Causality, Knowledge and Coordination in Distributed Systems

Effecting coordination across remote sites in a distributed system is an essential part of distributed computing, and also an inherent challenge. In 1978, an analysis of communication in asynchronous systems was suggested by Leslie Lamport. Lamport's analysis determines a notion of temporal precedence, a sort of weak notion of time, which is otherwise missing in asynchronous systems. This notion has been extensively utilized in various applications. Yet the analysis is limited to systems that are asynchronous. In this thesis we go beyond by investigating causality in synchronous systems. In such systems, the boundaries of causal influence are not charted out exclusively by message passing. Here time itself, passing at a uniform (or almost uniform) rate for all processes, is also a medium by which causal influence may fan out. This thesis studies, and characterizes, the combinations of time and message passing that govern causal influence in synchronous systems. It turns out that knowledge based analysis [FHMV] provides a well tailored formal framework within which causal notions can be studied. As we show, the formal notion of knowledge is highly appropriate for characterizing causal influence in terms of information flow, broadening the analysis of Chandy and Misra in [ChM]. We define several generic classes of coordination problems that pose various temporal ordering requirements on the participating processes. These coordination problems provide natural generalizations of real life requirements. We then analyze the causal conditions that underlie suitable solutions to these problems. The analysis is conducted in two stages: first, the temporal ordering requirements are reduced to epistemic conditions. Then, these epistemic conditions are characterized in terms of the causal communication patterns that are necessary and sufficient to bring them about.Comment: PhD Dissertatio

Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation

Background/Aims: Gq protein-coupled receptors (GqPCRs) regulate various cellular processes including mainly proliferation and differentiation. In a previous study, we found that in prostate cancer cells, the GqPCR of GnRH induces apoptosis by reducing the PKC-dependent AKT activity and elevating JNK phosphorylation. Since it was thought that GqPCR induces mainly activation of AKT, we undertook to examine how general is this phenomenon and understand its signaling. Methods: We used various cells to follow the phosphorylation of signaling components using western blotting. Results: In a screen of 21 cell lines, we found that PKC activation results in the reduction of AKT activity, which correlates nicely to JNK activation and in some cases to apoptosis. To further understand the signaling pathways involved in this stimulation, we studied in detail the SVOG-4O and αT3-1 cells. We found that PGF2α and GnRH agonist (GnRH-a) indeed induce significant Gq- and PKC- dependent apoptosis in these cells. This is mediated by two signaling branches downstream of PKC, which converge at the level of MLK3 upstream of JNK. One branch consists on c-Src activation of the JNK cascade and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3, to allow the flow of the c-Src signal to JNK. At the MAPKK level, we found that the signal is transmitted by MKK7 and not MKK4. Conclusion: Our results present a general mechanism that mediates a GqPCR-induced, death receptors-independent, apoptosis in physiological, as well as cancer-related systems

Children with seizures and radiological diagnosis of focal cortical dysplasia: can drug-resistant epilepsy be predicted earlier?

Objective: Focal cortical dysplasia (FCD) is a malformation of cortical development and is associated with drug-resistant epilepsy. Standard indication for epilepsy surgery is drug resistance (as defined by the ILAE). Given the high incidence of drug resistance in these children, this delay may not be warranted. The aim of the study was to determine the proportion of patients with a presumed FCD who develop drug resistance, and evaluate post-operative outcomes. Methods: This study incorporated a survey within a regional paediatric epilepsy network and a retrospective database review of a paediatric epilepsy center serving the network to identify children with epilepsy and a presumed FCD on MRI. Results: The survey revealed that 86% of the patients with epilepsy and presumed FCD on MRI within the network were referred to our centre. Of 139 pediatric patients included in the study, 131 (94.2%) had drug-resistant epilepsy. One hundred and ten (83.9%) patients were referred to epilepsy surgery, of whom 97 underwent surgery. Of 92 with one-year postoperative follow-up, 59.8% had an Engel Class 1 (seizure-free) outcome. Concordance of location between MRI and ictal EEG was strongly associated with Engel Class 1 outcome ( p <0.001), as was older age at seizure onset ( p =0.03). Time from diagnosis to surgery, number of medications, type of surgery and histology were not associated with improved outcome. Significance: Our data suggest that most children presenting with seizures and a radiological diagnosis of FCD will develop drug-resistant epilepsy and are candidates for epilepsy surgery. The main outcome predictors are the correlation between MRI and ictal EEG localization and age at onset. This suggests that patients with FCD and epilepsy may be considered for surgery before traditional criteria of drug resistance are met. This change in practice has the potential to improve quality of life and cognitive function, and reduce burden on epilepsy services

Brain volumetric changes in the general population following the COVID-19 outbreak and lockdown

The coronavirus disease 2019 (COVID-19) outbreak introduced unprecedented health-risks, as well as pressure on the economy, society, and psychological well-being due to the response to the outbreak. In a preregistered study, we hypothesized that the intense experience of the outbreak potentially induced stress-related brain modifications in the healthy population, not infected with the virus. We examined volumetric changes in 50 participants who underwent MRI scans before and after the COVID-19 outbreak and lockdown in Israel. Their scans were compared with those of 50 control participants who were scanned twice prior to the pandemic. Following COVID-19 outbreak and lockdown, the test group participants uniquely showed volumetric increases in bilateral amygdalae, putamen, and the anterior temporal cortices. Changes in the amygdalae diminished as time elapsed from lockdown relief, suggesting that the intense experience associated with the pandemic induced transient volumetric changes in brain regions commonly associated with stress and anxiety. The current work utilizes a rare opportunity for real-life natural experiment, showing evidence for brain plasticity following the COVID-19 global pandemic. These findings have broad implications, relevant both for the scientific community as well as the general public

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio