Glukokortikoidok és magatartási rendellenességek: agresszió, szorongás, és depresszió integrált vizsgálata = Glucocorticoids and behavioural disorders: a study integrating effects on aggression, anxiety and depression

Összehasonlító módon leírtuk az abnormális és normális agresszivitás idegrendszeri hátterét. Kidolgoztuk a stressz által indukált szorongásnak egy új modelljét, és leírtuk ennek idegrendszeri hátterét. Vizsgáltuk a depresszió stresszfüggését, és ennek idegrendszeri hátterét. Mindhárom viselkedési modell esetében (glukokotikoid-függő abnormális agresszió modell, stressz által kiváltott szociális elkerülés modell, szociális alárendeltség által kiváltott depresszió modell) tisztáztuk a glukokortikoidok szerepét. Farmakológiai kísérleteinkben új, potenciális gyógyszercélpontokat azonosítottunk (az NK1 receptort az abnoprmális agresszió esetében, illetve a CB1 receptort a stressz által kiváltott szorongás esetében). Megfigyeléseket tettünk a három magatartási zavar integrált szabályozására vonatkozólag. A projekt keretében végzett vizsgálatokból eddig 22 publikáció született, amelyek összesített impakt faktora megközelíti a 80-at. Az eredményekből még további 4-5 publikáció írását tervezzük. Az eltelt rövid idő alatt (a publikációk jelentős része 2007-ben illetve 2008-ban született) a projekt keretében írt publikációkra több mint 100-szor hivatkoztak. | We compared the neural background of normal and abnormal aggression in a model recently developed by us. We developed a new model of stress-induced anxiety, and characterized its neural background. The stress- dependence of depression symptoms was studied in a model involving chronic social submission. The role of glucocorticoids was clarified in all three models (i.e. the glucocorticoid-dependent abnormal aggression model, the stress-induced social avoidance model, and the submission-induced depression model). New pharmacological targets were identified for abnormal aggression and stress-induced anxiety (the NK1 receptor and the cannabinoid CB1 receptor, respectively). We also studied the integrated control of aggression, anxiety and depression. The project lead to 22 publications so far, the cumulative impact factor of which is close to 80. We plan to write 4-5 publications in addition. In the short time elapsed, the above mentioned 22 publications were cited more than 100 times. We mention that many of the publications were written in 2007 and 2008

Cannabinoidok szerepe a traumák által előidézett viselkedési zavarok kialakulásában = The role of cannabinoids in the development of trauma-induced behavioral deficits

A projekt fontos felismerése, hogy a traumák által előidézett poszt-traumás stressz zavar-szerű viselkedési zavarok neuronális háttere erősen függ a traumatikus élmény jellegétől, és attól a kihívástól, amelyet a kísérleti szituáció jelent. Sőt, a trauma által előidézett idegrendszeri változásoknak van egy olyan időbeli fejlődése, amely a viselkedés szintjén nem ismerhető fel. Ez a komplexitás tükörképe a humán zavar komplexitásának, és magyarázatul szolgálhat a zavar kezelésének nehézségeire. Eredményeink arra is rámutatnak, hogy a zavar laboratóriumi tanulmányozása komplex megközelítést igényel; a szokványosan alkalmazott kétnapos kondicionált félelem teszt nem alkalmas a traumák által előidézett viselkedési zavarok mechanizmusainak megértésére. Eredményeink szerint a cannabinoidok szerepét a viselkedés szabályozásában a ""coping"" stratégiákkal összefüggésben érthetjük meg. A fokozott anandamid és esetleg 2-AG jelátvitel az aktív coping stratégiákat erősíti. Azok az alapvető viselkedési stratégiák, amelyek alapján az egyed megválaszolja a környezeti kihívásokat (vagyis a coping), fontos szerepet játszanak a pszichiátriai zavarok kialakulásában, és az aktív coping stratégiák erősítését konkrét terápiás célként jelölték meg több pszichiátriai zavar esetében. Így az endocannabinoid jelátvitel fokozása terápiás opcióként jelenik meg olyan pszichiátriai zavaroknál, amelyeknél a coping stratégiák fontos szerepet játszanak, többek között a poszt-traumás stressz zavar esetében is. | Our studies revealed that neural changes underlying trauma-induced post-traumatic stress disorder-like behavioral deficits depend on the nature of the traumatic experience and the challenge subjects are exposed to during behavioral testing. Moreover, neural changes have a temporal evolution that is not reflected at behavioral level. This complexity mirrors the complexity of the human disorder and may explain why the treatment of this disorder is so difficult. Our findings also show that this field needs a complex, multidimensional approach; the frequently used 2-day long conditioned fear test is insufficient to understand the mechanisms of trauma-induced behavioral deficits. As it regards the role of cannabinoid signaling in trauma-induced behavioral deficits, we suggest that this role can be best described in terms of coping styles. Enhanced anandamide (and possibly 2-AG) signaling increases the predilection of animals to adopt an active coping style. Basic alternative strategies by which individuals respond to environmental challenges (i.e. coping styles) have wide-ranging health implications from immunity to psychopathology, and active coping has been indicated as a therapeutic goal for psychological interventions in various disorders. As such, the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders that are characterized changes in coping strategies e.g. in post-traumatic stress disorder

The effects anandamide signaling in the prelimbic cortex and basolateral amygdala on coping with environmental stimuli in rats.

RATIONALE: Several lines of recent evidence suggest that endocannabinoids affect behavior by influencing the general patterns of challenge responding. OBJECTIVES: Here, we investigated the brain mechanisms underlying this phenomenon in rats. METHODS: The anandamide hydrolysis inhibitor URB597 was condensed into the tip of stainless steel cannulae, which were chronically implanted slightly above the prelimbic cortex (PRL) or the basolateral amygdala (BLA), two important regions of coping and endocannabinoid action. Thereafter, we investigated behavioral responsiveness to ambient light level in the elevated plus-maze and conditioned fear tests. RESULTS: URB597 concentration was ~30 mug/mg protein in target areas; local brain anandamide levels increased threefold, without significant changes in 2-arachidonoylglycerol. High levels of illumination halved the time spent by controls in the open arms of the plus-maze. No similar decrease was observed in rats with URB597 implants in the PRL. High light decreased conditioned fear by 30 % in controls, but not in rats with prelimbic URB597 implants. Unresponsiveness to environmental challenges was not attributable to the anxiolytic effects of anandamide enhancement, as implants induced paradoxical anxiogenic-like effects under low light, which could be explained by effects on stimulus responsiveness rather than by effects on anxiety. URB597 implants targeting the BLA did not affect stimulus responsiveness. CONCLUSIONS: Our findings show that elevated prelimbic anandamide signaling leads to less environment-dependent (more autonomous) behavioral responses to challenges, which is an attribute of active coping styles. These findings are discussed in light of two emerging concepts of endocannabinoid roles, particularly "emotional homeostasis" and "active coping.

Harvey: A Greybox Fuzzer for Smart Contracts

We present Harvey, an industrial greybox fuzzer for smart contracts, which are programs managing accounts on a blockchain. Greybox fuzzing is a lightweight test-generation approach that effectively detects bugs and security vulnerabilities. However, greybox fuzzers randomly mutate program inputs to exercise new paths; this makes it challenging to cover code that is guarded by narrow checks, which are satisfied by no more than a few input values. Moreover, most real-world smart contracts transition through many different states during their lifetime, e.g., for every bid in an auction. To explore these states and thereby detect deep vulnerabilities, a greybox fuzzer would need to generate sequences of contract transactions, e.g., by creating bids from multiple users, while at the same time keeping the search space and test suite tractable. In this experience paper, we explain how Harvey alleviates both challenges with two key fuzzing techniques and distill the main lessons learned. First, Harvey extends standard greybox fuzzing with a method for predicting new inputs that are more likely to cover new paths or reveal vulnerabilities in smart contracts. Second, it fuzzes transaction sequences in a targeted and demand-driven way. We have evaluated our approach on 27 real-world contracts. Our experiments show that the underlying techniques significantly increase Harvey's effectiveness in achieving high coverage and detecting vulnerabilities, in most cases orders-of-magnitude faster; they also reveal new insights about contract code.Comment: arXiv admin note: substantial text overlap with arXiv:1807.0787

Median raphe region stimulation alone generates remote, but not recent fear memory traces

The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex

The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics

Background: The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD; NCT03036150) trial was designed to assess the effect of the sodium–glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin on kidney and cardiovascular events in participants with CKD with and without type 2 diabetes (T2D). This analysis reports the baseline characteristics of those recruited, comparing them with those enrolled in other trials. Methods: In DAPA-CKD, 4304 participants with a urinary albumin:creatinine ratio (UACR) ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 were randomized to dapagliflozin 10 mg once daily or placebo. Mean eGFR was 43.1 mL/min/1.73 m2 and median UACR was 949 mg/g (108 mg/mmol). Results: Overall, 2906 participants (68%) had a diagnosis of T2D and of these, 396 had CKD ascribed to a cause other than diabetes. The most common causes of CKD after diabetes (n = 2510) were ischaemic/hypertensive nephropathy (n = 687) and chronic glomerulonephritis (n = 695), of which immunoglobulin A nephropathy (n = 270) was the most common. A total of 4174 participants (97%) were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 1882 (43.7%) diuretics, 229 (5.3%) mineralocorticoid receptor antagonists and 122 (2.8%) glucagon-like peptide 1 receptor agonists. In contrast to the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), the DAPA-CKD trial enrolled participants with CKD due to diabetes and to causes other than diabetes. The mean eGFR of participants in the DAPA-CKD trial was 13.1 mL/min/1.73 m2 lower than in CREDENCE, similar to that in the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial and the Study Of diabetic Nephropathy with AtRasentan (SONAR). Conclusions: Participants with a wide range of underlying kidney diseases receiving renin–angiotensin system blocking therapy have been enrolled in the DAPA-CKD trial. The trial will examine the efficacy and safety of dapagliflozin in participants with CKD Stages 2–4 and increased albuminuria, with and without T2D

THE POLICE OFFICER’S SOLUTION TO MORAL DILEMMAS AND DILEMMAS CONNECTED TO THE ENFORCEMENT OF LAW

The procedural justice theory states that if legal authorities show respect to moral values and laws, citizens will collaborate with them and will better obey the law. Starting from this idea, the study analyses – based on an applied questionnaire – the way in which police officers solve moral problems and choose between moral and legal, between legal and illegal. The results show that police officers are not trained to understood moral and legal problems or to make the right choice: 40.8% of the police officers would sacrify five persons to save one; 68.3% did not recognize that they did not know a person who even did not exist; 26.3% would condemn a person who committed a crime, while 45.3% of them would condemn persons who, possibly, have moral responsibility for that crime; less than 12% did not try to intervene when being fined for the non-compliance to the traffic law, 83.1% would choose to pay the fine and only 59.5% understood the sense of the traffic law. These data put under question the way of selection and training of the police officer