Effective killing of the human pathogen Candida albicans by a specific inhibitor of non-essential mitotic kinesin Kip1p

Kinesins from the bipolar (Kinesin-5) family are conserved in eukaryotic organisms and play critical roles during the earliest stages of mitosis to mediate spindle pole body separation and formation of a bipolar mitotic spindle. To date, genes encoding bipolar kinesins have been reported to be essential in all organisms studied. We report the characterization of CaKip1p, the sole member of this family in the human pathogenic yeast Candida albicans. C. albicans Kip1p appears to localize to the mitotic spindle and loss of CaKip1p function interferes with normal progression through mitosis. Inducible excision of CaKIP1 revealed phenotypes unique to C. albicans, including viable homozygous Cakip1 mutants and an aberrant spindle morphology in which multiple spindle poles accumulate in close proximity to each other. Expression of the C. albicans Kip1 motor domain in Escherichia coli produced a protein with microtubule-stimulated ATPase activity that was inhibited by an aminobenzothiazole (ABT) compound in an ATP-competitive fashion. This inhibition results in ‘rigor-like’, tight association with microtubules in vitro. Upon treatment of C. albicans cells with the ABT compound, cells were killed, and terminal phenotype analysis revealed an aberrant spindle morphology similar to that induced by loss of the CaKIP1 gene. The ABT compound discovered is the first example of a fungal spindle inhibitor targeted to a mitotic kinesin. Our results also show that the non-essential nature and implementation of the bipolar motor in C. albicans differs from that seen in other organisms, and suggest that inhibitors of a non-essential mitotic kinesin may offer promise as cidal agents for antifungal drug discovery

Nf-κb Inhibition Rescues Cardiac Function By Remodeling Calcium Genes In A Duchenne Muscular Dystrophy Model

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-κB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function

Gender and Age Interact to Affect Early Outcome after Intracerebral Hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH.MethodsAdult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. ResultsIn this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death.ConclusionWhile independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings

Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p-4

<p><b>Copyright information:</b></p><p>Taken from "Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p"</p><p></p><p>Molecular Microbiology 2007;65(2):347-362.</p><p>Published online 01 Jul 2007</p><p>PMCID:PMC1976386.</p><p>© 2007 Cytokinetics, Incorporated; Journal compilation © 2007 Blackwell Publishing Ltd</p

Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p-2

<p><b>Copyright information:</b></p><p>Taken from "Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p"</p><p></p><p>Molecular Microbiology 2007;65(2):347-362.</p><p>Published online 01 Jul 2007</p><p>PMCID:PMC1976386.</p><p>© 2007 Cytokinetics, Incorporated; Journal compilation © 2007 Blackwell Publishing Ltd</p

Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p-0

<p><b>Copyright information:</b></p><p>Taken from "Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p"</p><p></p><p>Molecular Microbiology 2007;65(2):347-362.</p><p>Published online 01 Jul 2007</p><p>PMCID:PMC1976386.</p><p>© 2007 Cytokinetics, Incorporated; Journal compilation © 2007 Blackwell Publishing Ltd</p

Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p-3

<p><b>Copyright information:</b></p><p>Taken from "Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p"</p><p></p><p>Molecular Microbiology 2007;65(2):347-362.</p><p>Published online 01 Jul 2007</p><p>PMCID:PMC1976386.</p><p>© 2007 Cytokinetics, Incorporated; Journal compilation © 2007 Blackwell Publishing Ltd</p

Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p-1

<p><b>Copyright information:</b></p><p>Taken from "Effective killing of the human pathogen by a specific inhibitor of non-essential mitotic kinesin Kip1p"</p><p></p><p>Molecular Microbiology 2007;65(2):347-362.</p><p>Published online 01 Jul 2007</p><p>PMCID:PMC1976386.</p><p>© 2007 Cytokinetics, Incorporated; Journal compilation © 2007 Blackwell Publishing Ltd</p