TrustedKad - Application of Trust Mechanisms to a Kademlia-Based Peer-to-Peer Network

Peer-to-Peer-Netzwerke (P2P) sind verteilte Systeme, die aus gleichberechtigten Knoten („Peers“) bestehen. Im Gegensatz zu klassischen Client-Server-Systemen gibt es in P2P-Netzwerken keine hierarchischen Ebenen oder zentrale Kontrolleinheiten: Alle Peers bieten gleichzeitig Dienste an und nutzen sie. Im vergangenen Jahrzehnt ist eine Vielzahl verschiedener P2P-Anwendungen entwickelt worden – Filesharing-Anwendungen wie BitTorrent und eMule und Kommunikations-Anwendungen wie Skype gehören zu den bekanntesten von ihnen. Forschungsarbeiten haben gezeigt, dass P2P-Netzwerke anfällig für verschiedene Arten von Angriffen sind. Bekannte Angriffe sind z.B. die Sybil- und die Eclipse-Attack. Die üblichen Gegenmaßnahmen gegen die Angriffe sind Replikation und das Verwenden von disjunkten Routing-Pfaden, um die Wahrscheinlichkeit zu reduzieren, während einer Routing- oder Storage-Operation mit bösartigen Knoten zu interagieren. Seit einiger Zeit wird die Anwendung von Vertrauensmechanismen auf P2P-Netzwerke untersucht. Existierende Arbeiten betrachten meist unstrukturierte P2P-Netzwerke – in realen Umgebungen überwiegen jedoch die strukturierten Netzwerke. Insbesondere Implementierungen des Kademlia-Algorithmus‘ sind weit verbreitet, da er von BitTorrent und eMule genutzt wird. Dennoch versucht keiner der vertrauensbasierten Ansätze, die strukturierte Netzwerke behandeln, speziell die Sicherheit von Kademlia zu verbessern. Aufgrund der Verbreitung von Kademlia wird TrustedKad vom Autor entwickelt, um die Sicherheit des Kademlia-Algorithmus‘ zu verbessern. In dieser Arbeit wird TrustedKad eingeführt und die Funktionsweise erläutert. TrustedKad bewertet das Verhalten von Knoten nach Routing- oder Storage-Operationen als entweder positiv oder negativ. Dafür definiert TrustedKad unter Berücksichtigung der Funktionsweise von Kademlia die Regeln, nach denen gut- und bösartiges Verhalten identifiziert wird. Basierend auf diesen Bewertungen werden Vertrauenswerte für Routing und Storage berechnet, um gutartige und bösartige Knoten zu erkennen. Jeder Knoten nutzt Schwellwerte für diese Vertrauenswerte, um zu entscheiden, welche Knoten er als vertrauenswürdig ansieht. Nicht vertrauenswürdige Knoten werden während der eigenen Operationen eines Knotens vermieden. Darüber hinaus nutzt TrustedKad zusätzliche Sicherheitsfunktionen, um die Sicherheit des Systems weiter zu erhöhen. Diese werden im Verlauf dieser Arbeit vorgestellt. Um TrustedKad zu evaluieren, wird es in einer Simulationsumgebung implementiert und analysiert. Die in dieser Arbeit präsentierten Ergebnisse zeigen, dass TrustedKad in der Lage ist, gutartige und bösartige Knoten zu unterscheiden. Es wehrt verschiedene Variationen von bekannten Angriffen ab und verbessert die Sicherheit von Kademlia-basierten Netzwerken deutlich.Peer-to-peer networks (P2P) are distributed systems that consist of equal nodes (“peers”). In contrast to classic client/server systems, there is no hierarchy or central entity: All peers offer services and use them at the same time. In the past decade, a multitude of different P2P applications has been developed – filesharing applications such as BitTorrent and eMule and communication applications such as Skype are among the most popular of them. Research has shown that P2P networks are vulnerable to different kinds of attacks. Known attacks include, e.g., the Sybil attack and the Eclipse attack. Traditional countermeasures against the attacks are replication and the usage of disjoint routing paths to reduce the probability of interacting with malicious nodes during a routing or storage operation. More recently, trust mechanisms have been proposed and analyzed for applicability to P2P networks. The existing related work mostly targets unstructured P2P networks – however, in real-world environments, the structured networks prevail. Especially implementations of the Kademlia algorithm are widely spread, as it is used by BitTorrent and eMule. Nevertheless, none of the trust-based approaches that aim at structured networks specifically attempts to enhance Kademlia’s security. Due to Kademlia’s prevalence, TrustedKad is particularly designed by the author to improve the security of the Kademlia algorithm. In this thesis, TrustedKad is introduced and its functioning is explained. TrustedKad rates the behavior of nodes after routing and storage operations as either positive or negative. To do so, it defines the rules by which inoffensive and malicious behavior is identified in dependence of the functioning of the Kademlia algorithm. Based on the ratings, routing and storage trust values are calculated to identify inoffensive and malicious nodes. Every node uses thresholds for these trust values to decide which nodes it regards as trustworthy. Non-trustworthy nodes are avoided during a node’s own operations. Furthermore, TrustedKad uses additional security features to further increase the security of the system. They are introduced in this thesis. In order to evaluate TrustedKad, it is implemented and analyzed in a simulation environment. The results presented in this thesis show that TrustedKad is able to distinguish inoffensive and malicious nodes. It counters miscellaneous variations of known attacks and improves the security of Kademlia-based networks considerably

Correlation from undiluted vitreous cytokines of untreated central retinal vein occlusion with spectral domain optical coherence tomography

Purpose: To correlate inflammatory and proangiogenic key cytokines from undiluted vitreous of treatment-naïve central retinal vein occlusion (CRVO) patients with SD-OCT parameters. Methods: Thirty-five patients (age 71.1 years, 24 phakic, 30 nonischemic) underwent intravitreal combination therapy, including a single-site 23-gauge core vitrectomy. Twenty-eight samples from patients with idiopathic, non-uveitis floaterectomy served as controls. Interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF-A) levels were correlated with the visual acuity (logMar), category of CRVO (ischemic or nonischemic) and morphologic parameters, such as central macular thickness-CMT, thickness of neurosensory retina-TNeuro, extent of serous retinal detachment-SRT and disintegrity of the IS/OS and others. Results: The mean IL-6 was 64.7pg/ml (SD ± 115.8), MCP-1 1015.7 ( ± 970.1), and VEGF-A 278.4 ( ± 512.8), which was significantly higher than the control IL-6 6.2 ± 3.4pg/ml (P=0.06), MCP-1 253.2 ± 73.5 (P<0.0000001) and VEGF-A 7.0 ± 4.9 (P<0.0006). All cytokines correlated highly with one another (correlation coefficient r=0.82 for IL-6 and MCP-1; r=0.68 for Il-6 and VEGF-A; r=0.64 for MCP-1 and VEGF-A). IL-6 correlated significantly with CMT, TRT, SRT, dIS/OS, and dELM. MCP-1 correlated significantly with SRT, dIS/OS, and dELM. VEGF-A correlated not with changes in SD-OCT, while it had a trend to be higher in the ischemic versus the nonischemic CRVO group (P=0.09). Conclusions: The inflammatory cytokines were more often correlated with morphologic changes assessed by SD-OCT, whereas VEGF-A did not correlate with CRVO-associated changes in SD-OCT. VEGF inhibition alone may not be sufficient in decreasing the inflammatory response in CRVO therapy

Изучение гидролитической устойчивости и растворимости стампирина

Представлены результаты исследования гидролитической устойчивости стампирина I (1-фенил-2,3-диметил-4-стеароиламино-5-пиразолона)-нового противовоспалительного средства в различных средах и условиях и его растворимости в некоторых органических растворителях. Показано, что наиболее подходящими условиями полного гидролиза I является кипячение его на воздушной бане в 25% растворе соляной кислоты в течение 45 минут. В водной и щелочной средах I является гидролитически устойчивым. Определена растворимость I в граммах на 100 мл раствора при 20° С весовым методом. Она равна 1,31 в этиловом спирте, 1,01 в изопропиловом спирте, 0,07 в диэтиловом эфире, 3,77 в бензоле, 0,79 в четыреххлористом углероде. В воде I практически не растворим

The long-term treatment of restless legs syndrome/Willis–Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group

AbstractA Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis–Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6months or longer presented at meetings over the past 2years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, “What is the efficacy of this treatment in patients with RLS/WED?” and “What is the safety of this treatment in patients with RLS/WED?”The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5years: gabapentin enacarbil, pramipexole, and ropinirole (1year); levodopa (2years); and rotigotine (5years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED.The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or α2δ calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient’s severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions

Role of Janus-Kinases in Major Depressive Disorder

Background/Aims: Major depressive disorder is a severe, common and often chronic disease with a significant mortality due to suicide. The pathogenesis of major depression is still unknown. It is assumed that a reduction of neurogenesis in the hippocampus plays an important role in the development of major depressive disorder. However, the mechanisms that control proliferation of neuronal stem cells in the hippocampus require definition. Here, we investigated the role of Janus-Kinase 3 (Jak-3) for stress-induced inhibition of neurogenesis and the induction of major depression symptoms in mice. Methods: Stress was induced by the application of glucocorticosterone. Brain sections were stained with phospho-specific antibodies and analysed by confocal microscopy to measure phosphorylation of Jak-3 specifically in the hippocampus. Jak-3 inhibitors and the antidepressant amitriptyline were applied to counteract stress. The effects of the inhibitors were determined by a set of behavioural tests and analysis of Jak-3 phosphorylation in brain sections. Acid sphingomyelinase-deficient mice were employed to test whether Jak3 is downstream of ceramide. Results: The data show that stress reduces neurogenesis, which is restored by simultaneous application of Jak-3 inhibitors. Inhibition of neurogenesis correlated with an anxious-depressive behaviour that was also normalized upon application of a Jak-3-inhibitor. Confocal microscopy data revealed that stress triggers a phosphorylation and thereby activation of Jak-3 in the hippocampus. Amitriptyline, a commonly used antidepressant that blocks the acid sphingomyelinase, or acid sphingomyelinase-deficiency reduced stress-induced phosphorylation of Jak-3. Conclusion: Our data show that Jak-3 is activated by stress at least partially via the acid sphingomyelinase and is involved in the mediation of stress-induced major depression

Dealings between Cataract and Retinal Reattachment Surgery in PVR

Introduction. To evaluate the impact of the eye lens status and oil side effects on the outcome of vitreoretinal surgery in retinal detachment with proliferative vitreoretinopathy (PVR) and a temporary silicone oil tamponade (SOT). Methods. 101 eyes were analyzed retrospectively and 103 eyes prospectively in regard to their retinal reattachment success rate and key factors for the outcome. Subgroup analysis of 27 eyes with Scheimpflug lens photography (SLP) before and after retinal reattachment service with SOT was performed. For SLP (65% phakic eyes) a Pentacam densitometry reference body with 3 mm diameter was chosen and 3 segments (anterior/mid/posterior) were evaluated separately after a quality check. Results. The retinal reattachment rate was highest in the prospective pseudophakic group (p=0.039). Lens transparency loss occurred earlier in middle aged patients than in younger patients. Besides the nucleus, layers posterior and anterior to it showed specific transparency changes. The emulsification rate was higher when eyes had been operated on in the anterior chamber before retinal reattachment service. Conclusions. Retinal reattachment surgery seems to benefit from preoperative cataract removal. We found significant lens changes in the nucleus as well as in the layers anterior and posterior to it. This corresponds to the histology of the lens epithelium published before

Inhibition of PI-3-K and AKT Amplifies Kv1.3 Inhibitor-Induced Death of Human T Leukemia Cells

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Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide

Background/Aims: Major depressive disorder is one of the most common diseases in western countries. The disease is mainly defined by its psychiatric symptoms. However, the disease has also many symptoms outside the central nervous system, in particular cardiovascular symptoms. Recent studies demonstrated that the acid sphingomyelinase/ceramide system plays an important role in the development of major depressive disorder and functions as a target of antidepressants. Methods: Here, we investigated (i) whether ceramide accumulates in endothelial cells in the neurogenetic zone of the hippocampus after glucocorticosterone-mediated stress, (ii) whether ceramide is released into the extracellular space of the hippocampus and (iii) whether extracellular ceramide inhibits neuronal proliferation. Ceramide was determined in endothelial cell culture supernatants or extracellular hippocampus extracts by a kinase assay. Endothelial ceramide in the hippocampus was analyzed by confocal microscopy of brain sections stained with Cy3-labelled anti-ceramide antibodies and FITC-Isolectin B4. Neuronal proliferation was measured by incubation of pheochromocytoma neuronal cells with culture supernatants and extracellular hippocampus extracts. Results: Treatment of cultured endothelial cells with glucocorticosterone induces a release of ceramide into the supernatant. Likewise, treatment of mice with glucocorticosterone triggers a release of ceramide into the extracellular space of the hippocampus. The release of ceramide is inhibited by concomitant treatment with the antidepressant amitriptyline, which also inhibits the activity of the acid sphingomyelinase. Studies employing confocal microscopy revealed that ceramide is formed and accumulates exclusively in endothelial cells in the hippocampus of stressed mice, a process that was again prevented by co-application of amitriptyline. Ceramide released in the culture supernatant or into the extracellular space of the hippocampus reduced proliferation of neurons in vitro. Conclusion: The data suggest a novel model for the pathogenesis of major depressive disorder, i.e. the release of ceramide-enriched microvesicles from endothelial cells that negatively affect neuronal proliferation in the hippocampus, but may also induce cardiovascular disease and other systemic symptoms of patients with major depressive disorder

Melatonin Acts as an Antidepressant by Inhibition of the Acid Sphingomyelinase/Ceramide System

Background: Melatonin has been shown to have antidepressive effects. We tested whether melatonin inhibits the acid sphingomyelinase/ceramide system and mediates its antidepressive effects via inhibition of the acid sphingomyelinase and a reduction of ceramide in the hippocampus. Antidepressants such as amitriptyline and fluoxetine were previously shown to inhibit the acid sphingomyelinase/ceramide system, which mediates neurogenesis and behavioral changes induced by these drugs. Methods: The effect of melatonin on the activity of the acid sphingomyelinase prior to and after treatment with melatonin was determined in cultured neurons and in vivo in the hippocampus of mice by measuring the consumption of [14C] sphingomyelin. Ceramide was measured by DAG kinase assay and fluorescence microscopy of the hippocampus and of cultured neurons. Neurogenesis in the hippocampus was analyzed by in vivo labeling with bromodeoxyuridine. Behavior was assessed in standardized tests. Results: Melatonin treatment inhibited acid sphingomyelinase in vitro in cultured pheochromocytoma cells and in vivo in the hippocampus, which resulted in a reduction of ceramide in vitro and in vivo. The inhibition of the acid sphingomyelinase/ceramide system translated into increased neurogenesis in glucocorticosterone-stressed mice after treatment with melatonin, an effect that is abrogated in acid sphingomyelinase-deficient mice. Likewise, melatonin improved the depressive behavior of stressed mice, a therapeutic effect that was again absent in acid sphingomyelinase-deficient animals. Conclusion: These data indicate that the antidepressive effects of melatonin as well as the induction of neurogenesis triggered by this drug are mediated by an inhibition of the acid sphingomyelinase/ceramide system. This is the first study to identify melatonin as an inhibitor of the acid sphingomyelinase

Single-cell discovery and multiomic characterization of therapeutic targets in multiple myeloma

UNLABELLED: Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. SIGNIFICANCE: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy