They give you the keys and say ‘drive it!’ Managers, referred expertise, and other expertises

On the face of it, the directors of new large scientific projects have an impossible task. They have to make technical decisions about sciences in which they have never made a research contribution—sciences in which they have no contributory expertise. Furthermore, these decisions must be accepted and respected by the scientists who are making research contributions. The problem is discussed in two interviews conducted with two directors of large scientific projects. The paradox is resolved for the managers by their use of interactional and referred expertise. The same analysis might be applicable to management in general. An Appendix, co-authored with Jeff Shrager, compares the notion of referred expertise with contributory expertise.     

Antiviral activities of anthraquinones,bianthrones and hypericin derivatives from lichens

The antiviral activities of some naturally occurring anthraquinones bianthrones, and hypericin derivatives were compared by the end-point CPE (viral cytopathic effects) method and plaque assays. Under optimal conditions of exposure to light, hypericin, 7,7-dichlorohypericin and 5,7-dichloroemodin exhibited strong inhibitory activity against HSV-1 (herpes simplex virus type 1) in both assays. Partial inactivation of the virus was shown by emodin, 7-chloroemodin and 7-chloro-1-O-methylemodin; the bianthrones and other anthraquinones were found to be inactive. Antiviral activity appeared to be, positively correlated with increasing substitution of chlorine in the anthraquinone structure. In the absence of light, only hypericin and 7,7-dichlorohypericin displayed detectable activity.     

Monolayer cultures of perikarya isolated from postnatal rat cerebellum

Summary Viable cerebellar perikarya of mixed cell type obtained from 7–9-day-old rats were maintained in monolayer culture for up to 12 days. During this time extensive neurite formation and outgrowth occurred. The large majority of the cells developing in culture were tentatively identified as granule neurons. This identification was based on the large number isolated from the starting tissue, and the cells general morphological features in culture such as perikaryal and nuclear size, the bipolar nature of neurite extension, and their migratory behaviour.D.N. Currie was supported by a grant from Hoechst Pharmaceuticals, Ld, U.K.J.C. was supported by an S.R.C. Grant to S.P.R. RoseThe authors would like to thank Kathleen Tear for excellent technical assistance and members of the Brain Research Group for helpful discussions.     

脑及其自我先天本能和后天驱动力的神经生物化学观念

这本专著总结了作者多年来最重要的研究成果。研究表明，人的大脑皮层具有获得驱动力的独特能力．正是这种能力创造了人类社会，并促使人类社会不断进化。作者认为，人类社会目前还处于反复实验的发展阶段，但其最终必将由现在的不可知状态逐渐过渡到理性指导的平衡状态。通过对获得性驱动力的特殊分析及以前曾认为不可知的脑机理的发现，作者对社会生活的发展及艺术、科学的起源给出了合理的生理学解释。本书的目的是要论证即使在脑及其自我的关系中，自然规律仍然是简单的，而不是不可知的。     

Wolves in sheep’s clothing: three new cases of aggressive mimicry in Red Sea coral reef fishes

ABSTRACT

Here we document three cases of mimicry in coral reef fishes not previously reported in the literature involving two groupers (Epinephelus leucogrammicus and Plectropomus marisrubri) and a soapfish (Diploprion drachi) as mimics, and two wrasses (Larabicus quadrilineatus and Cheilinus quinquecinctus) and a blenny (Meiacanthus nigrolineatus) as models. All three cases are of aggressive mimicry, with a predatory species mimicking a harmless one, and in one of the cases, the mimicry is also Müllerian, where both the predator and harmless species are unpalatable.     

Clathrate nanostructures for mass spectrometry

The ability of mass spectrometry to generate intact biomolecular ions efficiently in the gas phase has led to its widespread application in metabolomics, proteomics, biological imaging, biomarker discovery and clinical assays (namely neonatal screens). Matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization have been at the forefront of these developments. However, matrix application complicates the use of MALDI for cellular, tissue, biofluid and microarray analysis and can limit the spatial resolution because of the matrix crystal size (typically more than 10 mum), sensitivity and detection of small compounds (less than 500 Da). Secondary-ion mass spectrometry has extremely high lateral resolution (100 nm) and has found biological applications although the energetic desorption/ionization is a limitation owing to molecular fragmentation. Here we introduce nanostructure-initiator mass spectrometry (NIMS), a tool for spatially defined mass analysis. NIMS uses 'initiator' molecules trapped in nanostructured surfaces or 'clathrates' to release and ionize intact molecules adsorbed on the surface. This surface responds to both ion and laser irradiation. The lateral resolution (ion-NIMS about 150 nm), sensitivity, matrix-free and reduced fragmentation of NIMS allows direct characterization of peptide microarrays, direct mass analysis of single cells, tissue imaging, and direct characterization of blood and urine.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.