Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.     

Structure of a ligand-binding intermediate in wild-type carbonmonoxy myoglobin

Small molecules such as NO, O2, CO or H2 are important biological ligands that bind to metalloproteins to function crucially in processes such as signal transduction, respiration and catalysis. A key issue for understanding the regulation of reaction mechanisms in these systems is whether ligands gain access to the binding sites through specific channels and docking sites, or by random diffusion through the protein matrix. A model system for studying this issue is myoglobin, a simple haem protein. Myoglobin has been studied extensively by spectroscopy, crystallography, computation and theory. It serves as an aid to oxygen diffusion but also binds carbon monoxide, a byproduct of endogenous haem catabolism. Molecular dynamics simulations, random mutagenesis and flash photolysis studies indicate that ligand migration occurs through a limited number of pathways involving docking sites. Here we report the 1.4 A resolution crystal structure of a ligand-binding intermediate in carbonmonoxy myoglobin that may have far-reaching implications for understanding the dynamics of ligand binding and catalysis.     

Computing the variance of the forecast error for the holt-winters seasonal models

This paper presents expressions for the variance of the forecast error for arbitrary lead times for both the additive and multiplicative Holt-Winters seasonal forecasting models. It is shown that even when the smoothing constants are chosen to have values between zero and one, when the period is greater than four, the variance may not be finite for some values of the smoothing constants. In addition, the regions where the variance becomes infinite are almost the same for both models. These results are of importance for practitioners, who may choose values for the smoothing constants arbitrarily, or by searching on the unit cube for values which minimize the sum of the squared errors when fitting the model to a data set. It is also shown that the variance of the forecast error for the multiplicative model is nonstationary and periodic.     

A new class of angiotensin-converting enzyme inhibitors

Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.     

Chromosome replication in cells of a continuous line derived fromAedes albopictus (Skuse) larvae

Resumen El análisis del cuadro de duplicación cromosómica en una linea celular derivada del mosquitoAedes albopictus (Skuse) reveló un período G2 de 3 horas y la presencia de varias areas de duplicación tardía. La mayor parte de estas aread correspondieron a la heterocromatina constitutiva. Sin embargo, la porción distal de ambos brazos en los pares 2 y 3 mostraron duplicación tardía no asociada con la heterocromatina constitutiva. Se sugiere que estas regiones corresponden al a heterocromatina facultative.     

Structural basis of latency in plasminogen activator inhibitor-1.

Human plasminogen activator inhibitor-1 (PAI-1) is the fast-acting inhibitor of tissue plasminogen activator and urokinase and is a member of the serpin family of protease inhibitors. Serpins normally form complexes with their target proteases that dissociate very slowly as cleaved species and then fold into a highly stable inactive state in which the residues that flank the scissile bond (P1 and P1';) are separated by about 70 A. PAI-1 also spontaneously folds into a stable inactive state without cleavage; this state is termed 'latent' because inhibitory activity can be restored through denaturation and renaturation. Here we report the structure of intact latent PAI-1 determined by single-crystal X-ray diffraction to 2.6 A resolution. The three-dimensional structure reveals that residues on the N-terminal side of the primary recognition site are inserted as a central strand of the largest beta sheet, in positions similar to the corresponding residues in the cleaved form of the serpin alpha 1-proteinase inhibitor (alpha 1-PI). Residues C-terminal to the recognition site occupy positions on the surface of the molecule distinct from those of the corresponding residues in cleaved serpins or in the intact inactive serpin homologue, ovalbumin, and its cleavage product, plakalbumin. The structure of latent PAI-1 is similar to one formed after cleavage in other serpins, and the stability of both latent PAI-1 and cleaved serpins may be derived from the same structural features.     

城市史:一个18世纪的学科?

18世纪,英国写作与出版的城市史在数量上出现了显著增长.城镇人口的快速增长、持续走强的财富创造,以及一种与众不同的城市文化和生活方式的出现,吸引了那个时代观察者的广泛注意,并催生出一种强烈的市民自豪感.城市史成为一种人们表达城市认同的载体,但同时也是一个媒介,人们藉此探索城镇在英国社会发展过程中扮演的角色,研究商业与贸易对现代政体的贡献,并评价都市社会在文化与道德上的优势与劣势.城市史学家来自不同的背景:有些是专业的古文物研究者,有些是书商.他们的读者群同样也五花八门.作为一个现象,城市史在18世纪的兴盛至少证明了两点:首先,英国在18世纪的进程中将自己重新概念化为一个城市国家;其次,都市社会提高了有关“过去”的价值,这种价值既是一种集合的市民感,也是一种文化商品.     

Crystal structure of an HIV-binding recombinant fragment of human CD4

CD4 glycoprotein on the surface of T cells helps in the immune response and is the receptor for HIV infection. The structure of a soluble fragment of CD4 determined at 2.3 A resolution reveals that the molecule has two intimately associated immunoglobulin-like domains. Residues implicated in HIV recognition by analysis of mutants and antibody binding are salient features in domain D1. Domain D2 is distinguished by a variation on the beta-strand topologies of antibody domains and by an intra-sheet disulphide bridge.