Qualitative and Quantitative Comparison of Plasma Exosomes from Neonates and Adults

Exosomes are extracellular vesicles that contain nucleic acids, lipids and metabolites, and play a critical role in health and disease as mediators of intercellular communication. The majority of extracellular vesicles in the blood are platelet-derived. Compared to adults, neonatal platelets are hyporeactive and show impaired granule release, associated with defects in Soluble N-ethylmaleimide-sensitive fusion Attachment protein REceptor (SNARE) proteins. Since these proteins participate in biogenesis of exosomes, we investigated the potential differences between newborn and adult plasma-derived exosomes. Plasma-derived exosomes were isolated by ultracentrifugation of umbilical cord blood from full-term neonates or peripheral blood from adults. Exosome characterization included size determination by transmission electron microscopy and quantitative proteomic analysis. Plasma-derived exosomes from neonates were significantly smaller and contained 65% less protein than those from adults. Remarkably, 131 proteins were found to be differentially expressed, 83 overexpressed and 48 underexpressed in neonatal (vs. adult) exosomes. Whereas the upregulated proteins in plasma exosomes from neonates are associated with platelet activation, coagulation and granule secretion, most of the underexpressed proteins are immunoglobulins. This is the first study showing that exosome size and content change with age. Our findings may contribute to elucidating the potential “developmental hemostatic mismatch risk” associated with transfusions containing plasma exosomes from adults.     

PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study

Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI.     

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

FMAP: Distributed cooperative multi-agent planning

This paper proposes FMAP (Forward Multi-Agent Planning), a fully-distributed multi-agent planning method that integrates planning and coordination. Although FMAP is specifically aimed at solving problems that require cooperation among agents, the flexibility of the domain-independent planning model allows FMAP to tackle multi-agent planning tasks of any type. In FMAP, agents jointly explore the plan space by building up refinement plans through a complete and flexible forward-chaining partial-order planner. The search is guided by h _{D T G} , a novel heuristic function that is based on the concepts of Domain Transition Graph and frontier state and is optimized to evaluate plans in distributed environments. Agents in FMAP apply an advanced privacy model that allows them to adequately keep private information while communicating only the data of the refinement plans that is relevant to each of the participating agents. Experimental results show that FMAP is a general-purpose approach that efficiently solves tightly-coupled domains that have specialized agents and cooperative goals as well as loosely-coupled problems. Specifically, the empirical evaluation shows that FMAP outperforms current MAP systems at solving complex planning tasks that are adapted from the International Planning Competition benchmarks.     

Gas hold-up, mixing time and gas-liquid volumetric mass transfer coefficient of various multiple-impeller configurations: Rushton turbine, pitched blade and techmix impeller and their combinations

Gas hold-up, mixing intensity of dispersion characterised by exchange flows between adjacent impellers and a volumetric mass transfer coefficient are presented for 18 impeller configurations in triple-impeller vessel of inner diameter . Rushton Turbines, six Pitched Blade impellers pumping down and hydrofoil impellers Techmix 335 (Techmix co., Czech republic) pumping up or down and their combinations were used. aqueous solution was used as a liquid phase, which represents non-coalescent batches. Gas hold-ups and volumetric mass transfer coefficients are presented for individual configurations as functions of specific power dissipated and superficial gas velocity. The regression of the mass transfer coefficients shows large standard deviation (30%). The power number included to the regression to express the impeller configuration effect did not improve the standard deviation significantly (23%). The impeller configurations with low power number (less than unity) provide higher dispersion mixing intensities, while the impeller configurations with high power number provide better mass transfer performance.     

Poly(p-tert-butoxycarbonyloxystyrene): a convenient precursor to p-hydroxystyrene resins

An efficient synthetic route to pure, high molecular weight poly(p-hydroxystyrene) is reported. The route involves synthesis of a new monomer, p-tert-butoxycarbonyloxystyrene, polymerization by radical initiation or by cationic initiation in liquid SO₂, followed by thermolysis or acidolysis of the tert-butoxycarbonyl protecting group. Porous, crosslinked resin beads containing the nucleophilic, phenol pendant group have been prepared in a similar fashion from the precursor terpolymer of p-tert-butoxycarbonyloxystyrene, styrene and divinylbenzene. The utility of this resin for solid-phase synthesis has been demonstrated.     

Geographic Variation in Alkaloid Production in <Emphasis Type="Italic">Conium maculatum</Emphasis> Populations Experiencing Differential Herbivory by <Emphasis Type="Italic">Agonopterix alstroemeriana</Emphasis>

Conium maculatum, a Eurasian weed naturalized in North America, contains high concentrations of piperidine alkaloids that act as chemical defenses against herbivores. C. maculatum was largely free from herbivory in the United States, until approximately 30 yr ago, when it was reassociated via accidental introduction with a monophagous European herbivore, the oecophorid caterpillar Agonopterix alstroemeriana. At present, A. alstroemeriana is found in a continuum of reassociation time and intensities with C. maculatum across the continent; in the Pacific Northwest, A. alstroemeriana can cause severe damage, resulting in some cases in complete defoliation. Studies in biological control and invasion biology have yet to determine whether plants reassociated with a significant herbivore from the area of indigeneity increase their chemical defense investment in areas of introduction. In this study, we compared three locations in the United States (New York, Washington, and Illinois) where C. maculatum experiences different levels of herbivory by A. alstroemeriana to determine the association between the intensity of the interaction, as measured by damage, and chemical defense production. Total alkaloid production in C. maculatum was positively correlated with A. alstroemeriana herbivory levels: plants from New York and Washington, with higher herbivory levels, invested two and four times more N to alkaloid synthesis than did plants from Illinois. Individual plants with lower concentrations of alkaloids from a single location in Illinois experienced more damage by A. alstroemeriana, indicative of a preference on the part of the insect for plants with less chemical defense. These results suggest that A. alstroemeriana may act either as a selective agent or inducing agent for C. maculatum and increase its toxicity in its introduced range.