The esoteric roles of Bcl-2 family proteins in glucose homeostasis and cell survival.

The esoteric roles of Bcl-2 family proteins in glucose homeostasis and cell survival

Kirin: Hitting the Internet with Millions of Distributed IPv6 Announcements

The Internet is a critical resource in the day-to-day life of billions ofusers. To support the growing number of users and their increasing demands,operators have to continuously scale their network footprint -- e.g., byjoining Internet Exchange Points -- and adopt relevant technologies -- such asIPv6. IPv6, however, has a vastly larger address space compared to itspredecessor, which allows for new kinds of attacks on the Internet routinginfrastructure. In this paper, we present Kirin: a BGP attack that sources millions of IPv6routes and distributes them via thousands of sessions across various IXPs tooverflow the memory of border routers within thousands of remote ASes. Kirin'shighly distributed nature allows it to bypass traditional route-floodingdefense mechanisms, such as per-session prefix limits or route flap damping. Weanalyze the theoretical feasibility of the attack by formulating it as aInteger Linear Programming problem, test for practical hurdles by deploying theinfrastructure required to perform a small-scale Kirin attack using 4 IXPs, andvalidate our assumptions via BGP data analysis, real-world measurements, androuter testbed experiments. Despite its low deployment cost, we find Kirincapable of injecting lethal amounts of IPv6 routes in the routers of thousandsof ASes.<br

Does the immune reaction cause malignant transformation by disrupting cell-to-cell or cell-to-matrix communications?

Tumor progression: In many (perhaps in all) tumor systems, a malignant cancer is preceded by a benign lesion. Most benign lesions do not transform to malignancy and many regress. The final transformative step to malignancy differs from the preceding steps in, among other things, that it often occurs in the absence of the original carcinogenic stimulus. Mechanism of immunostimulation: Relatively low titers of specific immune reactants are known to stimulate, but cell-to-cell or cell-to-matrix interactions appear to be major inhibitors of tumor-growth. Therefore, it seems reasonable to hypothesize that the mechanism of immunostimulation may be an interference with cell-to-cell or cell-to-matrix communication by a sub-lethal immune-reaction. Discussion: While the above hypothesis remains unproven, some evidence suggests that immunity may have a major facilitating effect on tumor growth especially at the time of malignant transformation. There is even some evidence suggesting that transformation in vivo may seldom occur in the absence of immunostimulation of the premalignant lesion. Positive selection by the immune reaction may be the reason that tumors are immunogenic

Immunostimulation and Immunoinhibition of Premalignant Lesions

BACKGROUND: The immune reaction may be either stimulatory or inhibitory to tumor growth, depending upon the local ratio of immune reactants to tumor cells. HYPOTHESIS: A tumor-stimulatory immune response may be essential for survival of a neoplasm in vivo and for the biological progression from a premalignant lesion to a malignancy. Neither a positive nor a negative correlation between the magnitude of an immune-cell infiltrate and a cancer's prognosis can reveal whether the infiltrate was stimulating or inhibiting to the tumor's growth unless the position on the nonlinear curve that relates tumor growth to the magnitude of the immune reaction is known. DISCUSSION: This hypothesis is discussed in relation to the development of human malignant melanomas and colorectal cancers

Cancer immunotherapy by immunosuppression

We have previously suggested that the stimulatory effect of a weak immune reaction on tumor growth may be necessary for the growth of incipient tumors. In the present paper, we enlarge upon and extend that idea by collecting evidence in the literature bearing upon this new hypothesis that a growing cancer, whether in man or mouse, is throughout its lifespan, probably growing and progressing because of continued immune stimulation by a weak immune reaction. We also suggest that prolonged immunosuppression might interfere with progression and thus be an aid to therapy. While most of the considerable evidence that supports the hypothesis comes from observations of experimental mouse tumors, there is suggestive evidence that human tumors may behave in much the same way, and as far as we can ascertain, there is no present evidence that necessarily refutes the hypothesis

How much of Me do I see in You: Neural correlates of self-other distinction in the affective domain

When inferring mental states of others, individuals’ judgments are influenced by their own state of mind, which has been referred to as egocentric bias. Especially in situations where one holds a different mental state than another person to be interpreted, self-other differentiation is key for an accurate interpretation on the other person’s mind. It has been suggested that the right supramarginal gyrus (rSMG) is involved in self-other differentiation and overcoming egocentric bias in the affective domain. In a double-blind, randomized study 47 healthy adults received active or sham anodal tDCS (1mA, 20min) or a sham stimulation to the rSMG prior to performing a newly developed emotional egocentricity paradigm (SOFE, Self-Other Facial Emotion Judgment Task). In SOFE, subjects are presented with emotionally ambiguous situations (happy or fearful) in which they have to continuously rate 1) their own emotion and 2) the emotion of another person whose facial expression is either congruent or incongruent to the subject’s emotion. Analyses confirmed the presence of an emotional egocentric bias in incongruent trials. We furthermore found that active tDCS applied to the rSMG increased subjects’ ability to overcome egocentric judgments. This effect was valence dependent with significant effects when inferring affective states of happy faces right after imagining oneself in a fear-evoking situation (p<0.05). Our findings extend previous research showing a causal role of the rSMG for emotional self-other distinction to the inferring of emotional states from pictorial stimuli. They additionally point towards valence-specific patterns of rSMG functionality. In a next step the SOFE task will be applied in autism spectrum disorder to characterize egocentric bias suppression and SMG network integrity in an effort to elucidate social cognitive dysfunction in affected individuals

Endoplasmic reticulum stress-mediated upregulation of miR-29a enhances sensitivity to neuronal apoptosis.

Disturbance of homeostasis within the endoplasmic reticulum (ER) lumen leads to the accumulation of unfolded and misfolded proteins. This results in the activation of an evolutionary conserved stress response termed ER stress that, if unresolved, induces apoptosis. Previously the Bcl-2 homology domain 3-Only Protein Puma was identified as a mediator of ER stress-induced apoptosis in neurons. In the search of alternative contributors to ER stress-induced apoptosis, a downregulation of the anti-apoptotic Bcl-2 family protein Mcl-1 was noted during ER stress in both mouse cortical neurons and human SH-SY5Y neuroblastoma cells. Downregulation of Mcl-1 was associated with an upregulation of microRNA-29a (miR-29a) expression, and subsequent experiments showed that miR-29a targeted the 3\u27-untranslated region of the anti-apoptotic Bcl-2 family protein, Mcl-1. Inhibition of miR-29a expression using sequence-specific antagomirs or the overexpression of Mcl-1 decreased cell death following tunicamycin treatment, while gene silencing of Mcl-1 increased cell death. miR-29a did not alter the signalling branches of the ER stress response, rather its expression was controlled by the ER stress-induced transcription factor activating-transcription-factor-4 (ATF4). The current data demonstrate that the ATF4-mediated upregulation of miR-29a enhances the sensitivity of neurons to ER stress-induced apoptosis

Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.

Exposure of rat hippocampal neurons or human D283 medulloblastoma cells to the apoptosis-inducing kinase inhibitor staurosporine induced rapid cytochrome c release from mitochondria and activation of the executioner caspase-3. Measurements of cellular tetramethylrhodamine ethyl ester fluorescence and subsequent simulation of fluorescence changes based on Nernst calculations of fluorescence in the extracellular, cytoplasmic, and mitochondrial compartments revealed that the release of cytochrome c was preceded by mitochondrial hyperpolarization. Overexpression of the anti-apoptotic protein Bcl-xL, but not pharmacological blockade of outward potassium currents, inhibited staurosporine-induced hyperpolarization and apoptosis. Dissipation of mitochondrial potassium and proton gradients by valinomycin or carbonyl cyanide p-trifluoromethoxy-phenylhydrazone also potently inhibited staurosporine-induced hyperpolarization, cytochrome c release, and caspase activation. This effect was not attributable to changes in cellular ATP levels. Prolonged exposure to valinomycin induced significant matrix swelling, and per se also caused release of cytochrome c from mitochondria. In contrast to staurosporine, however, valinomycin-induced cytochrome c release and cell death were not associated with caspase-3 activation and insensitive to Bcl-xL overexpression. Our data suggest two distinct mechanisms for mitochondrial cytochrome c release: (1) active cytochrome c release associated with early mitochondrial hyperpolarization, leading to neuronal apoptosis, and (2) passive cytochrome c release secondary to mitochondrial depolarization and matrix swelling