Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury

Consequences and Utility of the Zinc-Dependent Metalloprotease Activity of Anthrax Lethal Toxin

Anthrax is caused by the gram-positive bacterium Bacillus anthracis. The pathogenesis of this disease is dependent on the presence of two binary toxins, edema toxin (EdTx) and lethal toxin (LeTx). LeTx, the major virulence factor contributing to anthrax, contains the effector moiety lethal factor (LF), a zinc-dependent metalloprotease specific for targeting mitogen-activated protein kinase kinases. This review will focus on the protease-specific activity and function of LF, and will include a discussion on the implications and consequences of this activity, both in terms of anthrax disease, and how this activity can be exploited to gain insight into other pathologic conditions

Endocrine therapy in epithelial ovarian cancer

INTRODUCTION: The estrogen receptor (ER) is expressed at high levels in many epithelial ovarian cancers (EOC) and represents a potential target for endocrine therapy. Both anti-estrogens and aromatase inhibitors have been evaluated in phase II clinical trials. Areas covered: We present an overview of the phase II and phase III trials of anti-estrogens (tamoxifen and fulvestrant) and aromatase inhibitors (letrozole, anastrazole and exemestane) undertaken in epithelial ovarian cancer identified through a Pubmed search. We describe predictive biomarkers that are being investigated to identify responsive cancers. Expert commentary: The efficacy of endocrine therapy in epithelial ovarian cancer is likely to be confined to histological subtypes with the highest ER expression while low grade serous ovarian cancer appears to be one subgroup with good sensitivity to these agents. The low toxicity profile of these agents is favourable although their use is unlicensed and the optimal setting undefined. Prospective clinical trials of endocrine agents in the early relapse and maintenance settings are urgently required to establish their definitive role in the management of epithelial ovarian cancer

Buffy the vampire slayer: what being Jewish has to do with it

This article examines the whiteness in the television series Buffy the Vampire Slayer. The author argues that the show’s overwhelming whiteness is a product of a generalized white anxiety about the numerical loss of white dominance across the United States and, in particular, in California. The article goes on to think through the role that Jewishness plays in the program, discussing the relationship between the apparently Anglo-American Buffy, played by a Jewish actor, and her sidekick, Willow, who is characterized as Jewish but is played by a non-Jewish actor. The evil master in the first series is given Nazi characteristics and the destruction that he wants to inflict carries connotations of the Holocaust. Structurally, Buffy is produced as the Jew who saves the United States from this demonic destruction. In this traumatic renarrativising, the Holocaust comes to stand for the white-experienced crisis of the loss of white supremacy in the United States. With this reading we can begin to understand the show’s popularity among early adult, predominantly white Americans

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Training in hypoxia fails to further enhance endurance performance and lactate clearance in well-trained men and impairs glucose metabolism during prolonged exercise.

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (approximately 3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n = 7) or normoxia (NOR group, n = 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training x hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia (P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise

Anthrax Toxin Receptor Drives Protective Antigen Oligomerization and Stabilizes the Heptameric and Octameric Oligomer by a Similar Mechanism

Anthrax toxin is comprised of protective antigen (PA), lethal factor (LF), and edema factor (EF). These proteins are individually nontoxic; however, when PA assembles with LF and EF, it produces lethal toxin and edema toxin, respectively. Assembly occurs either on cell surfaces or in plasma. In each milieu, PA assembles into a mixture of heptameric and octameric complexes that bind LF and EF. While octameric PA is the predominant form identified in plasma under physiological conditions (pH 7.4, 37°C), heptameric PA is more prevalent on cell surfaces. The difference between these two environments is that the anthrax toxin receptor (ANTXR) binds to PA on cell surfaces. It is known that the extracellular ANTXR domain serves to stabilize toxin complexes containing the PA heptamer by preventing premature PA channel formation--a process that inactivates the toxin. The role of ANTXR in PA oligomerization and in the stabilization of toxin complexes containing octameric PA are not understood.Using a fluorescence assembly assay, we show that the extracellular ANTXR domain drives PA oligomerization. Moreover, a dimeric ANTXR construct increases the extent of and accelerates the rate of PA assembly relative to a monomeric ANTXR construct. Mass spectrometry analysis shows that heptameric and octameric PA oligomers bind a full stoichiometric complement of ANTXR domains. Electron microscopy and circular dichroism studies reveal that the two different PA oligomers are equally stabilized by ANTXR interactions.We propose that PA oligomerization is driven by dimeric ANTXR complexes on cell surfaces. Through their interaction with the ANTXR, toxin complexes containing heptameric and octameric PA oligomers are similarly stabilized. Considering both the relative instability of the PA heptamer and extracellular assembly pathway identified in plasma, we propose a means to regulate the development of toxin gradients around sites of infection during anthrax pathogenesis

Coagulation equations with gelation

Smoluchowski's equation for rapid coagulation is used to describe the kinetics of gelation, in which the coagulation kernel K ij models the bonding mechanism. For different classes of kernels we derive criteria for the occurrence of gelation, and obtain critical exponents in the pre- and postgelation stage in terms of the model parameters; we calculate bounds on the time of gelation t c , and give an exact postgelation solution for the model K ij =( ij ω ) (ω>1/2) and K ij =a i+j ( a >1). For the model K ij = i ω + j ω ( ω <1, without gelation) initial solutions are given. It is argued that the kernel K ij ∼ ij ω with ω≃1−1/d ( d is dimensionality) effectively models the sol-gel transformation in polymerizing systems and approximately accounts for the effects of cross-linking and steric hindrance neglected in the classical theory of Flory and Stockmayer ( Ω =1). For all Ω the exponents, t=Ω +3/2 and σ=Ω −1/2, γ =(3/2− Ω)/(Ω − 1/2) and Β =1, characterize the size distribution, at and slightly below the gel point, under the assumption that scaling is valid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45146/1/10955_2005_Article_BF01019497.pd

Pratos e mais pratos: louças domésticas, divisões culturais e limites sociais no Rio de Janeiro, século XIX

Reply to ten comments on a paper published in the last issue of this journal. The discussion follows along six main lines: History museums, identity, ideology and the category of nation; the need of material collections and their modalities: patrimonial, operational, virtual; theater versus laboratory; visitors and their ambiguities; Public History: the museum and the academy.Resposta aos comentários de dez especialistas que contribuíram no debate de texto publicado no último número desta revista. A discussão orientou-se segundo seis tópicos principais: museus históricos, identidade, ideologia e a categoria de nação; a necessidade de acervos materiais e suas modalidades: acervo patrimonial, operacional, virtual; teatro versus laboratório; o público e suas ambigüidades; História Pública: o museu e a Academia