An Emerging Natural History in the Development, Mechanisms and Worldwide Prevalence of Major Mental Disorders

Conciliating recent findings from molecular genetics, evolutionary biology, and clinical observations together point to new understandings regarding the mechanism, development and the persistent worldwide prevalence of major mental disorders (MMDs), which should be considered the result of an evolutionary downside trade off. Temperamental/trait variability, by facilitating choices for individual and group responses, confers robustness flexibility and resilience crucial to success of our species. Extreme temperamental variants, originating evolutionarily from the asocial aspect of human nature, also constitute the premorbid personality of the disorders. The latter create vulnerable individuals out of whom some will develop MMDs but at much higher rate to that of the general population. Significantly, similar temperamental “lopsidedness� enables many of these vulnerable individuals, if intelligent, tenacious, and curious, to be creative and contribute to our survival while some may also develop MMDs. All have a common neural-developmental origin and share characteristics in their clinical expression and pharmacological responses also expressed as mixed syndromes or alternating ones over time. Over-pruning of synaptic neurons may be considered the trigger of such occurrences or conversely, the failure to prevent them in spite of it. The symptoms of the major mental disorders are made up of antithetical substitutes as an expression of a disturbed over-all synchronizing property of brain function for all higher faculties previously unconsidered in their modeling. The concomitant presence of psychosis is a generic common occurrence

Home Network Management Policies: Putting the User in the Loop.

Home networks are becoming increasingly complex but existing management solutions are not simple to use since they are not tailored to the needs of typical home-users. In this paper we present a new approach to home network management that allows users to formulate quite sophisticated comic-strip policies using an attractive iPad application. The policies are based on the management wishes of home users elicited in a user study. Comic-strip policies are passed to a Policy engine running on a new Home Network Router designed to facilitate a variety of management tasks. We illustrate our approach via a number end-to-end experiments in an actual home deployment, using our prototype implementation. © 2012 IEEE

An Information Plane Architecture Supporting Home Network Management

Home networks have evolved to become small-scale versions of enterprise networks. The tools for visualizing and managing such networks are primitive and continue to require networked systems expertise on the part of the home user. As a result, non-expert home users must manually manage non-obvious aspects of the network - e.g., MAC address filtering, network masks, and firewall rules, using these primitive tools. The Homework information plane architecture uses stream database concepts to generate derived events from streams of raw events. This supports a variety of visualization and monitoring techniques, and also enables construction of a closed-loop, policy-based management system. This paper describes the information plane architecture and its associated policy-based management infrastructure. Exemplar visualization and closed-loop management applications enabled by the resulting system (tuned to the skills of non-expert home users) are discussed. © 2011 IEEE.Accepted versio

Conditional Genetic Elimination of Hepatocyte Growth Factor in Mice Compromises Liver Regeneration after Partial Hepatectomy

Hepatocyte growth factor (HGF) has been shown to be indispensable for liver regeneration because it serves as a main mitogenic stimulus driving hepatocytes toward proliferation. We hypothesized that ablating HGF in adult mice would have a negative effect on the ability of hepatocytes to regenerate. Deletion of the HGF gene was achieved by inducing systemic recombination in mice lacking exon 5 of HGF and carrying the Mx1-cre or Cre-ERT transgene. Analysis of liver genomic DNA from animals 10 days after treatment showed that a majority (70-80%) of alleles underwent cre-induced genetic recombination. Intriguingly, however, analysis by RT-PCR showed the continued presence of both unrecombined and recombined forms of HGF mRNA after treatment. Separation of liver cell populations into hepatocytes and non-parenchymal cells showed equal recombination of genomic HGF in both cell types. The presence of the unrecombined form of HGF mRNA persisted in the liver in significant amounts even after partial hepatectomy (PH), which correlated with insignificant changes in HGF protein and hepatocyte proliferation. The amount of HGF produced by stellate cells in culture was indirectly proportional to the concentration of HGF, suggesting that a decrease in HGF may induce de novo synthesis of HGF from cells with residual unrecombined alleles. Carbon tetrachloride (CCl4)-induced regeneration resulted in a substantial decrease in preexisting HGF mRNA and protein, and subsequent PH led to a delayed regenerative response. Thus, HGF mRNA persists in the liver even after genetic recombination affecting most cells; however, PH subsequent to CCl4 treatment is associated with a decrease in both HGF mRNA and protein and results in compromised liver regeneration, validating an important role of this mitogen in hepatic growth. © 2013 Nejak-Bowen et al

Neurosteroid Dehydroepiandrosterone Interacts with Nerve Growth Factor (NGF) Receptors, Preventing Neuronal Apoptosis

The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75NTR membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [3H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75NTR receptors (KD: 7.4±1.75 nM and 5.6±0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75NTR receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75NTR receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor

Policies for self tuning home networks.

A home network (HN) is usually managed by a user who does not possess knowledge and skills required to perform management tasks. When abnormalities are detected, it is desirable to let the network tune itself under the direction of certain policies. However, self tuning tasks usually require coordination between several network components and most of the network management policies can only specify local tasks. In this paper, we propose a state machine based policy framework to address the problem of fault and performance management in the context of HN. Policies can be specified for complex management tasks as global state machines which incorporate global system behaviour monitoring and reactions. We demonstrate the policy framework through a case study in which policies are specified for dynamic selection of frequency channel in order to improve wireless link quality in the presence of RF interference

From simulation to real deployments in WSN and back

The paper presents our efforts to validate some high-level aspects of the WSN simulator we have built as well as the operational functionality of our multiparameter MAC protocol. In order to do so, we resort to real deployments involving TelosB motes. The simulator, named Castalia, boasts the most accurate wireless channel and radio models for WSN found in current literature. These models are capturing some essential experimental findings. This does not guaranty though that the simulator will behave similarly with a real deployment at the high level (i.e., the protocol or application level). We investigate how our multiparameter MAC protocol behaves in a real deployment so as to take a first step towards validating and possibly tuning Castalia. The investigation starts by determining the connectivity map for the real deployment and then trying to reproduce it in the simulator. We then proceed with the protocol testing and comparing. We report the difficulties faced and our findings from this process. 1

A Configuration Service for Home Networks

Accepted versio

Selective and differential interactions of BNN27, a novel C17-spiroepoxy steroid derivative, with TrkA receptors, regulating neuronal survival and differentiation.

Nerve growth factor (NGF) holds a pivotal role in brain development and maintenance, been also involved in the pathophysiology of neurodegenerative diseases. Here, we provide evidence that a novel C17-spiroepoxy steroid derivative, BNN27, specifically interacts with and activates the TrkA receptor of NGF, inducing phosphorylation of TrkA tyrosine residues and down-stream neuronal survival-related kinase signaling. Additionally, BNN27 potentiates the efficacy of low levels of NGF, by facilitating its binding to the TrkA receptors and differentially inducing fast return of internalized TrkA receptors into neuronal cell membranes. Furthermore, BNN27 synergizes with NGF in promoting axonal outgrowth, effectively rescues from apoptosis NGF-dependent and TrkA positive sympathetic and sensory neurons, in vitro, ex vivo and in vivo in NGF null mice. Interestingly, BNN27 does not possess the hyperalgesic properties of NGF. BNN27 represents a lead molecule for the development of neuroprotective TrkA receptor agonists, with potential therapeutic applications in neurodegenerative diseases and in brain trauma