Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo.

The apicomplexan parasite Neospora caninum is an important causative agent of congenital neosporosis, resulting in abortion, birth of weak offspring and neuromuscular disorders in cattle, sheep, and many other species. Among several compound classes that are currently being developed, two have been reported to limit the effects of congenital neosporosis: (i) bumped kinase inhibitors (BKIs) target calcium dependent protein kinase 1 (CDPK1), an enzyme that is encoded by an apicoplast-derived gene and found only in apicomplexans and plants. CDPK1 is essential for host cell invasion and egress; (ii) endochin-like quinolones (ELQs) are inhibitors of the cytochrome bc1 complex of the mitochondrial electron transport chain and thus inhibit oxidative phosphorylation. We here report on the in vitro and in vivo activities of BKI-1748, and of ELQ-316 and its respective prodrugs ELQ-334 and ELQ-422, applied either as single-compounds or ELQ-BKI-combinations. In vitro, BKI-1748 and ELQ-316, as well as BKI-1748 and ELQ-334, acted synergistically, while this was not observed for the BKI-1748/ELQ-422 combination treatment. In a N. caninum-infected pregnant BALB/c mouse model, the synergistic effects observed in vitro were not entirely reproduced, but 100% postnatal survival and 100% inhibition of vertical transmission was noted in the group treated with the BKI-1748/ELQ-334 combination. In addition, the combined drug applications resulted in lower neonatal mortality compared to treatments with single drugs

Azimuthal anisotropy of K0S and Lambda + Lambda -bar production at midrapidity from Au+Au collisions at sqrt[sNN]=130 GeV

We report STAR results on the azimuthal anisotropy parameter v2 for strange particles K0S, Lambda , and Lambda -bar at midrapidity in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider. The value of v2 as a function of transverse momentum, pt, of the produced particle and collision centrality is presented for both particles up to pt~3.0 GeV/c. A strong pt dependence in v2 is observed up to 2.0 GeV/c. The v2 measurement is compared with hydrodynamic model calculations. The physics implications of the pt integrated v2 magnitude as a function of particle mass are also discussed.Alle Autoren: C. Adler, Z. Ahammed, C. Allgower, J. Amonett, B. D. Anderson, M. Anderson, G. S. Averichev, J. Balewski, O. Barannikova, L. S. Barnby, J. Baudot, S. Bekele, V. V. Belaga, R. Bellwied, J. Berger, H. Bichsel, A. Billmeier, L. C. Bland, C. O. Blyth, B. E. Bonner, A. Boucham, A. Brandin, A. Bravar, R. V. Cadman, H. Caines, M. Calderón de la Barca Sánchez, A. Cardenas, J. Carroll, J. Castillo, M. Castro, D. Cebra, P. Chaloupka, S. Chattopadhyay, Y. Chen, S. P. Chernenko, M. Cherney, A. Chikanian, B. Choi, W. Christie, J. P. Coffin, T. M. Cormier, J. G. Cramer, H. J. Crawford, W. S. Deng, A. A. Derevschikov, L. Didenko, T. Dietel, J. E. Draper, V. B. Dunin, J. C. Dunlop, V. Eckardt, L. G. Efimov, V. Emelianov, J. Engelage, G. Eppley, B. Erazmus, P. Fachini, V. Faine, K. Filimonov, E. Finch, Y. Fisyak, D. Flierl, K. J. Foley, J. Fu, C. A. Gagliardi, N. Gagunashvili, J. Gans, L. Gaudichet, M. Germain, F. Geurts, V. Ghazikhanian, O. Grachov, V. Grigoriev, M. Guedon, E. Gushin, T. J. Hallman, D. Hardtke, J. W. Harris, T. W. Henry, S. Heppelmann, T. Herston, B. Hippolyte, A. Hirsch, E. Hjort, G. W. Hoffmann, M. Horsley, H. Z. Huang, T. J. Humanic, G. Igo, A. Ishihara, Yu. I. Ivanshin, P. Jacobs, W. W. Jacobs, M. Janik, I. Johnson, P. G. Jones, E. G. Judd, M. Kaneta, M. Kaplan, D. Keane, J. Kiryluk, A. Kisiel, J. Klay, S. R. Klein, A. Klyachko, A. S. Konstantinov, M. Kopytine, L. Kotchenda, A. D. Kovalenko, M. Kramer, P. Kravtsov, K. Krueger, C. Kuhn, A. I. Kulikov, G. J. Kunde, C. L. Kunz, R. Kh. Kutuev, A. A. Kuznetsov, L. Lakehal-Ayat, M. A. C. Lamont, J. M. Landgraf, S. Lange, C. P. Lansdell, B. Lasiuk, F. Laue, A. Lebedev, R. Lednický, V. M. Leontiev, M. J. LeVine, Q. Li, S. J. Lindenbaum, M. A. Lisa, F. Liu, L. Liu, Z. Liu, Q. J. Liu, T. Ljubicic, W. J. Llope, G. LoCurto, H. Long, R. S. Longacre, M. Lopez-Noriega, W. A. Love, T. Ludlam, D. Lynn, J. Ma, R. Majka, S. Margetis, C. Markert, L. Martin, J. Marx, H. S. Matis, Yu. A. Matulenko, T. S. McShane, F. Meissner, Yu. Melnick, A. Meschanin, M. Messer, M. L. Miller, Z. Milosevich, N. G. Minaev, J. Mitchell, V. A. Moiseenko, C. F. Moore, V. Morozov, M. M. de Moura, M. G. Munhoz, J. M. Nelson, P. Nevski, V. A. Nikitin, L. V. Nogach, B. Norman, S. B. Nurushev, G. Odyniec, A. Ogawa, V. Okorokov, M. Oldenburg, D. Olson, G. Paic, S. U. Pandey, Y. Panebratsev, S. Y. Panitkin, A. I. Pavlinov, T. Pawlak, V. Perevoztchikov, W. Peryt, V. A Petrov, M. Planinic, J. Pluta, N. Porile, J. Porter, A. M. Poskanzer, E. Potrebenikova, D. Prindle, C. Pruneau, J. Putschke, G. Rai, G. Rakness, O. Ravel, R. L. Ray, S. V. Razin, D. Reichhold, J. G. Reid, F. Retiere, A. Ridiger, H. G. Ritter, J. B. Roberts, O. V. Rogachevski, J. L. Romero, A. Rose, C. Roy, V. Rykov, I. Sakrejda, S. Salur, J. Sandweiss, A. C. Saulys, I. Savin, J. Schambach, R. P. Scharenberg, N. Schmitz, L. S. Schroeder, A. Schüttauf, K. Schweda, J. Seger, D. Seliverstov, P. Seyboth, E. Shahaliev, K. E. Shestermanov, S. S. Shimanskii, V. S. Shvetcov, G. Skoro, N. Smirnov, R. Snellings, P. Sorensen, J. Sowinski, H. M. Spinka, B. Srivastava, E. J. Stephenson, R. Stock, A. Stolpovsky, M. Strikhanov, B. Stringfellow, C. Struck, A. A. P. Suaide, E. Sugarbaker, C. Suire, M. Šumbera, B. Surrow, T. J. M. Symons, A. Szanto de Toledo, P. Szarwas, A. Tai, J. Takahashi, A. H. Tang, J. H. Thomas, M. Thompson, V. Tikhomirov, M. Tokarev, M. B. Tonjes, T. A. Trainor, S. Trentalange, R. E. Tribble, V. Trofimov, O. Tsai, T. Ullrich, D. G. Underwood, G. Van Buren, A. M. VanderMolen, I. M. Vasilevski, A. N. Vasiliev, S. E. Vigdor, S. A. Voloshin, F. Wang, H. Ward, J. W. Watson, R. Wells, G. D. Westfall, C. Whitten, Jr., H. Wieman, R. Willson, S. W. Wissink, R. Witt, J. Wood, N. Xu, Z. Xu, A. E. Yakutin, E. Yamamoto, J. Yang, P. Yepes, V. I. Yurevich, Y. V. Zanevski, I. Zborovský, H. Zhang, W. M. Zhang, R. Zoulkarneev, and A. N. Zubarev (STAR Collaboration

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Avoidance behaviors and negative psychological responses in the general population in the initial stage of the H1N1 pandemic in Hong Kong

<p>Abstract</p> <p>Background</p> <p>During the SARS pandemic in Hong Kong, panic and worry were prevalent in the community and the general public avoided staying in public areas. Such avoidance behaviors could greatly impact daily routines of the community and the local economy. This study examined the prevalence of the avoidance behaviors (i.e. avoiding going out, visiting crowded places and visiting hospitals) and negative psychological responses of the general population in Hong Kong at the initial stage of the H1N1 epidemic.</p> <p>Methods</p> <p>A sample of 999 respondents was recruited in a population-based survey. Using random telephone numbers, respondents completed a structured questionnaire by telephone interviews at the 'pre-community spread phase' of the H1N1 epidemic in Hong Kong.</p> <p>Results</p> <p>This study found that 76.5% of the respondents currently avoided going out or visiting crowded places or hospitals, whilst 15% felt much worried about contracting H1N1 and 6% showed signs of emotional distress. Females, older respondents, those having unconfirmed beliefs about modes of transmissions, and those feeling worried and emotionally distressed due to H1N1 outbreak were more likely than others to adopt some avoidance behaviors. Those who perceived high severity and susceptibility of getting H1N1 and doubted the adequacy of governmental preparedness were more likely than others to feel emotionally distressed.</p> <p>Conclusions</p> <p>The prevalence of avoidance behaviors was very high. Cognitions, including unconfirmed beliefs about modes of transmission, perceived severity and susceptibility were associated with some of the avoidance behaviors and emotional distress variables. Public health education should therefore provide clear messages to rectify relevant perceptions.</p

Autochthonous West Nile virus infection in Germany: Increasing numbers and a rare encephalitis case in a kidney transplant recipient.

West Nile Virus (WNV) infections are increasingly detected in birds and horses in central Europe, with the first mosquito-borne autochthonous human infection detected in Germany in 2019. Human infections are typically asymptomatic, with occasional severe neurological disease. Because of a low number of cases in central Europe, awareness regarding potential cases is low and WNV diagnostic testing is not routine. We tested cerebrospinal fluid (CSF) samples from unsolved encephalitis and meningitis cases from Berlin from 2019 to 2020, and describe a WNV-encephalitis case in a 33-year-old kidney transplant recipient. The infectious course was resolved by serology, RT-PCR and sequencing of stored samples. Phylogenetic sequence analysis revealed a close relationship of the patient's WNV strain to German sequences from 2019 and 2020. A lack of travel history and patient self-isolation during the SARS-CoV-2 pandemic suggest the infection was acquired in the patient's home or garden. Serological tests of four people sharing the living space were negative. Retrospective RT-PCR and WNV-IgM testing of 671 CSF samples from unsolved encephalitis and meningitis cases from Berlin detected no additional infections. The recent increase of WNV cases illustrates the importance of considering WNV in cases of meningoencephalitis, especially in immunocompromised patients, as described here. Proper education and communication and a revised diagnostic strategy will help to raise awareness and to detect future WNV infections

SynBlast: Assisting the analysis of conserved synteny information

<p>Abstract</p> <p>Motivation</p> <p>In the last years more than 20 vertebrate genomes have been sequenced, and the rate at which genomic DNA information becomes available is rapidly accelerating. Gene duplication and gene loss events inherently limit the accuracy of orthology detection based on sequence similarity alone. Fully automated methods for orthology annotation do exist but often fail to identify individual members in cases of large gene families, or to distinguish missing data from traceable gene losses. This situation can be improved in many cases by including conserved synteny information.</p> <p>Results</p> <p>Here we present the <monospace>SynBlast</monospace> pipeline that is designed to construct and evaluate local synteny information. <monospace>SynBlast</monospace> uses the genomic region around a focal reference gene to retrieve candidates for homologous regions from a collection of target genomes and ranks them in accord with the available evidence for homology. The pipeline is intended as a tool to aid high quality manual annotation in particular in those cases where automatic procedures fail. We demonstrate how <monospace>SynBlast</monospace> is applied to retrieving orthologous and paralogous clusters using the vertebrate <it>Hox </it>and <it>ParaHox </it>clusters as examples.</p> <p>Software</p> <p>The <monospace>SynBlast</monospace> package written in <monospace>Perl</monospace> is available under the GNU General Public License at <url>http://www.bioinf.uni-leipzig.de/Software/SynBlast/</url>.</p

Oncoproteomic Analysis Reveals Co-Upregulation of RELA and STAT5 in Carboplatin Resistant Ovarian Carcinoma

Ovarian cancer is one of the most lethal types of female malignancy. Although most patients are initially responsive to platinum-based chemotherapy, almost all develop recurrent chemoresistant tumors and succumb to their diseases. Elucidating the pathogenesis underlying drug resistance is fundamental to the development of new therapeutics, leading to improved clinical outcomes in these patients.We compared the proteomes of paired primary and recurrent post-chemotherapy ovarian high-grade serous carcinomas from nine ovarian cancer patients using CIEF/Nano-RPLC coupled with ESI-Tandem MS. As compared to their primary tumors, more than half of the recurrent tumors expressed higher levels of several proteins including CP, FN1, SYK, CD97, AIF1, WNK1, SERPINA3, APOD, URP2, STAT5B and RELA (NF-kappaB p65), which were also validated by quantitative RT-PCR. Based on shRNA screening for the upregulated genes in in vitro carboplatin-resistant cells, we found that simultaneous knockdown of RELA and STAT5B was most effective in sensitizing tumor cells for carboplatin treatment. Similarly, the NF-kappaB inhibitor, BMS-345541, and the STAT5 inhibitor, Dasatinib, significantly enhanced cell sensitivity to carboplatin. Moreover, both RELA and STAT5 are known to bind to the promoter region of Bcl-X, regulating its promoter activity. In this regard, augmented Bcl-xL expression was detected in carboplatin-resistant cells. Combined ectopic expression of RELA and STAT5B enhanced Bcl-xL promoter activity while treatment with BMS-345541 and Dasatinib decreased it. Chromatin immunoprecipitation of the Bcl-X promoter region using a STAT5 antibody showed induction of RELA and STAT5 DNA-binding segments both in naïve cells treated with a high concentration of carboplatin as well as in carboplatin-resistant cells.Proteomic analysis identified RELA and STAT5 as two major proteins associated with carboplatin resistance in ovarian tumors. Our results further showed that NF-kappaB and STAT5 inhibitor could sensitize carboplatin-resistant cells and suggest that such inhibitors can be used to benefit patients with carboplatin-resistant recurrent ovarian cancer

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors.

BACKGROUND: Hepcidin is a major regulator of iron metabolism and plays a key role in anemia of chronic disease, reducing intestinal iron uptake and release from body iron stores. Hypoxia and chemical stabilizers of the hypoxia-inducible transcription factor (HIF) have been shown to suppress hepcidin expression. We therefore investigated the role of HIF in hepcidin regulation. METHODOLOGY/PRINCIPAL FINDINGS: Hepcidin mRNA was down-regulated in hepatoma cells by chemical HIF stabilizers and iron chelators, respectively. In contrast, the response to hypoxia was variable. The decrease in hepcidin mRNA was not reversed by HIF-1alpha or HIF-2alpha knock-down or by depletion of the HIF and iron regulatory protein (IRP) target transferrin receptor 1 (TfR1). However, the response of hepcidin to hypoxia and chemical HIF inducers paralleled the regulation of transferrin receptor 2 (TfR2), one of the genes critical to hepcidin expression. Hepcidin expression was also markedly and rapidly decreased by serum deprivation, independent of transferrin-bound iron, and by the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, indicating that growth factors are required for hepcidin expression in vitro. Hepcidin promoter constructs mirrored the response of mRNA levels to interleukin-6 and bone morphogenetic proteins, but not consistently to hypoxia or HIF stabilizers, and deletion of the putative HIF binding motifs did not alter the response to different hypoxic stimuli. In mice exposed to carbon monoxide, hypoxia or the chemical HIF inducer N-oxalylglycine, liver hepcidin 1 mRNA was elevated rather than decreased. CONCLUSIONS/SIGNIFICANCE: Taken together, these data indicate that hepcidin is neither a direct target of HIF, nor indirectly regulated by HIF through induction of TfR1 expression. Hepcidin mRNA expression in vitro is highly sensitive to the presence of serum factors and PI3 kinase inhibition and parallels TfR2 expression