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Background: [α.sub.1]-Acid glycoprotein ([α.sub.1]-AGP) is an acute phase protein in most mammalian species whose concentration rises 2-5-fold during an acute phase reaction. Its serum concentration has often been used as [...]

Summary Hydrogen is one of the most promising alternative fuels for the transportation industry. The use of hydrogen to enable lean burn in internal combustion engines is an attractive solution for reducing CO2 emissions from two points of views: the substitution of carbon‐based fuels and the increased thermal efficiency due to lean operation. Combining this strategy with the passive pre‐chamber ignition system with gasoline/hydrogen blends is even more interesting. The main limitations of the passive pre‐chamber concept in a high compression ratio spark‐ignition engine were shown through engine experiments. A numerical study was then performed to evaluate the chance of extending the dilution limit by using hydrogen along with this technology. Results show how the use of hydrogen provides considerable benefits in the main chamber combustion process by enhancing the thermo‐chemical properties of the mixture, increasing the flame speed, and improving the flame structure. Using an adequate gasoline‐hydrogen blend proved to enable optimum burning rates at lean conditions, leading to a relevant thermal efficiency gain. [ABSTRACT FROM AUTHOR]

The global burden of HIV remains unacceptably high despite significant progress made in HIV treatment and prevention. There is an urgent need to scale up the comprehensive HIV prevention strategies that include pre-exposure prophylaxis (PrEP). Oral PrEP is highly effective in preventing HIV acquisition when taken regularly, but this remains a challenge for some at-risk individuals. Therefore, there is a need for other HIV prevention options. The dapivirine vaginal ring (DVR) and long-acting injectable cabotegravir (CAB-LA) are novel biomedical interventions that are safe and efficacious for HIV pre-exposure prophylaxis, as demonstrated in recently completed clinical trials. Timely roll-out and scalability of efficacious interventions depend on the registration process with the national medicine regulatory authorities (NMRAs). The Medicines Control Authority of Zimbabwe (MCAZ) was the first NMRA globally to approve the DVR in July 2021 and the first in Africa to approve CAB-LA for HIV prevention in July 2022. The regulatory review process for DVR and CAB-LA by MCAZ took 4.5 and 5.5 months, respectively. This efficient review process of the two interventions by MCAZ, a regulatory body in a resource-limited setting, provides important lessons to shorten timelines between the completion of the clinical development process and the registration of essential medicines.

A hydroxypyrone-based matrix metalloproteinase (MMP) inhibitor was synthesized and assayed for its inhibitory capacity towards a panel of ten different MMPs. The compound exhibited selective inhibition towards MMP-12. The effects of inhibition of MMP-12 on endotoxemia and inflammation-induced blood-cerebrospinal fluid barrier (BCSFB) disruption were assessed both in vitro and in vivo. Similar to MMP-12 deficient mice, inhibitor-treated mice displayed significantly lower lipopolysaccharide- (LPS-) induced lethality compared to vehicle treated controls. Following LPS injection Mmp-12 mRNA expression was massively upregulated in choroid plexus tissue and a concomitant increase in BCSFB permeability was observed, which was restricted in inhibitor-treated mice. Moreover, an LPS-induced decrease in tight junction permeability of primary choroid plexus epithelial cells was attenuated by inhibitor application in vitro. Taken together, this hydroxypyrone-based inhibitor is selective towards MMP-12 and displays anti-inflammatory activity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Viral infections contribute to the pathogenesis of type 1 diabetes. Viruses, or viral products such as double-stranded RNA (dsRNA), affect pancreatic beta-cell survival and trigger autoimmunity by unknown mechanisms. We presently investigated the mediators and downstream effectors of dsRNA-induced beta-cell death. RESEARCH DESIGN AND METHODS: Primary rat beta-cells and islet cells from wild-type, toll-like receptor (TLR) 3, type I interferon receptor (IFNAR1), or interferon regulatory factor (IRF)-3 knockout mice were exposed to external dsRNA (external polyinosinic-polycytidylic acid [PICex]) or were transfected with dsRNA ([PICin]). RESULTS: TLR3 signaling mediated PICex-induced nuclear factor-kappaB (NF-kappaB) and IRF-3 activation and beta-cell apoptosis. PICin activated NF-kappaB and IRF-3 in a TLR3-independent manner, induced eukaryotic initiation factor 2 alpha phosphorylation, and triggered a massive production of interferon (IFN)-beta. This contributed to beta-cell death, as islet cells from IFNAR1(-/-) or IRF-3(-/-) mice were protected against PICin-induced apoptosis. CONCLUSIONS: PICex and PICin trigger beta-cell apoptosis via the TLR3 pathway or IRF-3 signaling, respectively. Execution of PICin-mediated apoptosis depends on autocrine effects of type I IFNs. [ABSTRACT FROM AUTHOR]

Investigates the possible role for increased serum levels of alpha-acid glycoprotein in the development of inflammatory bowel disease. Overexpression of alpha-acid glycoproteins in transgenic mice that leads to sensitization to acute colitis; Analysis of pertinent topics and relevant issues; Implications on gastroenterology and hepatology.

Necrostatin-1 (Nec-1) is widely used in disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantoin-tryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was ∼100 × less effective than Nec-1 in inhibiting human RIPK1 kinase activity in vitro, it was only 10 times less potent than Nec-1 and Nec-1s in a mouse necroptosis assay and became even equipotent at high concentrations. Along the same line, in vivo, high doses of Nec-1, Nec-1i and Nec-1s prevented tumor necrosis factor (TNF)-induced mortality equally well, excluding the use of Nec-1i as an inactive control. Paradoxically, low doses of Nec-1 or Nec-1i, but not Nec -1s, even sensitized mice to TNF-induced mortality. Importantly, Nec-1s did not exhibit this low dose toxicity, stressing again the preferred use of Nec-1s in vivo. Our findings have important implications for the interpretation of Nec-1-based data in experimental disease models.

Abstract Background There is a demand for serum markers for the routine assessment of the progression of liver cancer. We previously found that serum N-linked sugar chains are altered in hepatocellular carcinoma (HCC). Here, we studied glycomic alterations during development of HCC in a rat model. Results Rat HCC was induced by the hepatocarcinogen, diethylnitrosamine (DENA). N-glycans were profiled using the DSA-FACE technique developed in our laboratory. In comparison with control rats, DENA rats showed a gradual but significant increase in two glycans (R5a and R5b) in serum total N-glycans during progression of liver cirrhosis and cancer, and a decrease in a biantennary glycan (P5). The log of the ratio of R5a to P1 (NGA2F) and R5b to P1 [log(R5a/P1) and log(R5b/P1)] were significantly (p < 0.0001) elevated in HCC rats, but not in rats with cirrhosis or fibrosis or in control rats. We thus propose a GlycoTest model using the above-mentioned serum glycan markers to monitor the progression of cirrhosis and HCC in the DENA-treated rat model. When DENA-treated rats were subsequently treated with farnesylthiosalicyclic acid, an anticancer drug, progression to HCC was prevented and GlycoTest markers (P5, R5a and R5b) reverted towards non-DENA levels, and the HCC-specific markers, log(R5a/P1) and log(R5b/P1), normalized completely. Conclusions: We found an increase in core-α-1,6-fucosylated glycoproteins in serum and liver of rats with HCC, which demonstrates that fucosylation is altered during progression of HCC. Our GlycoTest model can be used to monitor progression of HCC and to follow up treatment of liver tumors in the DENA rat. This GlycoTest model is particularly important because a rapid non-invasive diagnostic procedure for tumour progression in this rat model would greatly facilitate the search for anticancer drugs.

The article describes a case of systemic candidosis in a guanaco kept in captivity. It is noted that the postmortem findings in reported cases of disseminated candidosis include the enlargement of lymph nodes, nephritis and hepatitis. The case elaborates that systemic candidosis should be considered after ineffective antibiotic treatment in captive, stressed animals.

Rabies virus is a neurovirulent RNA virus, which causes about 59,000 human deaths each year. Treatment for rabies does not exist due to incomplete understanding of the pathogenesis. MALT1 mediates activation of several immune cell types and is involved in the proliferation and survival of cancer cells. MALT1 acts as a scaffold protein for NF-kB signaling and a cysteine protease that cleaves substrates, leading to the expression of immunoregulatory genes. Here, we examined the impact of genetic or pharmacological MALT1 inhibition in mice on disease development after infection with the virulent rabies virus strain CVS-11. Morbidity and mortality were significantly delayed in Malt1-/- compared to Malt1-/- mice, and this effect was associated with lower viral load, proinflammatory gene expression, and infiltration and activation of immune cells in the brain. Specific deletion of Malt1 in T cells also delayed disease development, while deletion in myeloid cells, neuronal cells, or NK cells had no effect. Disease development was also delayed in mice treated with the MALT1 protease inhibitor mepazine and in knock-in mice expressing a catalytically inactive MALT1 mutant protein, showing an important role of MALT1 proteolytic activity. The described protective effect of MALT1 inhibition against infection with a virulent rabies virus is the precise opposite of the sensitizing effect of MALT1 inhibition that we previously observed in the case of infection with an attenuated rabies virus strain. Together, these data demonstrate that the role of immunoregulatory responses in rabies pathogenicity is dependent on virus virulence and reveal the potential of MALT1 inhibition for therapeutic intervention. IMPORTANCE Rabies virus is a neurotropic RNA virus that causes encephalitis and still poses an enormous challenge to animal and public health. Efforts to establish reliable therapeutic strategies have been unsuccessful and are hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protease that mediates the activation of several innate and adaptive immune cells in response to multiple receptors, and therapeutic MALT1 targeting is believed to be a valid approach for autoimmunity and MALT1-addicted cancers. Here, we study the impact of MALT1 deficiency on brain inflammation and disease development in response to infection of mice with the highly virulent CVS-11 rabies virus. We demonstrate that pharmacological or genetic MALT1 inhibition decreases neuroinflammation and extends the survival of CVS-11-infected mice, providing new insights in the biology of MALT1 and rabies virus infection. [ABSTRACT FROM AUTHOR]

• The passive TJI system fueled by CNG is experimentally and numerically evaluated. • 1D numerical methodology helps to gain knowledge and improve the pre-chamber design. • Experimental results support the findings of the numerical methodology. • Increasing the pre-chamber volume has benefits under restrictive conditions. • An optimum swirl level inside the pre-chamber helps to stabilize combustion. Passive pre-chamber ignition concept has been proven to be an excellent strategy to increase the ignition energy and enhance the combustion velocity even when spark-ignition engines are operating in diluted conditions. Other benefits of this system are the increased combustion stability and combustion efficiency, reducing hydrocarbons and carbon monoxide emissions. However, these advantages are limited at some operation conditions such as low engine load or diluted conditions since both the energy available in the pre-chamber and the scavenge of combustion products are compromised. In this framework, numerical studies using two different computational tools, based on one-dimensional modeling, are utilized to gain knowledge about the governing parameters and to improve the design of a pre-chamber when the engine operates at these restrictive conditions. In particular, the impact of the pre-chamber volume, the total cross sectional area of the holes and tangential angle of the nozzles have been numerically evaluated. Different pre-chamber designs were proposed and experimentally tested in a single-cylinder, high compression ratio turbocharged spark-ignition engine fueled with compressed natural gas and operating on Miller cycle. Results give valuable insight into the key aspects of the internal geometry and some relevant design paths to follow for a suitable pre-chamber definition. [ABSTRACT FROM AUTHOR]