Waiting for PARIS—A Biological Target in Search of a Drug

A recent breakthrough paper published in Science Translational Medicine has provided compelling evidence that inhibition of Parkin Interacting Substrate (PARIS) may offer clinical researchers an important new therapeutic approach since it shows considerable promise as an important biological target potentially capable of pharmaceutical intervention to slow long term neurodegeneration in patients with Parkinson’s disease (PD). We present several PD-relevant perspectives on this paper that were not discussed in that otherwise entirely scientific narrative. We also outline the some of the work leading up to it, including the massive drug screen that proved necessary to discover a clinically suitable inhibitor of PARIS (Farnesol), as well as relevant PD research within the wider drug class, issues surrounding its future formulation, and next steps in translating this new knowledge into the clinic to evaluate possible long-term PD patient benefits.

Generating individual intrinsic reward for cooperative multiagent reinforcement learning

Multiagent reinforcement learning holds considerable promise to deal with cooperative multiagent tasks. Unfortunately, the only global reward shared by all agents in the cooperative tasks may lead to the lazy agent problem. To cope with such a problem, we propose a generating individual intrinsic reward algorithm, which introduces an intrinsic reward encoder to generate an individual intrinsic reward for each agent and utilizes the hypernetworks as the decoder to help to estimate the individual action values of the decomposition methods based on the generated individual intrinsic reward. Experimental results in the StarCraft II micromanagement benchmark prove that the proposed algorithm can increase learning efficiency and improve policy performance.

Tunable Microstructures of Ultralong Organic Phosphorescence Materials

Three kinds of microstructures of one organic phosphor were perpared based on a solution-concentration-controlled self-assembly strategy. These microstructures show different phosphorescence efficiency, which holds considerable promise for the miniaturized optical...

Nanotechnologies light up the antitumor potency by combining chemotherapy with siRNA

Nanotechnology-based combination anticancer therapy offers novel approaches to overcome the limitations of single-agent administration. The emerging siRNA technology combined with chemotherapy has shown considerable promise in anticancer therapy. There are...

Partial (Neighbourhood) Singleton Arc Consistency for Constraint Satisfaction Problems

Algorithms based on singleton arc consistency (SAC) show considerable promise for improving backtrack search algorithms for constraint satisfaction problems (CSPs). The drawback is that even the most efficient of them is still comparatively expensive. Even when limited to preprocessing, they give overall improvement only when problems are quite difficult to solve with more typical procedures such as maintained arc consistency (MAC). The present work examines a form of partial SAC and neighbourhood SAC (NSAC) in which a subset of the variables in a CSP are chosen to be made SAC-consistent or neighbourhood-SAC-consistent. Such consistencies, despite their partial character, are still well-characterized in that algorithms have unique fixpoints. Heuristic strategies for choosing an effective subset of variables are described and tested, the best being choice by highest degree and a more complex strategy of choosing by constraint weight after random probing. Experimental results justify the claim that these methods can be nearly as effective as the corresponding full version of the algorithm in terms of values discarded or problems proven unsatisfiable, while significantly reducing the effort required to achieve this.

Violence and the New Internationalism, 1988–2003

This chapter looks at the first intifada—a grassroots resistance movement that emerged in the West Bank and Gaza in late 1987 and showed considerable promise before being crushed by Israeli military might. Its collapse also coincided with the disintegration of the Soviet Union and the end of the Cold War, marking the beginning of a new American tactic of supposed humanitarian concern for ethnically or communally defined victims of a regime as a pretext for military action intended to ensure resource access, especially to oil. These arguments for and practices of occupation not only invigorated and intensified internal ethnic and communal tensions within the Iraqi state, but also fueled new forms of Islamist opposition that had never before flourished in the Mashriq.

Ecology of Terrestrial Arthropods in Freshwater Wetlands

The terrestrial arthropod fauna of wetlands has been largely ignored by scientists compared to other ecological elements, yet these organisms are among the most important influences on the ecology of these systems, with the vast majority of the biodiversity in wetlands found among the terrestrial arthropods. Wetlands present a range of habitat for terrestrial arthropods, with unique faunas being associated with soils and ground litter, living-plant substrates, and peatlands. Myriapoda, Araneae, Collembola, Carabidae, Formicidae, and assorted herbivorous Coleoptera and Lepidoptera are the terrestrial arthropod groups that most influence the ecology of wetlands. Despite their success, most terrestrial arthropods possess fairly rudimentary adaptations for life in wetlands, with most simply moving to higher ground or up vegetation during floods, although some species can tolerate immersion. Many terrestrial arthropods are environmentally sensitive and show considerable promise as bioindicators of wetland ecological conditions.

Towards HCP-Style Macaque Connectomes: 24-Channel 3T Multi-Array Coil, MRI Sequences and Preprocessing

Macaque monkeys are an important model species for understanding cortical organization of primates, yet tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the relatively thin macaque cortex, high spatial, temporal, and angular resolutions are required while maintaining high signal-to-noise ratio to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enabled adaptation of the Human Connectome Project (HCP) image acquisition protocols to the macaque brain. We also adapted HCP preprocessing methods optimized for the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provided high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold acceleration for dMRI and fMRI, respectively. Automated parcellation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available for humans.Highlights➢24-channel 3T MR receive coil designed for the smaller macaque brain.➢In vivo macaque imaging protocols adapted according to guidelines from the HCP.➢Parallel imaging yields five- and four-fold acceleration in fMRI and dMRI sampling.➢HCP’s minimal preprocessing and denoising pipelines adapted for macaques.➢The multi-modal MRI data show considerable promise for HCP-style analyses.

Deliberative Ideals Across Diverse Cultures

In the scheme of history, most political deliberation has taken place outside the modern West. But the study of deliberation, however extensive it has become, has largely ignored this wider world. Examining how deliberation manifests across different societies has considerable promise for both explanatory and normative political theory. To explain why people deliberate—which should be among the first questions deliberative democrats ponder—it is first necessary to examine how people deliberate, and why this varies. Doing so with a comparative and historical perspective, even in the preliminary fashion presented here, reveals how social and political ideals can motivate and shape deliberative practice. And there are normative stakes in this agenda. If collective deliberation is to prevail in global governance, we must fashion political ideals which motivate diverse peoples to come together in discourse, rather than confront their problems, or compound them, by less desirable means.

Intraperitoneal aerosolization of albumin-stabilized paclitaxel nanoparticles (Abraxane™) for peritoneal carcinomatosis – a phase I first-in-human study

BackgroundNanoparticles hold considerable promise for aerosol-based intraperitoneal delivery in patients with carcinomatosis. Recently, results from preclinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane™) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol™). Here, we propose a phase I study of pressurized intraperitoneal aerosol chemotherapy (PIPAC) using ABP in patients with upper Gastrointestinal, breast, or ovarian cancer.MethodsEligible patients with advanced, biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin will undergo three PIPAC treatments using ABP with a 4-week interval. The dose of ABP will be escalated from 35 to 140 mg/m² using a Bayesian approach until the maximally tolerated dose is determined. The primary end point is dose-limiting toxicity. Secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life, and exploratory circulating biomarker analyses.DiscussionABP holds considerable promise for intraperitoneal aerosol delivery. The aim of this study is to determine the dose level for future randomized phase II trials using ABP in PIPAC therapy.Trial registrationThis trial is registered as EudraCT: 2017-001688-20 and Clinicaltrials.gov: NCT03304210.