scholarly journals Therapeutic Efficacy of Bumped Kinase Inhibitor 1369 in a Pig Model of Acute Diarrhea Caused byCryptosporidium hominis

2018 ◽  
Vol 62 (7) ◽  
pp. e00147-18 ◽  
Author(s):  
Sangun Lee ◽  
Melanie Ginese ◽  
Gillian Beamer ◽  
Hillary R. Danz ◽  
Donald J. Girouard ◽  
...  
Keyword(s):  
Acute Diarrhea ◽  
Kinase Inhibitor ◽  
Day Treatment ◽  
Parasite Burden ◽  
Symptomatic Improvement ◽  
Control Measures ◽  
Pig Model ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Bumped Kinase Inhibitor

ABSTRACTRecent reports highlighting the global significance of cryptosporidiosis among children have renewed efforts to develop control measures. We evaluated the efficacy of bumped kinase inhibitor (BKI) 1369 in the gnotobiotic piglet model of acute diarrhea caused byCryptosporidium hominis, the species responsible for most human cases. Five-day treatment with BKI 1369 reduced signs of disease early during treatment compared to those of untreated animals. Piglets treated with BKI 1369 exhibited significant reductions of oocyst excretion, mucosal colonization byC. hominis, and mucosal lesions, which resulted in considerable symptomatic improvement. BKI 1369 reduced the parasite burden and disease severity in the gnotobiotic pig model. Together these data suggest that a BKI-mediated therapeutic may be an effective treatment against cryptosporidiosis.

scholarly journals Genomic Variation in IbA10G2 and Other Patient-Derived Cryptosporidium hominis Subtypes

2016 ◽  
Vol 55 (3) ◽  
pp. 844-858 ◽  
Author(s):  
Per Sikora ◽  
Sofia Andersson ◽  
Jadwiga Winiecka-Krusnell ◽  
Björn Hallström ◽  
Cecilia Alsmark ◽  
...  
Keyword(s):  
Parasite Burden ◽  
Genomic Variation ◽  
Loss Of Function ◽  
Oocyst Wall ◽  
Gene Encoding ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Successful Isolation ◽  
Target Dna ◽  
Stool Samples

ABSTRACTIn order to improve genotyping and epidemiological analysis ofCryptosporidiumspp., genomic data need to be generated directly from a broad range of clinical specimens. Utilizing a robust method that we developed for the purification and generation of amplified target DNA, we present its application for the successful isolation and whole-genome sequencing of 14 differentCryptosporidium hominispatient specimens. Six isolates of subtype IbA10G2 were analyzed together with a single representative each of 8 other subtypes: IaA20R3, IaA23R3, IbA9G3, IbA13G3, IdA14, IeA11G3T3, IfA12G1, and IkA18G1. Parasite burden was measured over a range of more than 2 orders of magnitude for all samples, while the genomes were sequenced to mean depths of between 17× and 490× coverage. Sequence homology-based functional annotation identified several genes of interest, including the gene encodingCryptosporidiumoocyst wall protein 9 (COWP9), which presented a predicted loss-of-function mutation in all the sequence subtypes, except for that seen with IbA10G2, which has a sequence identical to theCryptosporidium parvumreference Iowa II sequence. Furthermore, phylogenetic analysis showed that all the IbA10G2 genomes form a monophyletic clade in theC. hoministree as expected and yet display some heterogeneity within the IbA10G2 subtype. The current report validates the aforementioned method for isolating and sequencingCryptosporidiumdirectly from clinical stool samples. In addition, the analysis demonstrates the potential in mining data generated from sequencing multiple whole genomes ofCryptosporidiumfrom human fecal samples, while alluding to the potential for a higher degree of genotyping withinCryptosporidiumepidemiology.

scholarly journals Bumped Kinase Inhibitor 1294 Treats Established Toxoplasma gondii Infection

2014 ◽  
Vol 58 (6) ◽  
pp. 3547-3549 ◽  
Author(s):  
J. Stone Doggett ◽  
Kayode K. Ojo ◽  
Erkang Fan ◽  
Dustin J. Maly ◽  
Wesley C. Van Voorhis
Keyword(s):  
Toxoplasma Gondii ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Content Type ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Orally Bioavailable ◽  
Toxoplasma Gondii Infection ◽  
Bumped Kinase Inhibitor

ABSTRACTToxoplasma gondiiis a unicellular parasite that causes severe brain and eye disease. Current drugs forT. gondiiare limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogensT. gondii, cryptosporidia, and plasmodia. A lead anti-ToxoplasmaBKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosisin vivo.

scholarly journals In VitroandIn VivoEffects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum

2015 ◽  
Vol 59 (10) ◽  
pp. 6361-6374 ◽  
Author(s):  
Pablo Winzer ◽  
Joachim Müller ◽  
Adriana Aguado-Martínez ◽  
Mahbubur Rahman ◽  
Vreni Balmer ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Vertical Transmission ◽  
Kinase Inhibitor ◽  
Neospora Caninum ◽  
Antigen Expression ◽  
Pregnant Mouse ◽  
Content Type ◽  
Elevated Expression ◽  
Bumped Kinase Inhibitor

ABSTRACTWe report on thein vitroeffects of the bumped kinase inhibitor 1294 (BKI-1294) in cultures of virulentNeospora caninumisolates Nc-Liverpool (Nc-Liv) and Nc-Spain7 and in two strains ofToxoplasma gondii(RH and ME49), all grown in human foreskin fibroblasts. In these parasites, BKI-1294 acted with 50% inhibitory concentrations (IC50s) ranging from 20 nM (T. gondiiRH) to 360 nM (N. caninumNc-Liv), and exposure of intracellular stages to 1294 led to the nondisjunction of newly formed tachyzoites, resulting in the formation of multinucleated complexes similar to complexes previously observed in BKI-1294-treatedN. caninumbeta-galactosidase-expressing parasites. However, such complexes were not seen in a transgenicT. gondiistrain that expressed CDPK1 harboring a mutation (G to M) in the gatekeeper residue. InT. gondiiME49 andN. caninumNc-Liv, exposure of cultures to BKI-1294 resulted in the elevated expression of mRNA coding for the bradyzoite marker BAG1. Unlike in bradyzoites, SAG1 expression was not repressed. Immunofluorescence also showed that these multinucleated complexes expressed SAG1 and BAG1 and the monoclonal antibody CC2, which binds to a yet unidentified bradyzoite antigen, also exhibited increased labeling. In a pregnant mouse model, BKI-1294 efficiently inhibited vertical transmission in BALB/c mice experimentally infected with one of the two virulent isolates Nc-Liv or Nc-Spain7, demonstrating proof of concept that this compound protected offspring from vertical transmission and disease. The observed deregulated antigen expression effect may enhance the immune response during BKI-1294 therapy and will be the subject of future studies.

scholarly journals Neospora caninumDense Granule Protein 7 Regulates the Pathogenesis of Neosporosis by Modulating Host Immune Response

2018 ◽  
Vol 84 (18) ◽  
Author(s):  
Yoshifumi Nishikawa ◽  
Naomi Shimoda ◽  
Ragab M. Fereig ◽  
Tomoya Moritaka ◽  
Kousuke Umeda ◽  
...  
Keyword(s):  
Parental Strain ◽  
Neospora Caninum ◽  
Parasite Burden ◽  
Dense Granule ◽  
Effector Proteins ◽  
Control Measures ◽  
Luciferase Reporter ◽  
Sequencing Analysis ◽  
Chemokine Production ◽  
Content Type

ABSTRACTNeospora caninumis a protozoan parasite closely related toToxoplasma gondii. Neosporosis caused byN. caninumis considered one of the main causes of abortion in cattle and nervous-system dysfunction in dogs, and identification of the virulence factors of this parasite is important for the development of control measures. Here, we used a luciferase reporter assay to screen the dense granule proteins genes ofN. caninum, and we found that NcGRA6, NcGRA7, and NcGRA14 are involved in the activation of the NF-κB, calcium/calcineurin, and cAMP/PKA signals. To analyze the functions of these proteins andNeosporacyclophilin, we successfully knocked out their genes in the Nc1 strain using plasmids containing the CRISPR/Cas9 components. Among the deficient lines, theNcGRA7-deficient parasites showed reduced virulence in mice. An RNA sequencing analysis of infected macrophage cultures showed that NcGRA7 mainly regulates the host cytokine and chemokine production. The levels of gamma interferon in the ascites fluid, CXCL10 expression in the peritoneal cells, and CCL2 expression in the spleen were lower 5 days after infection with theNcGRA7-deficient parasite than after infection with the parental strain. The parasite burden and the degree of necrosis in the brains of mice infected with theNcGRA7-deficient parasite were also lower than in those of the parental strain. Collectively, our data suggest that both the NcGRA7-dependent activation of the inflammatory response and the parasite burden are important inNeosporavirulence.IMPORTANCENeospora caninuminvades and replicates in a broad range of host species and cells within those hosts. The effector proteins exported byNeosporainduce its pathogenesis by modulating the host immunity. We show that most of the transcriptomic effects inN. caninum-infected cells depend upon the activity of NcGRA7. A deficiency in NcGRA7 reduced the virulence of the parasite in mice. This study demonstrates the importance of NcGRA7 in the pathogenesis of neosporosis.

scholarly journals Etiological, epidemiological, and clinical features of acute diarrhea in China

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Li-Ping Wang ◽  
◽  
Shi-Xia Zhou ◽  
Xin Wang ◽  
Qing-Bin Lu ◽  
...  
Keyword(s):  
Clinical Features ◽  
Acute Diarrhea ◽  
Vibrio Parahaemolyticus ◽  
Bacterial Pathogens ◽  
Control Measures ◽  
Viral Pathogens ◽  
Rotavirus A ◽  
Positive Rate ◽  
Prevention And Control Measures ◽  
And Control

AbstractNational-based prospective surveillance of all-age patients with acute diarrhea was conducted in China between 2009‒2018. Here we report the etiological, epidemiological, and clinical features of the 152,792 eligible patients enrolled in this analysis. Rotavirus A and norovirus are the two leading viral pathogens detected in the patients, followed by adenovirus and astrovirus. Diarrheagenic Escherichia coli and nontyphoidal Salmonella are the two leading bacterial pathogens, followed by Shigella and Vibrio parahaemolyticus. Patients aged <5 years had higher overall positive rate of viral pathogens, while bacterial pathogens were more common in patients aged 18‒45 years. A joinpoint analysis revealed the age-specific positivity rate and how this varied for individual pathogens. Our findings fill crucial gaps of how the distributions of enteropathogens change across China in patients with diarrhea. This allows enhanced identification of the predominant diarrheal pathogen candidates for diagnosis in clinical practice and more targeted application of prevention and control measures.

Relational governance in outsourcing partnerships

2016 ◽  
Vol 26 (4) ◽  
pp. 435-452 ◽  
Author(s):  
Anuradha Mathrani ◽  
Sanjay Mathrani
Keyword(s):  
Real Life ◽  
Service Level ◽  
Positive Influence ◽  
Control Measures ◽  
Offshore Outsourcing ◽  
Relational Exchange ◽  
Relational Governance ◽  
Content Type ◽  
Governance Practices ◽  
Narrative Storylines

Purpose The paper aims to capture the nuances of two client–supplier relationships to offer new insights on the influences of transactional, knowledge and social elements in outsourcing partnerships. Design/methodology/approach The study has used descriptive case studies with narrative storylines. Interviews were conducted with three relationship managers (boundary gatekeepers) to understand preferred governance practices between clients and suppliers in diverse economic markets. Findings Experiences of three real-life cases engaged in offshore outsourcing have helped to identify the market, operational knowledge and social influences in a relational exchange. Findings reveal that offshore partnerships are first constituted with service-level agreements, which set control measures and layout business expectations from both partners. Boundary gatekeepers bring further accountability across firms by designing social networks for capturing and sharing of knowledge, thereby reducing each partner’s perception of risk. As firms evaluate transactional, knowledge and social elements for building a futuristic relational exchange, more disaggregated and dispersed enterprises evolve as new opportunities are explored in foreign markets. Research limitations/implications The retrospective nature of the client–supplier partnership is a limitation in this research study. However, retrospection adds to experience, and to practice perspectives made in hindsight, and therefore has a positive influence in this study. Originality/value This paper shares real-world experiences that can be used by scholars and practitioners to better understand how relational governance practices operate in a global socio-economic setting.

Influence of occupational heat stress on labour productivity – a case study from Chennai, India

2016 ◽  
Vol 65 (2) ◽  
pp. 245-255 ◽  
Author(s):  
Jeremiah Chinnadurai ◽  
Vidhya Venugopal ◽  
Kumaravel P ◽  
Paramesh R
Keyword(s):  
Climate Change ◽  
Heart Rate ◽  
Heat Stress ◽  
Pearson Correlation ◽  
Labour Productivity ◽  
Productivity Loss ◽  
Threshold Limit Value ◽  
Control Measures ◽  
Economic Losses ◽  
Content Type

Purpose – Raise in temperatures due to climate change is likely to increase the heat stress in occupations that are physically exerting and performed outdoors which might potentially have adverse health and productivity consequences. The purpose of this paper is to estimate the productivities in construction work under the influence of heat stress using the predicted mean vote (PMV) index. Design/methodology/approach – Field studies were conducted during May 2014 which is summer time in Chennai. Continuous heart rate of workers and wet bulb globe temperature measurements are conducted for workers engaged in different jobs in construction. Metabolic rates and the workload of the workers from heart rate were calculated using the ISO method 8996 and the PMV values are calculated using the tool developed by Malchaire based on the method ISO 7730. Direct observations and personal interviews were conducted to substantiate the productivity estimations. Findings – The results showed that workers working outdoors with moderate and heavy workload exceeded the threshold limit value of 28°C and had adverse productivity impacts (18-35 per cent productivity loss), whereas the workers engaged in light indoor work was not affected by heat stress and consequent productivity losses. The productivity estimations using the PMV index is found to be statistically significant for three types of construction works (Pearson correlation coefficient value of −0.78) and also correlated well with the observations and self-reported productivities of the workers. Originality/value – The method used in this paper provides a scientific and reliable estimation of the productivities which may benefit the industry to set realistic project completion goals in hot weather and also implement interventions and policies to protect workers’ health. Developing adaptive strategies and implementing control measures are the need of the hour to protect worker’s health and economic losses in the face of climate change.

scholarly journals Molecular and Epidemiological Characterization of IMP-Type Metallo-β-Lactamase-Producing Enterobacter cloacae in a Large Tertiary Care Hospital in Japan

2014 ◽  
Vol 58 (6) ◽  
pp. 3441-3450 ◽  
Author(s):  
Kayoko Hayakawa ◽  
Tohru Miyoshi-Akiyama ◽  
Teruo Kirikae ◽  
Maki Nagamatsu ◽  
Kayo Shimada ◽  
...  
Keyword(s):  
Hospital Mortality ◽  
Tertiary Care ◽  
Enterobacter Cloacae ◽  
Control Measures ◽  
Care Hospital ◽  
Invasive Procedures ◽  
Content Type ◽  
Infection Control Measures ◽  
Large Tertiary Care ◽  
Close Relationship

ABSTRACTIMP-type metallo-β-lactamase enzymes have been reported in different geographical areas and in various Gram-negative bacteria. However, the risk factors and epidemiology pertaining to IMP-type metallo-β-lactamase-producingEnterobacter cloacae(IMP-producingE. cloacae) have not been systematically evaluated. We conducted a retrospective, matched case-control study of patients from whom IMP-producingE. cloacaeisolates were obtained, in addition to performing thorough molecular analyses of the clinically obtained IMP-producingE. cloacaeisolates. Unique cases with IMP-producingE. cloacaeisolation were included. Patients with IMP-producingE. cloacaewere matched to uninfected controls at a ratio of 1 to 3. Fifteen IMP-producingE. cloacaecases were identified, with five of the isolates being obtained from blood, and they were matched to 45 uninfected controls. All (100%) patients from whom IMP-producingE. cloacaeisolates were obtained had indwelling devices at the time of isolation, compared with one (2.2%) uninfected control. Independent predictors for isolation of IMP-producingE. cloacaewere identified as cephalosporin exposure and invasive procedures within 3 months. Although in-hospital mortality rates were similar between cases and controls (14.3% versus 13.3%), the in-hospital mortality of patients with IMP-producingE. cloacae-caused bacteremia was significantly higher (40%) than the rate in controls. IMP-producingE. cloacaeisolates were frequently positive for other resistance determinants. The MICs of meropenem and imipenem were not elevated; 10 (67%) and 12 (80%) of the 15 IMP-producingE. cloacaeisolates had a MIC of ≤1 μg/ml. A phylogenetic tree showed a close relationship among the IMP-producingE. cloacaesamples. Indwelling devices, exposure to cephalosporin, and a history of invasive procedures were associated with isolation of IMP-producingE. cloacae. Screening for carbapenemase production is important in order to apply appropriate clinical management and infection control measures.

Investigating the causal complexity of corruption in project-based organizations: a scenario analysis of bidding activity in the Chinese construction sector

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Zhixiu Wang ◽  
Junying Liu ◽  
Xinya Guan
Keyword(s):  
Role Playing ◽  
Control Measures ◽  
Construction Sector ◽  
Content Type ◽  
Organizational Corruption ◽  
Global Construction ◽  
Role Playing Game ◽  
Multiple Configuration ◽  
Corrupt Behavior ◽  
Causal Complexity

PurposeAlthough the global construction industry has made great contributions to economic development, industry corruption is a challenge for governments all over the world. This paper aims to investigate the causal complexity of organizational corruption by exploring the configuration effect of multiple induced conditions of corruption in the construction sector.Design/methodology/approachThis study is focused on bribery, a specific form of corrupt behavior through a scenario-based survey role-playing game in which participants encounter bribery. A total of 400 Chinese construction sector participants were randomly recruited to complete this survey.FindingsCompared with studies that have identified a number of factors associated with corruption in the construction sector, this study found asymmetry and complexity in the causality of organizational corruption. That is, when a variable causing corruption changes from one condition to its opposite – for example, from fierce to mild competition – the degree of corruption is not necessarily reduced as one may expect.Practical implicationsAnti-corruption measures should not rely solely on the net effects of discrete conditions and the interactions between multiple factors should not be ignored. In other words, anti-corruption strategies should not be implemented in isolation of their context, and pairing control measures with configurations is critical in controlling corruption. Finally, multiple configuration paths should be reconsidered when considering the degree of corruption reduction.Originality/valueThis study proposes a comprehensive analysis framework for addressing organizational corruption in the construction sector by investigating configuration effects of multiple induced conditions and offers a useful method for addressing corruption.

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