Exosomal Hsp70 Induces a Pro-Inflammatory Response to Foreign Particles Including Mycobacteria

© 2010 Anand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Exosomes are endosome-derived vesicles that are released when multi-vesicular bodies (MVBs) fuse with the plasma membrane. Exosomes released from mycobacteria-infected cells have recently been shown to be pro-inflammatory. A prominent host molecule that is found within these exosomes is Hsp70, a member of the heat-shock family of proteins. Methodology/Principal Findings: We first characterized the exosomes purified from control and mycobacteria-infected cells. We found that relative to uninfected cells, macrophages infected with M. smegmatis and M. avium release more exosomes and the exosomes they released had more Hsp70 on their surface. Both exosomes and exogenous Hsp70 treatment of macrophages led to NF-kB activation and TNFa release in uninfected macrophages; Hsp70 levels were elevated in mycobacteria-infected cells. Macrophage treatment with Hsp70 also led to increase in the phagocytosis and maturation of latex-bead phagosomes. Finally, Hsp70 pre-incubation of M. smegmatis- and M. avium-infected cells led to increased phago-lysosome fusion, as well as more killing of mycobacteria within macrophages. Conclusions/Significance: Our results fit into an emerging concept whereby exosomes-containing Hsp70 are effective inducers of inflammation, also in response to mycobacterial infection.E.A. was supported by Fundação para a Ciência e a Tecnologia (FCT) Grant PIC/IC/82859/2007 and PTDC/SAU-MII/098024/2008. P.K.A was supported by a post-doctoral research grant from Alexander von Humboldt foundation, Germany and Marie-Curie fellowship from European Union, FP6 programme MIF1-CT- 2006-039351. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection

Enteropathogenic and enterohemorrhagic bacterial infections in humans are a severe cause of morbidity and mortality. Although NOD-like receptors (NLRs) NOD2 and NLRP3 have important roles in the generation of protective immune responses to enteric pathogens, whether there is crosstalk among NLRs to regulate immune signaling is not known. Here, we show that mice and macrophages deficient in NOD2, or the downstream adaptor RIP2, have enhanced NLRP3-and caspases-11-dependent non-canonical inflammasome activation in a mouse model of enteropathogenic Citrobacter rodentium infection. Mechanistically, NOD2 and RIP2 regulate reactive oxygen species (ROS) production. Increased ROS in Rip2-deficient macrophages subsequently enhances c-Jun N-terminal kinase (JNK) signaling resulting in increased caspase-11 expression and activation, and more non-canonical NLRP3-dependant inflammasome activation. Intriguingly, this leads to protection of the colon epithelium for up to 10 days in Rip2-deficient mice infected with C. rodentium. Our findings designate NOD2 and RIP2 as key regulators of cellular ROS homeostasis and demonstrate for the first time that ROS regulates caspase-11 expression and non-canonical NLRP3 inflammasome activation through the JNK pathway

Adaptive Global Carbon Monoxide Kinetic Mechanism over Platinum/Alumina Catalysts

Carbon monoxide (CO) oxidation is one of the more widely researched mechanisms given its pertinence across many industrial platforms. Because of this, ample information exists as to the detailed reaction steps in its mechanism. While detailed kinetic mechanisms are more accurate and can be written as a function of catalytic material on the surface, global mechanisms are more widely used because of their computational efficiency advantage. This paper merges the theory behind detailed kinetics into a global kinetic model for the singular CO oxidation reaction while formulating expressions that adapt to catalyst properties on the surface such as dispersion and precious metal loading. Results illustrate that the model is able to predict the light-off and extinction temperatures during a hysteresis experiment as a function of different inlet CO concentrations and precious metal dispersion

Dependently-Typed Formalisation of Typed Term Graphs

We employ the dependently-typed programming language Agda2 to explore formalisation of untyped and typed term graphs directly as set-based graph structures, via the gs-monoidal categories of Corradini and Gadducci, and as nested let-expressions using Pouillard and Pottier's NotSoFresh library of variable-binding abstractions.Comment: In Proceedings TERMGRAPH 2011, arXiv:1102.226

Amorphous Silk Fibroin Membranes for Separation of CO2

Amorphous silk fibroin has shown promise as a polymeric material derivable from natural sources for making membranes for use in removing CO2 from mixed-gas streams. For most applications of silk fibroin, for purposes other than gas separation, this material is used in its highly crystalline, nearly natural form because this form has uncommonly high tensile strength. However, the crystalline phase of silk fibroin is impermeable, making it necessary to convert the material to amorphous form to obtain the high permeability needed for gas separation. Accordingly, one aspect of the present development is a process for generating amorphous silk fibroin by treating native silk fibroin in an aqueous methanol/salt solution. The resulting material remains self-standing and can be prepared as thin film suitable for permeation testing. The permeability of this material by pure CO2 has been found to be highly improved, and its mixed-gas permeability has been found to exceed the mixed-gas permeabilities of several ultrahigh-CO2-permeable synthetic polymers. Only one of the synthetic polymers poly(trimethylsilylpropyne) [PTMSP] may be more highly permeable by CO2. PTMSP becomes unstable with time, whereas amorphous silk should not, although at the time of this reporting this has not been conclusively proven

Is There a Patient Profile That Characterizes a Patient With Adult Spinal Deformity as a Candidate for Minimally Invasive Surgery?

Study designRetrospective review.ObjectivesThe goal of this study was to evaluate the baseline characteristics of patients chosen to undergo traditional open versus minimally invasive surgery (MIS) for adult spinal deformity (ASD).MethodsA multicenter review of 2 databases including ASD patients treated with surgery. Inclusion criteria were age >45 years, Cobb angle minimum of 20°, and minimum 2-year follow-up. Preoperative radiographic parameters and disability outcome measures were reviewed.ResultsA total of 350 patients were identified: 173 OPEN patients and 177 MIS. OPEN patients were significantly younger than MIS patients (61.5 years vs 63.74 years, P = .013). The OPEN group had significantly more females (87% vs 76%, P = .006), but both groups had similar body mass index. Preoperative lumbar Cobb was significantly higher for the OPEN group (34.2°) than for the MIS group (26.0°, P < .001). The mean preoperative Oswestry Disability Index was significantly higher in the MIS group (44.8 in OPEN patients and 49.8 in MIS patients, P < .011). The preoperative Numerical Rating Scale value for back pain was 7.2 in the OPEN group and 6.8 in the MIS group preoperatively, P = .100.ConclusionsPatients chosen for MIS for ASD are slightly older and have smaller coronal deformities than those chosen for open techniques, but they did not have a substantially lesser degree of sagittal malalignment. MIS surgery was most frequently utilized for patients with an sagittal vertical axis under 6 cm and a baseline pelvic incidence and lumbar lordosis mismatch under 30°

Using z14 Fused-Multiply-Add Instructions to Accelerate Elliptic Curve Cryptography

Due to growing commercial applications like Blockchain, the performance of large-integer arithmetic is the focus of both academic and industrial research. IBM introduced a new integer fused multiply-add instruction in z14, called VMSL, to accelerate such workloads. Unlike their floating-point counterparts, there are a variety of integer fused multiply-add instruction designs. VMSL multiplies two pairs of radix $2^{56}$ inputs, sums the two results together with an additional 128-bit input, and stores the resulting 128-bit value in a vector register. In this paper, we will describe the unique features of VMSL, the ways in which it is inherently more efficient than alternative specifications, in particular by enabling multiple carry strategies. We will then look at the issues we encountered implementing Montgomery Modular Multiplication for Elliptic Curve Cryptography on z14, including radix choice, mixed radices, instruction selection to trade instruction count for latency, and VMSL-specific optimizations for Montgomery-friendly moduli. The best choices resulted in a 20% increase in throughput

Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

New horizons in the role of digital data in the healthcare of older people

There are national and global moves to improve effective digital data design and application in healthcare. This New Horizons commentary describes the role of digital data in healthcare of the ageing population. We outline how health and social care professionals can engage in the proactive design of digital systems that appropriately serve people as they age, carers and the workforce that supports them.// Key Points: //Healthcare improvements have resulted in increased population longevity and hence multimorbidity.// //Shared care records to improve communication and information continuity across care settings hold potential for older people.// Data structure and coding are key considerations.// A workforce with expertise in caring for older people with relevant knowledge and skills in digital healthcare is important./

Electrooxidation of methanol on Ag, AgNi, and AgCo catalysts prepared by combustion synthesis technique

Herein, we report the synthesis of silver-based electrocatalysts (Ag/C, AgCo/C, and AgNi/C) using solution combustion method and their performance towards methanol oxidation reaction. Detailed structural and microscopic analysis confirmed the formation of graphitic carbon, synthesis of crystalline phases with high porosity in all the three electrocatalysts. X-ray photoelectron spectroscopic (XPS) analysis showed a high concentration of Ag2O (or Ag+) on AgNi/C, whereas AgCo/C exhibited a high concentration AgO (or Ag2+) on the surface. XPS analysis on C 1s confirmed the highest concentrations of the sp2 hybridized C-C bond on Ag/C, C-O on AgNi/C, and O-C-O bond on AgCo/C, respectively. The X-ray absorption spectroscopy (XAS) analysis on Ag edge showed a similarity in the bond lengths in AgCo and AgNi samples to that of bulk silver, that has a bond length of 2.89 Å, with only silver-silver scattering and the absence of a different or a nonsilver metal in the nanoparticles. This indicates that there is no Ag-M alloying. Nonetheless, a significant difference in particle sizes was observed, with 2.5 and 6 nm, respectively for AgNi and AgCo. Methanol electrooxidation experiments performed on the electrocatalysts indicated AgNi/C to show better performance in comparison to AgCo/C and Ag/C. Anodic polarization curves obtained from linear sweep voltammetry (LSV) measurements demonstrated a superior performance of AgNi/C with an onset potential of 0.41 V. In addition, 20 h chronoamperometry experiment also confirmed a sustained superior performance of AgNi/C catalyst, which could be due to smaller particle size and stabilization of Ag+ on the surface of the catalyst.This work was made possible by the NPRP grant (NPRP13S‐0109‐200029 and NPRP8‐145‐2‐066) from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors. Use of the Advanced Photon Source is supported by the U.S. Department of Energy, Office of Science, and Office of Basic Energy Sciences, under contract DE‐AC02‐06CH11357. Authors would also like to acknowledge Dr. Md. Abdul Matin for his initial support on catalysts synthesis and characterization. The authors would also like to acknowledge QEERI Core Labs for their support related to the TEM characterization