Correction of asymmetries of the breasts.

The problem of asymmetries of the breasts is discussed. The technical details of one operation for unilateral reduction are described.     

试论云阳县人口激增与土地锐减的矛盾及对策

土地是人们赖以生存的物质基础,是其它任何东西不可代替的生产资料。离开了土地,人就不能生存下去,这是众所周知的真理。但是,目前人口的激增与土地锐减的矛盾越来越尖锐。据有关统计资料表明,1978—1988年全国耕地面积减少3.66×10~6ha,与此同时全国人口又猛增1.33亿,给农业粮食生产、     

Mechanisms of dysfunction of the nitric oxide pathway in vascular diseases.

Vascular nitric oxide (NO) is involved in many physiologic and pathophysiologic processes throughout the body. Many vascular diseases have a reduction in the activity of endothelium-derived NO as an important component involved in the initiation and/or progression of the disease. It is now known that there are multiple mechanisms for this reduction in NO activity with one or more mechanisms operating depending on the specific condition or stage of a disease. In other instances, the therapy for certain diseases is responsible for the reduction in NO activity and contributes to the acceleration of vascular disease. This review details the known mechanisms of dysfunction of the NO pathway leading to vascular diseases, which provides the rationale for why certain therapies can improve while other therapies adversely affect vascular health.     

Modeling protein-protein complexes involved in the cytochrome C oxidase copper-delivery pathway

Proper assembly and function of cytochrome c oxidase, which catalyzes the reduction of O2 and generates the proton gradient driving ATP synthesis, depend on correct copper delivery and incorporation. Structural details about the protein-protein complexes involved in this process are still missing. We describe here models of four complexes along this pathway obtained by combining bioinformatics interface predictions with information-driven docking and discuss their relevance with respect to known and pathogenic mutations.     

Unravelling the association of partial T-cell immunodeficiency and immune dysregulation

Partial T-cell immunodeficiencies constitute a heterogeneous cluster of disorders characterized by an incomplete reduction in T-cell number or activity. The immune deficiency component of these diseases is less severe than that of the severe T-cell immunodeficiencies and therefore some ability to respond to infectious organisms is retained. Unlike severe T-cell immunodeficiencies, however, partial immunodeficiencies are commonly associated with hyper-immune dysregulation, including autoimmunity, inflammatory diseases and elevated IgE production. This causative association is counter-intuitive--immune deficiencies are caused by loss-of-function changes to the T-cell component, whereas the coincident autoimmune symptoms are the consequence of gain-of-function changes. This Review details the genetic basis of partial T -cell immunodeficiencies and draws on recent advances in mouse models to propose mechanisms by which a reduction in T-cell numbers or function may disturb the population-dependent balance between activation and tolerance.     

Mechanism of NAD(P)H:quinone reductase: Ab initio studies of reduced flavin

NAD(P)H:quinone oxidoreductase type 1 (QR1, NQO1, formerly DT-diaphorase; EC 1.6.99.2) is an FAD-containing enzyme that catalyzes the nicotinamide nucleotide-dependent reduction of quinones, quinoneimines, azo dyes, and nitro groups. Animal cells are protected by QR1 from the toxic and neoplastic effects of quinones and other electrophiles. Alternatively, in tumor cells QR can activate a number of cancer chemotherapeutic agents such as mitomycins and aziridylbenzoquinones. Thus, the same enzyme that protects the organism from the deleterious effects of quinones can activate cytotoxic chemotherapeutic prodrugs and cause cancer cell death. The catalytic mechanism of QR includes an important initial step in which FAD is reduced by NAD(P)H. The unfavorable charge separation that results must be stabilized by the protein. The details of this charge stabilization step are inaccessible to easy experimental verification but can be studied by quantum chemistry methods. Here we report ab initio quantum mechanical calculations in and around the active site of the enzyme that provide information about the fine details of the contribution of the protein to the stabilization of the reduced flavin. The results show that (1) protein interactions provide approximately 2 kcal/mol to stabilize the planar conformation of the reduced flavin isoalloxazine ring observed in the X-ray structure; (2) the charge separation present in the reduced planar form of the flavin is stabilized by interactions with groups of the protein; (3) even after stabilization, the reduction potential of the cofactor remains more negative than that of the free flavin, making it a better reductant for a larger variety of quinones; and (4) the more negative reduction potential may also result in faster kinetics for the quinone reduction step.     

Discovery of orally available spirodiketopiperazine-based CCR5 antagonists

Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure–activity relationship (SAR) study are presented.     

Alternative protein-protein interfaces are frequent exceptions

The intricate molecular details of protein-protein interactions (PPIs) are crucial for function. Therefore, measuring the same interacting protein pair again, we expect the same result. This work measured the similarity in the molecular details of interaction for the same and for homologous protein pairs between different experiments. All scores analyzed suggested that different experiments often find exceptions in the interfaces of similar PPIs: up to 22% of all comparisons revealed some differences even for sequence-identical pairs of proteins. The corresponding number for pairs of close homologs reached 68%. Conversely, the interfaces differed entirely for 12-29% of all comparisons. All these estimates were calculated after redundancy reduction. The magnitude of interface differences ranged from subtle to the extreme, as illustrated by a few examples. An extreme case was a change of the interacting domains between two observations of the same biological interaction. One reason for different interfaces was the number of copies of an interaction in the same complex: the probability of observing alternative binding modes increases with the number of copies. Even after removing the special cases with alternative hetero-interfaces to the same homomer, a substantial variability remained. Our results strongly support the surprising notion that there are many alternative solutions to make the intricate molecular details of PPIs crucial for function.     

Structure of the bound dioxygen species in the cytochrome oxidase reaction of cytochrome cd1 nitrite reductase

Reduction of dioxygen to water is a key process in aerobic life, but atomic details of this reaction have been elusive because of difficulties in observing active oxygen intermediates by crystallography. Cytochrome cd(1) is a bifunctional enzyme, capable of catalyzing the one-electron reduction of nitrite to nitric oxide, and the four-electron reduction of dioxygen to water. The latter is a cytochrome oxidase reaction. Here we describe the structure of an active dioxygen species in the enzyme captured by cryo-trapping. The productive binding mode of dioxygen in the active site is very similar to that of nitrite and suggests that the catalytic mechanisms of oxygen reduction and nitrite reduction are closely related. This finding has implications to the understanding of the evolution of oxygen-reducing enzymes. Comparison of the dioxygen complex to complexes of cytochrome cd(1) with stable diatomic ligands shows that nitric oxide and cyanide bind in a similar bent conformation to the iron as dioxygen whereas carbon monoxide forms a linear complex. The significance of these differences is discussed.     

Lumping analysis of biochemical reaction systems with time scale separation

Due to the complexity of the systems, successful modelling of intracellular reaction networks must rely on lumping techniques which systematically reduce the number of variables and parameters. Fortunately, the time scale separation characteristics of biochemical systems provide opportunities for eliminating unnecessary details. Through the proper interpretation of eigenvalues and eigenvectors, this article presents a theoretical basis for systematic model reduction. Results are generalized as a semiheuristic basis for lumping systems without complete kinetic information. It is also illustrated that the simplified system can yield new insight which is otherwise unavailable.     

Sodium butyrate enhances the cytotoxic effect of cisplatin by abrogating the cisplatin imposed cell cycle arrest

Background  

Histone deacetylase inhibitors have been proposed as potential enhancers of the cytotoxic effect of cisplatin and other anticancer drugs. Their application would permit the use of lower therapeutic doses and reduction of the adverse side effects of the drugs. However, the molecular mechanisms by which they sensitize the cells towards anticancer drugs are not known in details, which is an obstacle in developing effective therapeutic protocols.     

Superoxide dismutases—a review of the metal-associated mechanistic variations

Superoxide dismutases are enzymes that function to catalytically convert superoxide radical to oxygen and hydrogen peroxide. These enzymes carry out catalysis at near diffusion controlled rate constants via a general mechanism that involves the sequential reduction and oxidation of the metal center, with the concomitant oxidation and reduction of superoxide radicals. That the catalytically active metal can be copper, iron, manganese or, recently, nickel is one of the fascinating features of this class of enzymes. In this review, we describe these enzymes in terms of the details of their catalytic properties, with an emphasis on the mechanistic differences between the enzymes. The focus here will be concentrated mainly on two of these enzymes, copper, zinc superoxide dismutase and manganese superoxide dismutase, and some relatively subtle variations in the mechanisms by which they function.     

Zooming of states and parameters using a lumping approach including back-translation

Background  

Systems biology models tend to become large since biological systems often consist of complex networks of interacting components, and since the models usually are developed to reflect various mechanistic assumptions of those networks. Nevertheless, not all aspects of the model are equally interesting in a given setting, and normally there are parts that can be reduced without affecting the relevant model performance. There are many methods for model reduction, but few or none of them allow for a restoration of the details of the original model after the simplified model has been simulated.     

Fast ECG data compression algorithms suitable for microprocessor systems

ECG data compression techniques have received extensive attention in ECG analysis. Numerous data compression algorithms for ECG signals have been proposed during the last three decades. We describe two algorithms based on the scan-along polygonal approximation algorithm (SAPA) that are suitable for multichannel ECG data reduction on a microprocessor-based system. One represents a modification of SAPA (MSAPA) which adopts the method of integer division table searching to speed up data reduction; the other (CSAPA) combines MSAPA and TP, a turning-point algorithm, to preserve ST segment signals. Results show that our algorithms achieve a compression ratio of more than 5:1 and a percent rms difference (PRD) to the original signal of less than 3.5%. In addition, the maximum execution time of MSAPA for processing one data point is about 50μ s. Moreover, the CSAPA algorithm retains all of the details of the ST segment, which are important in ischaemia diagnosis, by employing the TP algorithm.     

Some critical qualitative details of lorica construction in the type species of Calliacantha Leadbeater (Choanoflagellata).

Qualitative structural details, amplifying or correcting previous accounts in the literature on this species have been compiled by means of light and/or electron microscopy of dry whole mounts, prepared in situ from freshly gathered wild material mainly from temperate sources in Denmark, Britain and south Alaska. The more important findings are summarized diagrammatically. These include elaborate and constant details of assembly at the anterior end of the lorica, combined with much greater variability at the hind end. The absence of continuity between the three anterior spines and any of the six longitudinal costae present at the front end of the lorica chamber is confirmed, but a range of conditions involving numerical reduction in costal numbers at the hind end is illustrated. The overall size range encountered in the three temperate localities listed is illustrated photographically, but the large cells characteristic of arctic sources are represented, for a qualitative purpose only, by means of a single photograph recording a specimen collected beneath sea ice in N. Alaska, a source which will be considered more fully on a later occasion.     

Golgi Method without Osmium Tetroxide for the Study of the Central Nervous System

A variant Golgi technique was developed that consisted of substituting osmium tetroxide with formaldehyde as the initial fixative in intracardiac perfusion, along with the addition of glacial acetic acid to the chromating fluid. This procedure avoids disposal of dangerous waste substances into the environment. Other advantages include 1) reduction of cost, danger to lab workers, and risk of disruption of the tissue slices during their handling by eliminating the osmium tetroxide, 2) clear tissue background, 3) greater quantity of impregnated neurons than in the classical procedure, with distinct morphological details easily identified even in gross sections and 4) reduction in processing time.     

Simple theoretical models for biochemical systems,with applications to DNA

A set oflogically connected models, to study chemical systems ofbiological interest, is presented. The sequence in the set is dictated by a progressive reduction of details with a corresponding enlargement of the field of application. The exposition starts with models suitable for interactions among a finite number of molecules, passes then to models considering also solvent effects and ends with models specialized for DNA containing systems.     

Golgi Method without Osmium Tetroxide for the Study of the Central Nervous System

A variant Golgi technique was developed that consisted of substituting osmium tetroxide with formaldehyde as the initial fixative in intracardiac perfusion, along with the addition of glacial acetic acid to the chromating fluid. This procedure avoids disposal of dangerous waste substances into the environment. Other advantages include 1) reduction of cost, danger to lab workers, and risk of disruption of the tissue slices during their handling by eliminating the osmium tetroxide, 2) clear tissue background, 3) greater quantity of impregnated neurons than in the classical procedure, with distinct morphological details easily identified even in gross sections and 4) reduction in processing time.     

The disulfide bond formation (Dsb) system

In oxidative folding of proteins in the bacterial periplasmic space, disulfide bonds are introduced by the oxidation system and isomerized by the reduction system. These systems utilize the oxidizing and the reducing equivalents of quinone and NADPH, respectively, that are transmitted across the cytoplasmic membrane through integral membrane components DsbB and DsbD. In both pathways, alternating interactions between a Cys-XX-Cys-containing thioredoxin domain and other regulatory domain lead to the maintenance of oxidized and reduced states of the specific terminal enzymes, DsbA that oxidizes target cysteines and DsbC that reduces an incorrect disulfide to allow its isomerization into the physiological one. Molecular details of these remarkable biochemical cascades are being rapidly unraveled by genetic, biochemical, and structural analyses in recent years.     

Nitrates and NO release: contemporary aspects in biological and medicinal chemistry

Nitroglycerine has been used clinically in the treatment of angina for 130 years, yet important details on the mechanism of action, biotransformation, and the associated phenomenon of nitrate tolerance remain unanswered. The biological activity of organic nitrates can be said to be nitric oxide mimetic, leading to recent, exciting progress in realizing the therapeutic potential of nitrates. Unequivocally, nitroglycerine and most other organic nitrates, including NO-NSAIDs, do not behave as NO donors in the most fundamental action: in vitro activation of sGC to produce cGMP. The question as to whether the biological activity of nitrates results primarily or exclusively from NO donation will not be satisfactorily answered until the location, the apparatus, and the mechanism of reduction of nitrates to NO are defined. Similarly, the therapeutic potential of nitrates will not be unlocked until this knowledge is attained. Aspects of the therapeutic and biological activity of nitrates are reviewed in the context of the chemistry of nitrates and the elusive efficient 3e- reduction required to generate NO.