The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent type I interferon (IFN) inducer, was evaluated as a chemotherapeutic agent in mouse cancer models and proved to be well tolerated in human cancer clinical trials. Despite its multiple biological functions, DMXAA has not been fully characterized for the potential application as a vaccine adjuvant. In this report, we show that DMXAA does act as an adjuvant due to its unique property as a soluble innate immune activator. Using OVA as a model antigen, DMXAA was demonstrated to improve on the antigen specific immune responses and induce a preferential Th2 (Type-2) response. The adjuvant effect was directly dependent on the IRF3-mediated production of type-I-interferon, but not IL-33. DMXAA could also enhance the immunogenicity of influenza split vaccine which led to significant increase in protective responses against live influenza virus challenge in mice compared to split vaccine alone. We propose that DMXAA can be used as an adjuvant that targets a specific innate immune signaling pathway via IRF3 for potential applications including vaccines against influenza which requires a high safety profile

A comparative study on the abundance and elemental composition of POM in three interconnected basins: the Black, the Marmara and the Mediterranean Seas

The abundance and elemental composition of suspended particulate organic matter in the upper layers of the interconnected Mediterranean, Marmara and Black Seas having different ecosystems were determined in 1990-1998. The aim was principally to compare the C:N:P ratio of seston and understand factors controlling the seston composition in near- and off-shore waters of these seas. In the Marmara Sea, euphotic zone average particulate concentrations varied regionally and seasonally between 10-35 ìM for POC, 0.4-4.5 ìM for PON and 0.05-0.45 ìM for PP. These concentrations are mostly above the off-shore Black Sea values but much greater than those measured in the open waters of the north-eastern Mediterranean whose near-shore data are comparable with the seston content of the deep Black Sea. Comparison of C:N:P ratios of seston reveals that atmospheric and land-based phosphorus input influences the C:P and N:P ratios in the near-shore waters. Apparent nutrient deficiencies observed in the water column were not as remarkable in the elemental composition of seston. Unexpectedly, in the NE Mediterranean, N:P ratios from regression analyses of particulate data are very low (7-9) in the coastal region but slightly increase to levels of 10-15 in the open sea. In the Sea of Marmara, the N:P ratios (7-12) of seston are as low as in the Mediterranean, being consistent with the particulate ratios of the Black Sea inflow and NO3:PO4 ratios of the Marmara sub-halocline water. The Black Sea seston is relatively rich in carbonaceous compounds with N:P ratio ranging merely between 15-17 in the open sea but 9-27 in coastal waters where riverine discharges markedly influence the stoichiometry of seston

Discovery of Delta Scuti variables in eclipsing binary systems II.Southern TESS field search

The presence of pulsating stars in eclipsing binary systems (EBs) makes these objects significant since they allow us to investigate the stellar interior structure and evolution. Different types of pulsating stars could be found in EBs such as Delta Scuti variables. Delta Scuti stars in EBs have been known for decades and the increasing number of such systems is important for understanding pulsational structure. Hence, in this study, a research was carried out on the southern TESS field to discover new Delta Scuti stars in EBs. We produced an algorithm to search for detached and semi-detached EBs considering three steps; the orbital period (P$_{orb}$)'s harmonics in the Fourier spectrum, skewness of the light curves, and classification of \textsc{UPSILON} program. If two of these steps classify a system as an EB, the algorithm also identifies it as an EB. The TESS pixel files of targets were also analyzed to see whether the fluxes are contaminated by other systems. No contamination was found. We researched the existence of pulsation through EBs with a visual inspection. To confirm Delta Scuti-type oscillations, the binary variation was removed from the light curve, and residuals were analyzed. Consequently, we identified 42 Delta Scuti candidates in EBs. The P$_{orb}$, $L$, and M$_{V}$ of systems were calculated. Their positions on the H-R diagram and the known orbital-pulsation period relationship were analyzed. We also examined our targets to find if any of them show frequency modulation with the orbital period and discovered one candidate of tidally tilted pulsators.Comment: Published in MNRA

Malarial Hemozoin Is a Nalp3 Inflammasome Activating Danger Signal

BACKGROUND: Characteristic symptoms of malaria include recurrent fever attacks and neurodegeneration, signs that are also found in patients with a hyperactive Nalp3 inflammasome. Plasmodium species produce a crystal called hemozoin that is generated by detoxification of heme after hemoglobin degradation in infected red blood cells. Thus, we hypothesized that hemozoin could activate the Nalp3 inflammasome, due to its particulate nature reminiscent of other inflammasome-activating agents. METHODOLOGY/PRINCIPAL FINDINGS: We found that hemozoin acts as a proinflammatory danger signal that activates the Nalp3 inflammasome, causing the release of IL-1beta. Similar to other Nalp3-activating particles, hemozoin activity is blocked by inhibiting phagocytosis, K(+) efflux and NADPH oxidase. In vivo, intraperitoneal injection of hemozoin results in acute peritonitis, which is impaired in Nalp3-, caspase-1- and IL-1R-deficient mice. Likewise, the pathogenesis of cerebral malaria is dampened in Nalp3-deficient mice infected with Plasmodium berghei sporozoites, while parasitemia remains unchanged. SIGNIFICANCE/CONCLUSIONS: The potent pro-inflammatory effect of hemozoin through inflammasome activation may possibly be implicated in plasmodium-associated pathologies such as cerebral malaria

Malarial Hemozoin Is a Nalp3 Inflammasome Activating Danger Signal

BACKGROUND: Characteristic symptoms of malaria include recurrent fever attacks and neurodegeneration, signs that are also found in patients with a hyperactive Nalp3 inflammasome. Plasmodium species produce a crystal called hemozoin that is generated by detoxification of heme after hemoglobin degradation in infected red blood cells. Thus, we hypothesized that hemozoin could activate the Nalp3 inflammasome, due to its particulate nature reminiscent of other inflammasome-activating agents. METHODOLOGY/PRINCIPAL FINDINGS: We found that hemozoin acts as a proinflammatory danger signal that activates the Nalp3 inflammasome, causing the release of IL-1beta. Similar to other Nalp3-activating particles, hemozoin activity is blocked by inhibiting phagocytosis, K(+) efflux and NADPH oxidase. In vivo, intraperitoneal injection of hemozoin results in acute peritonitis, which is impaired in Nalp3-, caspase-1- and IL-1R-deficient mice. Likewise, the pathogenesis of cerebral malaria is dampened in Nalp3-deficient mice infected with Plasmodium berghei sporozoites, while parasitemia remains unchanged. SIGNIFICANCE/CONCLUSIONS: The potent pro-inflammatory effect of hemozoin through inflammasome activation may possibly be implicated in plasmodium-associated pathologies such as cerebral malaria

Characterisation and mechanical modelling of polyacrylonitrile-based nanocomposite membranes reinforced with silica nanoparticles

In this study, neat polyacrylonitrile (PAN) and fumed silica (FS)-doped PAN membranes (0.1, 0.5 and 1 wt% doped PAN/FS) are prepared using the phase inversion method and are characterised extensively. According to the Fourier Transform Infrared (FTIR) spectroscopy analysis, the addition of FS to the neat PAN membrane and the added amount changed the stresses in the membrane structure. The Scanning Electron Microscope (SEM) results show that the addition of FS increased the porosity of the membrane. The water content of all fabricated membranes varied between 50% and 88.8%, their porosity ranged between 62.1% and 90%, and the average pore size ranged between 20.1 and 21.8 nm. While the neat PAN membrane’s pure water flux is 299.8 L/m2 h, it increased by 26% with the addition of 0.5 wt% FS. Furthermore, thermal gravimetric analysis (TGA) and differential thermal analysis (DTA) techniques are used to investigate the membranes’ thermal properties. Finally, the mechanical characterisation of manufactured membranes is performed experimentally with tensile testing under dry and wet conditions. To be able to provide further explanation to the explored mechanics of the membranes, numerical methods, namely the finite element method and Mori–Tanaka mean-field homogenisation are performed. The mechanical characterisation results show that FS reinforcement increases the membrane rigidity and wet membranes exhibit more compliant behaviour compared to dry membranes

Accounting Problems Under the Excess Profits Tax

DNA vaccines based on subunits from pathogens have several advantages over other vaccine strategies. DNA vaccines can easily be modified, they show good safety profiles, are stable and inexpensive to produce, and the immune response can be focused to the antigen of interest. However, the immunogenicity of DNA vaccines which is generally quite low needs to be improved. Electroporation and co-delivery of genetically encoded immune adjuvants are two strategies aiming at increasing the efficacy of DNA vaccines. Here, we have examined whether targeting to antigen-presenting cells (APC) could increase the immune response to surface envelope glycoprotein (Env) gp120 from Human Immunodeficiency Virus type 1 (HIV- 1). To target APC, we utilized a homodimeric vaccine format denoted vaccibody, which enables covalent fusion of gp120 to molecules that can target APC. Two molecules were tested for their efficiency as targeting units: the antibody-derived single chain Fragment variable (scFv) specific for the major histocompatilibility complex (MHC) class II I-E molecules, and the CC chemokine ligand 3 (CCL3). The vaccines were delivered as DNA into muscle of mice with or without electroporation. Targeting of gp120 to MHC class II molecules induced antibodies that neutralized HIV-1 and that persisted for more than a year after one single immunization with electroporation. Targeting by CCL3 significantly increased the number of HIV-1 gp120-reactive CD8(+) T cells compared to non-targeted vaccines and gp120 delivered alone in the absence of electroporation. The data suggest that chemokines are promising molecular adjuvants because small amounts can attract immune cells and promote immune responses without advanced equipment such as electroporation.Funding Agencies|Research Council of Norway; Odd Fellow</p

Photometry of GS UMa: a suspected delta Scuti variable

We present the time series analysis of GS UMa. GS UMa is a suspected Scuti variable with a primary frequency of 6.0987 d

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis

Purpose We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Methods Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. Results We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. Conclusion In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome