Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter

Inhibitory non-adrenergic non-cholinergic (NANC) nerves are thought to be important in the autonomic innervation of the gastrointestinal tract and other organ systems. The nature of their neurotransmitter is still debated. Speculation that nitric oxide (NO), formed from L-arginine in neuronal structures and other cells, could act as a neurotransmitter, is not yet supported by demonstration of its release upon nerve stimulation. Using a superfusion bioassay, we report the release of a vasorelaxant factor upon stimulation of the NANC nerves in the canine ileocolonic junction. Several pieces of evidence, including the selectivity of the bioassay tissues, chemical instability, inactivation by superoxide anion and haemoglobin, inhibition by NG-nitro-L-arginine (L-NNA) and potentiation by L-arginine all indicated that NO accounted for the biological activity of this transferable NANC factor.     

Forms of Causal Explanation

In the literature on scientific explanation two types of pluralism are very common. The first concerns the distinction between explanations of singular facts and explanations of laws: there is a consensus that they have a different structure. The second concerns the distinction between causal explanations and uni.cation explanations: most people agree that both are useful and that their structure is different. In this article we argue for pluralism within the area of causal explanations: we claim that the structure of a causal explanation depends on the causal structure of the relevant fragment of the world and on the interests of the explainer.     

When will a Computer Write the Auditor's Report?

Most corporations are required by law to produce annual reports on their financial positions. These financial reports are accompanied by an auditor's report, which is an independent auditor's opinion on the fairness of the financial statements. To formulate their reports, auditors use a “personal-judgement” approach that heavily depends on their experience and expertise. This approach may be (1) ineffective and may lead to (2) different decisions, (3) personal bias, and (4) misleading judgements. These four drawbacks of a human auditor are a source of doubt and hesitation for every corporation. Therefore, the challenging question is: Can a computer do a better job? This paper focuses on the construction and implementation of a knowledge-based system, called the “Auditor's Report EXpert” (AREX), that is capable of formulating the opinion on financial statements, as expressed in the auditor's report. The knowledge used by AREX is acquired from the literature, and from a slate of practicing and academic auditors by means of questionnaires and in-depth interviews. A preliminary validation of AREX indicates that AREX is successful in performing the auditor's report task. Hence, we tentatively conclude that currently a computer program can support an auditor in his/her task. Moreover, in the foreseeable futur's reports that are effective, universal in their decisions, do not show a personal bias, and do not have misleading statements.     

Extinction risk from climate change

Climate change over the past approximately 30 years has produced numerous shifts in the distributions and abundances of species and has been implicated in one species-level extinction. Using projections of species' distributions for future climate scenarios, we assess extinction risks for sample regions that cover some 20% of the Earth's terrestrial surface. Exploring three approaches in which the estimated probability of extinction shows a power-law relationship with geographical range size, we predict, on the basis of mid-range climate-warming scenarios for 2050, that 15-37% of species in our sample of regions and taxa will be 'committed to extinction'. When the average of the three methods and two dispersal scenarios is taken, minimal climate-warming scenarios produce lower projections of species committed to extinction ( approximately 18%) than mid-range ( approximately 24%) and maximum-change ( approximately 35%) scenarios. These estimates show the importance of rapid implementation of technologies to decrease greenhouse gas emissions and strategies for carbon sequestration.     

X-ray structure of a protein-conducting channel

A conserved heterotrimeric membrane protein complex, the Sec61 or SecY complex, forms a protein-conducting channel, allowing polypeptides to be transferred across or integrated into membranes. We report the crystal structure of the complex from Methanococcus jannaschii at a resolution of 3.2 A. The structure suggests that one copy of the heterotrimer serves as a functional translocation channel. The alpha-subunit has two linked halves, transmembrane segments 1-5 and 6-10, clamped together by the gamma-subunit. A cytoplasmic funnel leading into the channel is plugged by a short helix. Plug displacement can open the channel into an 'hourglass' with a ring of hydrophobic residues at its constriction. This ring may form a seal around the translocating polypeptide, hindering the permeation of other molecules. The structure also suggests mechanisms for signal-sequence recognition and for the lateral exit of transmembrane segments of nascent membrane proteins into lipid, and indicates binding sites for partners that provide the driving force for translocation.     

Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11-q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20-alpha-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments.     

Cardenolide biosynthesis in chrysomelid beetles

Summary Labeling experiments have shown that the chrysomelid beetleChrysolina coerulans is able to biosynthesize its own defensive cardenolides from cholesterol, via a pathway involving a C₂₁ intermediate, as in plants.