PULP: an Adaptive Gossip-Based Dissemination Protocol for Multi-Source Message Streams

Gossip-based protocols provide a simple, scalable, and robust way to disseminate messages in large-scale systems. In such protocols, messages are spread in an epidemic manner. Gossiping may take place between nodes using push, pull, or a combination. Push-based systems achieve reasonable latency and high resilience to failures but may impose an unnecessarily large redundancy and overhead on the system. At the other extreme, pull-based protocols impose a lower overhead on the network at the price of increased latencies. A few hybrid approaches have been proposed-typically pushing control messages and pulling data-to avoid the redundancy of high-volume content and single-source streams. Yet, to the best of our knowledge, no other system intermingles push and pull in a multiple-senders scenario, in such a way that data messages of one help in carrying control messages of the other and in adaptively adjusting its rate of operation, further reducing overall cost and improving both on delays and robustness. In this paper, we propose an efficient generic push-pull dissemination protocol, Pulp, which combines the best of both worlds. Pulp exploits the efficiency of push approaches, while limiting redundant messages and therefore imposing a low overhead, as pull protocols do. Pulp leverages the dissemination of multiple messages from diverse sources: by exploiting the push phase of messages to transmit information about other disseminations, Pulp enables an efficient pulling of other messages, which themselves help in turn with the dissemination of pending messages. We deployed Pulp on a cluster and on PlanetLab. Our results demonstrate that Pulp achieves an appealing trade-off between coverage, message redundancy, and propagation delay. © 2011 Springer Science+Business Media, LLC

Hedgehog Signaling Modulates Glial Proteostasis and Lifespan

The conserved Hedgehog signaling pathway has well-established roles in development. However, its function during adulthood remains largely unknown. Here, we investigated whether the Hedgehog signaling pathway is active during adult life in Drosophila melanogaster, and we uncovered a protective function for Hedgehog signaling in coordinating correct proteostasis in glial cells. Adult-specific depletion of Hedgehog reduces lifespan, locomotor activity, and dopaminergic neuron integrity. Conversely, increased expression of Hedgehog extends lifespan and improves fitness. Moreover, Hedgehog pathway activation in glia rescues the lifespan and age-associated defects of hedgehog mutants. The Hedgehog pathway regulates downstream chaperones, whose overexpression in glial cells was sufficient to rescue the shortened lifespan and proteostasis defects of hedgehog mutants. Finally, we demonstrate the protective ability of Hedgehog signaling in a Drosophila Alzheimer's disease model expressing human amyloid beta in the glia. Overall, we propose that Hedgehog signaling is requisite for lifespan determination and correct proteostasis in glial cells

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA

Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. This 12-week, double-blind phase II trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor 80 mg, elafibranor 120 mg or placebo. The primary endpoint was the relative change of ALP at 12 weeks (NCT03124108). At 12 weeks, ALP was reduced by -48.3±14.8% in the elafibranor 80 mg group (p 15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor 80 mg group and 79% patients in the elafibranor 120 mg group, vs. 6.7% patients in the placebo group. Levels of gamma-glutamyltransferase decreased by 37.0±25.5% in the elafibranor 80 mg group (p <0.001) and 40.0±24.1% in the elafibranor 120 mg group (p <0.01) compared to no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5’-nucleotidase or high-sensitivity C-reactive protein were likewise reduced by elafibranor. Pruritus was not induced or exacerbated by elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug-related non-serious adverse events were mild to moderate. In this randomized phase II trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and an incomplete response to ursodeoxycholic acid. Patients with primary biliary cholangitis (a rare chronic liver disease) that do not respond to standard therapy remain at risk of disease progression toward cirrhosis and impaired quality of life. Elafibranor is a nuclear receptor agonist that we tested in a randomized clinical trial over 12 weeks. It successfully decreased levels of disease activity markers, including alkaline phosphatase. Thus, this study is the foundation for a larger prospective study that will determine the efficacy and safety of this drug as a second-line therapy. Clinical Trials.gov NCT03124108 [Display omitted] •In a phase II trial in PBC, the dual PPARα and δ agonist elafibranor achieved the primary endpoint of reducing ALP.•Compared to placebo, the 80 mg and 120 mg dose had positive effects on prognostically important composite endpoints.•In patients with pruritus at baseline, an improvement was noted in both elafibranor arms.•Elafibranor was generally well-tolerated over the duration of treatment