Clindamycin and lincomycin alter miniature endplate current decay.

Antibiotic-induced muscle paralysis has frequently been found in both experimental animals and man with three distinct classes of antibiotic: (1) streptomycin and related aminoglycoside compounds, (2) polymyxins and (3) tetracyclines. Recently lincomycin and its chemical congener, clindamycin, have been reported to produce muscle paralysis which has different characteristics from those seen with other classes of antibiotic. Although closely related in chemical structure, lincomycin and clindamycin also seem to produce muscle paralysis by different mechanisms. Clindamycin is considered to exert a direct depressant action on muscle contractility whereas the action of lincomycin is considered to be primarily a depression of neuromuscular transmission. We report here that each of these antibiotics had a significant but different influence on endplate channel behaviour. Clindamycin increased the rate of miniature endplate current (m.e.p.c.) decay and reduced its voltage sensitivity without altering its exponential nature. Lincomycin split m.e.p.c. decay into an initial rapid phase followed by a prolonged phase.     

Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line.

A significant aspect of primary hepatic carcinoma in man is the high positive correlation of hepatocellular carcinoma with infection with hepatitis B virus (HBV)1. Analysis of the relationship between HBV infection and oncogenesis is difficult because natural infection with HBV is limited to man and experimental infection has been achieved only in chimpanzees and gibbons. Furthermore, because HBV has not been successfully propagated in cell culture, basic study of virus-cell interaction of the aetiological agent of one of the most widespread infections of man has been impossible. Recently, however, a cell line (PLC/PRF/5) derived from a human hepatoma biopsy was described which produces the HRV surface antigen (HBsAg) and so provides a tool for the experimental investigation of HBV in viro. We now report the derivation and characterisation of two additional cell lines primary liver carcinomas. In contrast to the PLC/PRF/5 cell line, these cell lines retain the capacity to synthesise many human plasma proteins, including both albumin and alpha-fetoprotein (AFP). One of these lines also produces BHsAg. We also present evidence that HBsAg synthesis and secretion in this cell line are correlated with the growth state of the culture. This finding is in contrast to the continuous HBsAg production found in the PLC/PRF/5 cell line.     

Captopril (SQ 14225) depresses drinking and aldosterone in rats lacking vasopressin.

Angiotensin II is dipsogenic, and vasopressin (ADH) regulates renal water excretion. Together, these hormones govern overall mammalian water balance. The Brattleboro rat with inherited diabetes insipidus (DI) lacks ADH and is therefore a convenient model with which to elucidate mechanisms regulating water metabolism. In the present studies, angiotensin II has also been removed from DI rats by the administration of an inhibitor (captopril, SQ 14225; D-2-methyl-3-mercaptopropanoyl-L-proline) of the enzyme which converts angiotensin I, the relatively inert component of the renin-angiotensin system, to angiotensin II, the biologically active substance. SQ 14225 reduced the drinking rates, and after 6 days lowered peripheral plasma aldosterone concentrations were associated with hyperkalaemia. We conclude that the polydipsia of diabetes insipidus partly results from elevated plasma renin activities and angiotensin II concentrations seen in this syndrome. Further, the apparent hypoaldosteronism of DI Brattleboro rats reflects differences in both tissue usage of the steroid and adrenocortical sensitivities associated with polyuria, hyperosmolarity and possibly potassium wasting.     

凸曲面平头立铣刀刀位轨迹的计算方法

采用球面刀在三坐标数控机床上加工具有凸曲面工位的零部件时，往往会导致几何形状误差，对此，运用点涉法原理，推导出在凸曲面上确定平头立铣刀五轴和三轴数控联动加工刀位轨迹的计算方法。     

Persistence of soil organic matter as an ecosystem property

Globally, soil organic matter (SOM) contains more than three times as much carbon as either the atmosphere or terrestrial vegetation. Yet it remains largely unknown why some SOM persists for millennia whereas other SOM decomposes readily--and this limits our ability to predict how soils will respond to climate change. Recent analytical and experimental advances have demonstrated that molecular structure alone does not control SOM stability: in fact, environmental and biological controls predominate. Here we propose ways to include this understanding in a new generation of experiments and soil carbon models, thereby improving predictions of the SOM response to global warming.     

Crystal structure of the β2 adrenergic receptor-Gs protein complex

G protein-coupled receptors (GPCRs) are responsible for the majority of cellular responses to hormones and neurotransmitters as well as the senses of sight, olfaction and taste. The paradigm of GPCR signalling is the activation of a heterotrimeric GTP binding protein (G protein) by an agonist-occupied receptor. The β(2) adrenergic receptor (β(2)AR) activation of Gs, the stimulatory G protein for adenylyl cyclase, has long been a model system for GPCR signalling. Here we present the crystal structure of the active state ternary complex composed of agonist-occupied monomeric β(2)AR and nucleotide-free Gs heterotrimer. The principal interactions between the β(2)AR and Gs involve the amino- and carboxy-terminal α-helices of Gs, with conformational changes propagating to the nucleotide-binding pocket. The largest conformational changes in the β(2)AR include a 14 ? outward movement at the cytoplasmic end of transmembrane segment 6 (TM6) and an α-helical extension of the cytoplasmic end of TM5. The most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain. This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR.     

Modular and predictable assembly of porous organic molecular crystals

Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules.     

Human nutrition, the gut microbiome and the immune system

Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems.