “hotspot” loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.
Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.
Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00×10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22×10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78×10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.
Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.
Why do humans cooperate and often punish norm violations of others? In the present study, we sought to investigate the genetic bases of altruistic punishment (AP), which refers to the costly punishment of norm violations with potential benefit for other individuals. Recent evidence suggests that norm violations and unfairness are indexed by the feedback-related negativity (FRN), an anterior cingulate cortex (ACC) generated neural response to expectancy violations. Given evidence on the role of serotonin and dopamine in AP as well as in FRN-generation, we explored the impact of genetic variation of serotonin and dopamine function on FRN and AP behavior in response to unfair vs. fair monetary offers in a Dictator Game (DG) with punishment option. In a sample of 45 healthy participants we observed larger FRN amplitudes to unfair DG assignments both for 7-repeat allele carriers of the dopamine D4 receptor (DRD4) exon III polymorphism and for l/l-genotype carriers of the serotonin transporter gene-linked polymorphic region (5-HTTLRP). Moreover, 5-HTTLPR l/l-genotype carriers punished unfair offers more strongly. These findings support the role of serotonin and dopamine in AP, potentially via their influence on neural mechanisms implicated in the monitoring of expectancy violations and their relation to impulsive and punishment behavior.
Telemonitoring devices can be used to screen consumers' characteristics and mitigate information asymmetries that lead to adverse selection in insurance markets. However, some consumers value their privacy and dislike sharing private information with insurers. In the second-best efficient Wilson-Miyazaki-Spence framework, we allow for consumers to reveal their risk type for an individual subjective cost and show analytically how this affects insurance market equilibria as well as utilitarian social welfare. Our analysis shows that the choice of information disclosure with respect to revelation of their risk type can substitute deductibles for consumers whose transparency aversion is sufficiently low. This can lead to a Pareto improvement of social welfare and a Pareto efficient market allocation. However, if all consumers are offered cross-subsidizing contracts, the introduction of a transparency contract decreases or even eliminates cross-subsidies. Given the prior existence of a WMS equilibrium, utility is shifted from individuals who do not reveal their private information to those who choose to reveal. Our analysis provides a theoretical foundation for the discussion on consumer protection in the context of digitalization. It shows that new technologies bring new ways to challenge crosssubsidization in insurance markets and stresses the negative externalities that digitalization has on consumers who are not willing to take part in this development.
This paper investigates the effects of a rise in interest rate and lapse risk of endowment life insurance policies on the liquidity and solvency of life insurers. We model the book and market value balance sheet of an average German life insurer, subject to both GAAP and Solvency II regulation, featuring an existing back book of policies and an existing asset allocation calibrated by historical data. The balance sheet is then projected forward under stochastic financial markets. Lapse rates are modeled stochastically and depend on the granted guaranteed rate of return and prevailing level of interest rates. Our results suggest that in the case of a sharp increase in interest rates, policyholders sharply increase lapses and the solvency position of the insurer deteriorates in the short-run. This result is particularly driven by the interaction between a reduction in the market value of assets, large guarantees for existing policies, and a very slow adjustment of asset returns to interest rates. A sharp or gradual rise in interest rates is associated with substantial and persistent liquidity needs, that are particularly driven by lapse rates.
Under Solvency II, corporate governance requirements are a complementary, but nonetheless essential, element to build a sound regulatory framework for insurance undertakings, also to address risks not specifically mitigated by the sole solvency capital requirements. After recalling the provisions of the Second Pillar concerning the system of governance, the paper highlights the emerging regulatory trends in the corporate governance of insurance firms. Among others things, it signals the exceptional extension of the duties and responsibilities assigned to the board of directors, far beyond the traditional role of both monitoring the chief executive officer, and assessing the overall direction and strategy of the business. However, a better risk governance is not necessarily built on narrow rule-based approaches to corporate governance.
A tontine provides a mortality driven, age-increasing payout structure through the pooling of mortality. Because a tontine does not entail any guarantees, the payout structure of a tontine is determined by the pooling of individual characteristics of tontinists. Therefore, the surrender decision of single tontinists directly affects the remaining members' payouts. Nevertheless, the opportunity to surrender is crucial to the success of a tontine from a regulatory as well as a policyholder perspective. Therefore, this paper derives the fair surrender value of a tontine, first on the basis of expected values, and then incorporates the increasing payout volatility to determine an equitable surrender value. Results show that the surrender decision requires a discount on the fair surrender value as security for the remaining members. The discount intensifies in decreasing tontine size and increasing risk aversion. However, tontinists are less willing to surrender for decreasing tontine size and increasing risk aversion, creating a natural protection against tontine runs stemming from short-term liquidity shocks. Furthermore we argue that a surrender decision based on private information requires a discount on the fair surrender value as well.
Under Solvency II, corporate governance requirements are a complementary, but nonetheless essential, element to build a sound regulatory framework for insurance undertakings, also to address risks not specifically mitigated by the sole solvency capital requirements. After recalling the provisions of the second pillar concerning the system of governance, the paper is devoted to highlight the emerging regulatory trends in the corporate governance of insurance firms. Among others, it signals the exceptional extension of the duties and responsibilities assigned to the Board of directors, far beyond the traditional role of both monitoring the chief executive officer, and assessing the overall direction and strategy of the business. However, a better risk governance is not necessarily built on narrow rule-based approaches to corporate governance.