Thimet oligopeptidase (EC 3.4.24.15) key functions suggested by knockout mice phenotype characterization

Thimet oligopeptidase (THOP1) is thought to be involved in neuropeptide metabolism, antigen presentation, neurodegeneration, and cancer. Herein, the generation of THOP1 C57BL/6 knockout mice (THOP1(-/-)) is described showing that they are viable, have estrus cycle, fertility, and a number of puppies per litter similar to C57BL/6 wild type mice (WT). In specific brain regions, THOP1(-/-) exhibit altered mRNA expression of proteasome beta5, serotonin 5HT2a receptor and dopamine D2 receptor, but not of neurolysin (NLN). Peptidomic analysis identifies differences in intracellular peptide ratios between THOP1(-/-) and WT mice, which may affect normal cellular functioning. In an experimental model of multiple sclerosis THOP1(-/-) mice present worse clinical behavior scores compared to WT mice, corroborating its possible involvement in neurodegenerative diseases. THOP1(-/-) mice also exhibit better survival and improved behavior in a sepsis model, but also a greater peripheral pain sensitivity measured in the hot plate test after bradykinin administration in the paw. THOP1(-/-) mice show depressive-like behavior, as well as attention and memory retention deficits. Altogether, these results reveal a role of THOP1 on specific behaviors, immune-stimulated neurodegeneration, and infection-induced inflammation

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Preliminary contributions towards auto-resilience

Abstract. The variability in the conditions of deployment environments introduces new challenges for the resilience of our computer systems. As a response to said challenges, novel approaches must be devised so that identity robustness be guaranteed autonomously and with minimal overhead. This paper provides the elements of one such approach. First, building on top of previous results, we formulate a metric framework to compare specific aspects of the resilience of systems and environments. Such framework is then put to use by sketching the elements of a handshake mechanism between systems declaring their resilience figures and environments stating their minimal resilience requirements. Despite its simple formulation it is shown how said mechanism enables scenarios in which resilience can be autonomously enhanced, e.g., through forms of social collaboration. This paves the way to future “auto-resilient ” systems, namely systems able to reason and revise their own architectures and organisations so as to optimally guarantee identity persistence.

Antimicrobial Resistance Of Staphylococcus Aureus And Oral Streptococci Strains From High-risk Endocarditis Patients

This study sought to determine the antimicrobial susceptibility of Staphylcoccus aureus and viridans group streptococci strains collected from the forearm skin and saliva of 30 patients at high risk of endocarditis. Agar susceptibility tests of antibiotics routinely utilized in dentistry were used to verify antimicrobial resistance of bacterial strains. Of the Staphylcoccus aureus strains, 50% were resistant to ampicillin, 53.3% to amoxicillin, 60.0% to penicillin G, 13.3% to amoxicillin/clavulanate, 20.0% to azithromycin, 27.6% to clarithromycin, 23.3% to erythromycin, 3.3% to cefazolin, and 6.7% to clindamycin. Regarding streptococci, 16.7% of the strains were resistant to ampicillin, 16.7% to amoxicillin, 23.3% to azithromycin, 23.3% to clarithromycin, 30.0% to erythromycin, 13.3% to cefazolin, 26.7% to clindamycin, 16.7% to penicillin G, and 3.3% to amoxicillin/clavulanate. Pathogens associated with bacterial endocarditis exhibited elevated resistance rates against the antibiotics used for prophylaxis in dentistry.536410413Benn, M., Hagelskjaer, L.H., Tvede, M., Infective endocarditis, 1984 through 1993: A clinical and microbiological survey (1997) J Intern Med, 242, pp. 15-22Mansur, A.J., Grinberg, M., Gallucci, S.D., Bellotti, G., Jatene, A., Pileggi, F., Infective endocarditis: Analysis of 300 episodes (1990) Arq Bras Cardiol, 54, pp. 13-21Ruiz Jr., E., Schirmbeck, T., Figueiredo, L.T., A study of infectious endocarditis in Ribeirao Preto, SP-Brazil. Analysis of cases occurring between 1992 and 1997 (2000) Arq Bras Cardiol, 74, pp. 225-231Dajani, A.S., Taubert, K.A., Wilson, W., Bolger, A.F., Bayer, A., Ferrieri, P., Gewitz, M.H., Zuccaro Jr., G., Prevention of bacterial endocarditis. Recommendations by the American Heart Association (1997) Circulation, 96, pp. 358-366Moreillon, P., Que, Y.A., Infective endocarditis (2004) Lancet, 363, pp. 139-149Hogevik, H., Olaison, L., Andersson, R., Lindberg, J., Alestig, K., Epidemiologic aspects of infective endocarditis in an urban population. A 5-year prospective study (1995) Medicine, 74, pp. 324-339. , BaltimoreSandre, R.M., Shafran, S.D., Infective endocarditis: Review of 135 cases over 9 years (1996) Clin Infect Dis, 22, pp. 276-286McCartney, A.C., Changing trends in infective endocarditis (1992) J Clin Pathol, 45, pp. 945-948Carmona, I.T., Diz Dios, P., Scully, C., An update on the controversies in bacterial endocarditis of oral origin (2002) Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 93, pp. 660-670Eykyn, S.J., The treatment of staphylococcal endocarditis (1987) J Antimicrob Chemother, 20 (SUPPL. A), pp. 161-171Petti, C.A., Fowler Jr., V.G., Staphylococcus aureus bacteremia and endocarditis (2002) Infect Dis Clin North Am, 16, pp. 413-435Roman, R.S., Smith, J., Walker, M., Byrne, S., Ramotar, K., Dyck, B., Kabani, A., Nicolle, L.E., Rapid geographic spread of a methicillin-resistant Staphylococcus aureus strain (1997) Clin Infect Dis, 25, pp. 698-705Farias, W.V., Sader, H.S., Lerne, I.L., Pignatari, A.C., Sensitivity pattern of 117 clinical isolates of Staphylococcus aureus from 12 hospitals (1997) Rev Assoc Med Bras, 43, pp. 199-204Perl, T.M., Golub, J.E., New approaches to reduce Staphylococcus aureus nosocomial infection rates: Treating S. aureus nasal carriage (1998) Ann Pharmacother, 32, pp. S7-S16Herzberg, M.C., Meyer, M.W., Effects of oral flora on platelets: Possible consequences in cardiovascular disease (1996) J Periodontol, 67, pp. 1138-1142Baquero, F., Gram-positive resistance: Challenge for the development of new antibiotics (1997) J Antimicrob Chemother, 39 (SUPPL. A), pp. 1-6Martinez, F., Martin-Luengo, F., Garcia, A., Valdes, M., Treatment of experimental endocarditis caused by penicillin-resistant Streptococcus sanguis with different doses of teicoplanin (1994) Methods Find Exp Clin Pharmacol, 16, pp. 247-251Doern, G.V., Ferraro, M.J., Brueggemann, A.B., Ruoff, K.L., Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States (1996) Antimicrob Agents Chemother, 40, pp. 891-894Levy, C.S., Kogulan, P., Gill, V.J., Croxton, M.B., Kane, J.G., Lucey, D.R., Endocarditis caused by penicillin-resistant viridans streptococci: 2 Cases and controversies in therapy (2001) Clin Infect Dis, 33, pp. 577-579Hall, G.E., Baddour, L.M., Apparent failure of endocarditis prophylaxis caused by penicillin-resistant Streptococcus mitis (2002) Am J Med Sci, 324, pp. 51-53Koneman, E.W., Allen, S.D., Janda, W.M., Schreckenberger, P.C., Winn, W.C., (1994) Introduction to Diagnostic Microbiology, Ed. 1, pp. 187-216. , Philadelphia: Lippincott Williams & Wilkins(2002) Performance Standards for Antimicrobial Susceptibility Testing, 22, pp. 50-69. , Document M100-S12Hoen, B., Platelets and platelet inhibitors in infective endocarditis (2002) Curr Infect Dis Rep, 4, pp. 299-303Tak, T., Reed, K.D., Haselby, R.C., McCauley Jr., C.S., Shukla, S.K., An update on the epidemiology, pathogenesis and management of infective endocarditis with emphasis on Staphylococcus aureus (2002) WMJ, 101, pp. 24-33Moore, P.A., Dental therapeutic indications for the newer long-acting macrolide antibiotics (1999) J Am Dent Assoc, 130, pp. 1341-1343Kohli, V., Infective endocarditis (2002) Indian J Pediatr, 69, pp. 333-339Scavizzi, M.R., Labia, R., Petitjean, O.J., Elbhar, A., Antimicrobial susceptibility test: From bacterial population analysis to therapy (2002) Int J Antimicrob Agents, 19, pp. 9-20Felten, A., Grandry, B., Lagrange, P.H., Casin, I., Evaluation of three techniques for detection of low-level methicillin-resistant Staphylococcus aureus (MRSA): A disk diffusion method with cefoxitin and moxalactam, the Vitek 2 system, and the MRSA-screen latex agglutination test (2002) J Clin Microbiol, 40, pp. 2766-2771Grignon, B., Tankovic, J., Megraud, F., Glupczynski, Y., Husson, M.O., Conroy, M.C., Emond, J.P., Fauchere, J.L., Validation of diffusion methods for macrolide susceptibility testing of Helicobacter pylori (2002) Microb Drug Resist, 8, pp. 61-66Chang, S.C., Hsieh, W.C., Liu, C.Y., High prevalence of antibiotic resistance of common pathogenic bacteria in Taiwan (2000) Diag Microbiol Infect Dis, 36, pp. 107-112. , The Antibiotic Resistance Study Group of the Infectious Disease Society of the Republic of ChinaSandor, G.K., Carmichael, R.P., Vasilakos, J.S., Revised American Heart Association guidelines for the prevention of bacterial endocarditis: Highlights of specific changes for the dental profession (1998) J Can Dent Assoc, 64, pp. 114-117Creighton, J.M., Dental care for the pediatric cardiac patient (1992) J Can Dent Assoc, 58, pp. 201-202Steckelberg, J.M., Melton III, L.J., Ilstrup, D.M., Rouse, M.S., Wilson, W.R., Influence of referral bias on the apparent clinical spectrum of infective endocarditis (1990) Am J Med, 88, pp. 582-588Jacobson, J.J., Patel, B., Asher, G., Woolliscroft, J.O., Schaberg, D., Oral staphylococcus in older subjects with rheumatoid arthritis (1997) J Am Geriatr Soc, 45, pp. 590-593Alcaide, F., Linares, J., Pallares, R., Carratala, J., Benitez, M.A., Gudiol, F., Martin, R., In vitro activities of 22 beta-lactam antibiotics against penicillin-resistant and penicillin-susceptible viridans group streptococci isolated from blood (1995) Antimicrob Agents Chemother, 39, pp. 2243-2247Teng, L.J., Hsueh, P.R., Chen, Y.C., Ho, S.W., Luh, K.T., Antimicrobial susceptibility of viridans group streptococci in Taiwan with an emphasis on the high rates of resistance to penicillin and macrolides in Streptococcus oralis (1998) J Antimicrob Chemother, 41, pp. 621-627Chayakul, P., Hortiwakul, R., Yipintsoi, T., Ingviya, N., Viridans streptococci in the oral flora of the patients at risk for infective endocarditis: Species and penicillin susceptibilities (2002) J Med Assoc Thai, 85, pp. 825-830Monroe, S., Polk, R., Antimicrobial use and bacterial resistance (2000) Curr Opin Microbiol, 3, pp. 496-501Seymour, R.A., Whitworth, J.W., Antibiotic prophylaxis for endocarditis, prosthetic joints, and surgery (2002) Dent Clin North Am, 46, pp. 635-65

Differential behavioral outcomes of 3,4-methylenedioxymethamphetamine (MDMA-ecstasy) in anxiety-like responses in mice

Anxiolytic and anxiogenic-like behavioral outcomes have been reported for methylenedioxymethamphetamine (MDMA or ecstasy) in rodents. In the present experiment, we attempted to identify behavioral, hormonal and neurochemical outcomes of MDMA treatment to clarify its effects on anxiety-related responses in 2-month-old Balb/c male mice (25-35 g; N = 7-10 mice/group). The behavioral tests used were open field, elevated plus maze, hole board, and defensive behavior against predator odor. Moreover, we also determined striatal dopamine and dopamine turnover, and serum corticosterone levels. MDMA was injected ip at 0.2, 1.0, 5.0, 8.0, 10, or 20 mg/kg. MDMA at 10 mg/kg induced the following significant (P < 0.05) effects: a) a dose-dependent increase in the distance traveled and in the time spent moving in the open field; b) decreased exploratory activity in the hole board as measured by number of head dips and time spent in head dipping; c) increased number of open arm entries and increased time spent in open arm exploration in the elevated plus maze; d) increased time spent away from an aversive stimulus and decreased number of risk assessments in an aversive odor chamber; e) increased serum corticosterone levels, and f) increased striatal dopamine level and turnover. Taken together, these data suggest an anxiogenic-like effect of acute MDMA treatment, despite the fact that behavioral anxiety expression was impaired in some of the behavioral tests used as a consequence of the motor stimulating effects of MDMA