Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity

Neuropathy target esterase (NTE) is involved in neural development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. We generated mice with disruptions in Nte, the gene encoding NTE. Nte(-/-) mice die after embryonic day 8, and Nte(+/-) mice have lower activity of Nte in the brain and higher mortality when exposed to the Nte-inhibiting compound ethyl octylphosphonofluoridate (EOPF) than do wild-type mice. Nte(+/-) and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging.     

Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy

Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.     

Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection, the data have been controversial. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.     

On local realism and commutativity

James D. Malley and Arthur Fine have argued that interest in noncontextual hidden variable theories is misplaced because at bottom such theories are simply attempts to turn noncommuting quantities into commuting ones. We disagree and argue that the issues are richer and more complex.     

Timing, distribution, and abundance of kokanees spawning in a Lake Tahoe tributary

We counted kokanee spawners and carcasses every 1-7 days from mid-September through mid-November in 1991 and 1992 in Taylor Creek, a tributary to Lake Tahoe, California-Nevada. Less than 1% of the spawning run entered Taylor Creek before flow from Fallen Leaf Lake was increased on 2 October 1991; in 1992 the peak occurred on 30 September or 1 October after flows increased on 29 September. In both years spawners concentrated in the middle three of five stream reaches below the impassable Fallen Leaf Lake dam. From tab-and-recovery experiments, the average longevity of male spawners in the stream was 3.5 days in 1991 and 2.8 days in 1992, whereas the average female longevity was 2.0 days in 1991 and 2.3 days in 1992. Observed carcasses accounted for less than 10% of spawners counted, suggesting removal by scavengers or high predation on prespawners. An estimated 1928 males and 1309 females spawned in 1991, and 8021 males and 8712 females spawned in 1992. Our estimate of 3237 spawners in 1991 compared favorably to our estimate of 3520 ± 1474 prespawners staging in Lake Tahoe in mid-September. An index of kokanee abundance in Lake Tahoe has historically been based on 1-day surveys every 1 November since 1960; however, estimated total spawner abundance was 19 times higher than the annual index of 158 spawners in 1991, 141 times higher than the index count of 100 spawners in 1992. The index count and mean fork lengths of spawners (278 ± 10 mm [2 SE] for males, and 248 ± 3 mm for females) in 1991 and 1992 were the lowest on record.     

Popper and Dingle on special relativity and the issue of symmetry

Karl Popper and Herbert Dingle engaged in a fascinating debate concerning the kind of theory the special theory of relativity is. One of the issues was whether applications of the theory could be made consistent with the principle of relativity, a cornerstone of the theory itself. The principle of relativity seems to imply some sort of symmetry in results obtained for similar experiments as observed in two different inertial reference frames. Peter Hayes has recently dealt with the Dingle–Popper debate on this matter, as well as other issues. The present paper seeks to clarify what kind of symmetry is appropriate in a situation discussed by Popper, Dingle, and Hayes.     

Occurrence,distribution and nature of neuropeptide Y in the rat pancreas

Summary Significant quantities of a newly discovered peptide, neuropeptide Y, were found in the rat pancreas, where they were localized to nerves in the exocrine parenchyma and around arterial and ductal structures. Although unaffected by surgical parasympathectomy, the periarterial and periductal nerves were abolished by chemical sympathectomy, suggesting that NPY is partially costored with sympathetic transmitters in nerve fibers.     

Influence of pinealectomy on corticotropin (ACTH)

Sensory deprivation produced by removing the eyes and olfactory bulbs in male rats allowed pinealectomy to markedly augment the post-adrenalectomy elevation of ACTH levels. Pineal removal or sensory deprivation separately did not have this effect. Thus, intact sensory input and an intact pineal gland are independently capable of restricting the post-adrenalectomy rise in ACTH levels.     

Translocation of vesicles from squid axoplasm on flagellar microtubules

Directed intracellular particle movement is a fundamental process characteristic of all cells. During fast axonal transport, membranous organelles move at rapid rates, from 1 to 5 micron s-1, in either the orthograde or retrograde direction along the neurone and can traverse distances as long as 1 m (for reviews, see refs 1-3). Recent studies indicate that this extreme example of intracellular motility can occur along single microtubules, but the molecules generating the motile force have not been identified or localized. It is not known whether the force-transducing 'motor' is associated with the moving particle or with the microtubule lattice. To distinguish between these hypotheses and to characterize the membrane-cytoskeletal interactions that occur during vesicle translocations, we have developed a reconstituted model for microtubule-based motility. We isolated axoplasmic vesicles from the giant axon of the squid Loligo pealei as described previously. The vesicles (35-475 nm in diameter) were then added to axonemes of Arbacia punctulata spermatozoa that served as a source of microtubules. Axonemes were used because the tubulin subunit lattice of the A-subfibre of a given outer doublet is the same as the subunit lattice of neuronal microtubules along which motility occurs. Moreover, all the microtubules of a single axoneme show the same structural polarity, indicating that the axoneme represents an oriented microtubule substrate. Here we demonstrate that vesicle motility is ATP-dependent, that it is not mediated by the flagellar force-transducing molecule dynein and that the direction of movement is not specified by microtubule polarity.