INTERPOL: A Primer

Since its formation, the International Criminal Police Organization (Interpol) has remained steadfast in its mission and objectives.  Interpol has always been a non-governmental organization that promotes law enforcement cooperation and intelligence sharing among member countries.  Interpol does not have authority to investigate violations of law, and it does not intervene in activities of a political, military, religious, or racial character.  In the post-9/11 environment, law enforcement agencies from across the globe have come to increasingly rely on Interpol as a repository of intelligence.  Interpol is able to succeed as an organization in part because of its relatively narrow focus.  The organization is able to avoid the significant political and ideological differences between member countries, such as between the United States and China, by having a single goal of combating crime

4-aminopyridyl-based lead compounds targeting CYP51 prevent spontaneous parasite relapse in a chronic model and improve cardiac pathology in an acute model of Trypanosoma cruzi infection.

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.Methodology/principal findingsBoth acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart.Conclusions/significanceThe positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life

Mapping of host-parasite-microbiome interactions reveals metabolic determinants of tropism and tolerance in Chagas disease

Chagas disease (CD) is a parasitic disease caused by Trypanosoma cruzi protozoa, presenting with cardiomyopathy, megaesophagus, and/or megacolon. To determine the mechanisms of gastrointestinal (GI) CD tissue tropism, we systematically characterized the spatial localization of infection-induced metabolic and microbiome alterations, in a mouse model of CD. Notably, the impact of the transition between acute and persistent infection differed between tissue sites, with sustained large-scale effects of infection in the esophagus and large intestine, providing a potential mechanism for the tropism of CD within the GI tract. Infection affected acylcarnitine metabolism; carnitine supplementation prevented acute-stage CD mortality without affecting parasite burden by mitigating infection-induced metabolic disturbances and reducing cardiac strain. Overall, results identified a previously-unknown mechanism of disease tolerance in CD, with potential for new therapeutic regimen development. More broadly, results highlight the potential of spatially resolved metabolomics to provide insight into disease pathogenesis and infectious disease drug development.Open Access fees paid for in whole or in part by the University of Oklahoma Libraries. This work was supported by start-up funds from the University of Oklahoma to L.-I.M. and the National Institute of Allergy and Infectious Diseases of the NIH under award number R21AI148886 to L.-I.M. Initial tissue collection was supported by a postdoctoral fellowship to L.-I.M. from the Canadian Institutes of Health Research (award number 338511; www.cihr-irsc.gc.ca/). Microbial community analysis was supported, in part, by an NIH grant (award number NIH 2R01-GM089886 to K.S). Immunological characterization was performed on instrumentation from the OU Protein Production and Characterization Core facility, supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH under grant number P20GM103640. Histology samples were processed by the University of Oklahoma Health Sciences Center, Stephenson Cancer Center Tissue Pathology Shared Resource, supported by the National Cancer Institute Cancer Center Support Grant P30CA225520 and COBRE P20GM103639. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.Ye

Furance and carbon dioxide laser densification of sol-gel derived silicon oxide-titanium oxide-aluminum oxide planar optical waveguides

An experimental investigation on the furnace and CO₂ laser densification of sol-gel derived SiO₂-TiO₂-Al₂O₃ planar optical waveguides was performed. Solutions containing equal mole fractions of tetraethoxysiline [Si(C₂H₅O)₄], titanium ethoxide [Ti(C₂H₅O)₄], aluminum tri-sec-butoxide [Al(C₄H₉O)₃] were used to spin films with a nominal 2:2:1 molar SiO₂-TiO₂-Al₂O₃ composition. Emphasis was placed on determining what effects the densification techniques had on film shrinkage, index change, crystallization and composition. Film shrinkage and refractive index change were found to be similar for both densification techniques. Fully dense, amorphous film were obtained with both methods. After densification, further heating caused titania crystalline phases to form with both processing techniques. However, anatase formed in the furnace fired films while rutile formed in the laser irradiated films

Metabolite Profiling Of Experimental Cutaneous Leishmaniasis Lesions Demonstrates Significant Perturbations In Tissue Glycerophosphocholines

Each year 700,000 to 1.2 million new cases of cutaneous leishmaniasis (CL) are reported and yet CL remains one of thirteen diseases classified as neglected tropical diseases (NTDs). Leishmania major is one of several different species of that same genus that can cause CL. Current CL treatments are limited by adverse effects and rising resistance. Studying disease metabolism at the site of infection can lead to new drug targets. In this study, samples were collected from mice infected in the ear and footpad with L. major and analyzed by untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differences in overall metabolite profiles were noted in the ear at the site of the lesion. Interestingly, lesion-adjacent, macroscopically healthy sites also showed alterations in specific metabolites, including select phosphocholines (PCs). Host-derived PCs in the lower m/z range (m/z 200-799) showed an increase with infection in the ear at the lesion site, while those in the higher m/z range (m/z 800-899) were decreased with infection at the lesion site. Overall, our results expanded our understanding of the mechanisms of CL pathogenesis through the host metabolism and may lead to new curative measures against infection with Leishmania