A Flexible and Modular Framework for Implementing Infrastructures for Global Computing

We present a Java software framework for building infrastructures to support the development of applications for systems where mobility and network awareness are key issues. The framework is particularly useful to develop run-time support for languages oriented towards global computing. It enables platform designers to customize communication protocols and network architectures and guarantees transparency of name management and code mobility in distributed environments. The key features are illustrated by means of a couple of simple case studies

Development and validation of a reinforcement learning algorithm to dynamically optimize mechanical ventilation in critical care.

The aim of this work was to develop and evaluate the reinforcement learning algorithm VentAI, which is able to suggest a dynamically optimized mechanical ventilation regime for critically-ill patients. We built, validated and tested its performance on 11,943 events of volume-controlled mechanical ventilation derived from 61,532 distinct ICU admissions and tested it on an independent, secondary dataset (200,859 ICU stays; 25,086 mechanical ventilation events). A patient "data fingerprint" of 44 features was extracted as multidimensional time series in 4-hour time steps. We used a Markov decision process, including a reward system and a Q-learning approach, to find the optimized settings for positive end-expiratory pressure (PEEP), fraction of inspired oxygen (FiO2) and ideal body weight-adjusted tidal volume (Vt). The observed outcome was in-hospital or 90-day mortality. VentAI reached a significantly increased estimated performance return of 83.3 (primary dataset) and 84.1 (secondary dataset) compared to physicians' standard clinical care (51.1). The number of recommended action changes per mechanically ventilated patient constantly exceeded those of the clinicians. VentAI chose 202.9% more frequently ventilation regimes with lower Vt (5-7.5 mL/kg), but 50.8% less for regimes with higher Vt (7.5-10 mL/kg). VentAI recommended 29.3% more frequently PEEP levels of 5-7 cm H2O and 53.6% more frequently PEEP levels of 7-9 cmH2O. VentAI avoided high (>55%) FiO2 values (59.8% decrease), while preferring the range of 50-55% (140.3% increase). In conclusion, VentAI provides reproducible high performance by dynamically choosing an optimized, individualized ventilation strategy and thus might be of benefit for critically ill patients

Microphytobenthos of Arctic Kongsfjorden (Svalbard, Norway): biomass and potential primary production along the shore line

During summer 2007, Arctic microphytobenthic potential primary production was measured at several stations around the coastline of Kongsfjorden (Svalbard, Norway) at ?5 m water depth and at two stations at five different water depths (5, 10, 15, 20, 30 m). Oxygen planar optode sensor spots were used ex situ to determine oxygen exchange in the overlying water of intact sediment cores under controlled light (ca. 100 ?mol photons m?2 s?1) and temperature (2–4°C) conditions. Patches of microalgae (mainly diatoms) covering sandy sediments at water depths down to 30 m showed high biomass of up to 317 mg chl a m?2. In spite of increasing water depth, no significant trend in “photoautotrophic active biomass” (chl a, ratio living/dead cells, cell sizes) and, thus, in primary production was measured at both stations. All sites from ?5 to 30 m water depth exhibited variable rates of net production from ?19 to +40 mg O2 m?2 h?1 (?168 to +360 mg C m?2 day?1) and gross production of about 2–62 mg O2 m?2 h?1 (17–554 mg C m?2 day?1), which is comparable to other polar as well as temperate regions. No relation between photoautotrophic biomass and gross/net production values was found. Microphytobenthos demonstrated significant rates of primary production that is comparable to pelagic production of Kongsfjorden and, hence, emphasised the importance as C source for the zoobenthos

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell–mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell–mediated inflammatory disease

Different osteosyntheses for Colles' fracture: A mechanical study in 42 cadaver bones

Background and purpose In recent years several different plate designs for internal fixation of fractures of the distal radius have been developed. However, few biomechanical studies have been performed to compare these new implants. The purpose of this study was to compare the mechanical properties of 5 different commercially available plates (3 volar and 2 dorsal) with standard K-wire fixation using a distal radial cadaver model

Circulating extracellular DNA is an independent predictor of mortality in elderly patients with venous thromboembolism.

Venous thromboembolism (VTE) is a major cause of morbidity and mortality in elderly patients. Extracellular DNA is a pro-inflammatory and pro-thrombotic mediator in vitro and in animal models. Levels of circulating extracellular DNA (ceDNA) are increased in VTE patients, but the association of ceDNA with VTE extent and clinical outcome is poorly understood. We analyzed the association of ceDNA with the extent of VTE, categorized as distal and proximal deep vein thrombosis and pulmonary embolism, and with the clinical outcomes VTE recurrence and mortality. We quantified ceDNA by a fluorescent probe, as well as circulating nucleosomes and neutrophil extracellular traps (NETs) by ELISA in plasma from 611 patients aged ≥ 65 years with acute VTE of a prospective cohort study (SWITCO65+). Levels of ceDNA and nucleosomes, but not NETs, correlated with VTE extent. Infectious comorbidities independently increased ceDNA levels in VTE. CeDNA strongly correlated with C-reactive protein and leukocytosis, suggesting an association of ceDNA with inflammation in VTE patients. CeDNA furthermore predicted PE-related and all-cause mortality, but not VTE recurrence, during a 3-year follow-up. Our study suggests that ceDNA levels in VTE patients reflect the degree of inflammation and may serve as a biomarker to stratify VTE patients at risk for mortality

A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer

Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-γ-producing T cells; augment tumor apoptosis; and increase CD4+ and CD8+ T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1-insensitive TNBC

The Carrot or the Stick? Evaluation of Education and Enforcement as Management Tools for Human-Wildlife Conflicts

Evidence-based decision-making is critical for implementing conservation actions, especially for human-wildlife conflicts, which have been increasing worldwide. Conservation practitioners recognize that long-term solutions should include altering human behaviors, and public education and enforcement of wildlife-related laws are two management actions frequently implemented, but with little empirical evidence evaluating their success. We used a system where human-black bear conflicts were common, to experimentally test the efficacy of education and enforcement in altering human behavior to better secure attractants (garbage) from bears. We conducted 3 experiments in Aspen CO, USA to evaluate: 1) on-site education in communal dwellings and construction sites, 2) Bear Aware educational campaign in residential neighborhoods, and 3) elevated law enforcement at two levels in the core business area of Aspen. We measured human behaviors as the response including: violation of local wildlife ordinances, garbage availability to bears, and change in use of bear-resistance refuse containers. As implemented, we found little support for education, or enforcement in the form of daily patrolling in changing human behavior, but found more support for proactive enforcement, i.e., dispensing warning notices. More broadly we demonstrated the value of gathering evidence before and after implementing conservation actions, and the dangers of measuring responses in the absence of ecological knowledge. We recommend development of more effective educational methods, application of proactive enforcement, and continued evaluation of tools by directly measuring change in human behavior. We provide empirical evidence adding to the conservation managers' toolbox, informing policy makers, and promoting solutions to human-wildlife conflicts