Why do Plasmodium falciparumm-infected erythrocytes form spontaneous erythrocyte rosettes?

Plasmodium falciparum malaria is one o f the most widespread o f human parasitic diseases and is responsible for the deaths of several million people in subtropical and tropical regions o f the world. The interaction o f malarial merozoites with erythrocytes and the adherence o f infected erythrocytes to the endothelium are among the cellular interactions extensively studied to define candidate antigens for a blood stage vaccine. However, the exact mechanisms underlying the invasion o f erythrocytes by P. falciparum merozoites and their subsequent binding to endothelium are not yet understood. Here Mats Wahlgren, Johan Carlson, Rachonee Udomsangpetch and Peter Perlmonn discuss a novel cytoodherence phenomenon which may be o f great importance in this context, that is, the spontaneous binding o f uninfected erythrocytes to those infected with late-stage parasites (trophozoites/schizonts).     

湖北长阳青铜时代人类乳齿特征的研究

对在湖北长阳县深潭湾崖葬墓出土的青铜时代人类乳齿形态特征的观察研究显示在人类恒齿出现的大多数具有种族识别价值的形态特征在乳齿有相等程度的表现,其中部分特征的出现率和表现程度高于恒齿。与其他地区人群相比,长阳青铜时代人类乳齿特征在总体上与东北亚人类具有的“中国型牙齿”特征接近。同时,在个别牙齿特征上呈现出南亚蒙古人种的特点。作者对产生这种现象的原因进行了分析。本文还就长阳青铜时代人类乳齿测量数据的表现特点进行了探讨。     

Complementation in Zellweger syndrome: biochemical analysis of newly generated peroxisomes.

The Zellweger syndrome is characterized by a defect which results in the abnormal biogenesis of peroxisomes. As a consequence, metabolic activities associated with peroxisomes such as the oxidation of very long chain fatty acids, the synthesis of plasmalogens, and the catabolism of phytanic and pipecolic acids are impaired. Since this disorder is genetically heterogeneous and several complementation groups are known, we were able to study the normalization of peroxisomal activity during the process of complementation. The restoration of catalase and dihydroxyacetone phosphate acyltransferase activities peaked within 3-4 days postfusion while the oxidation of lignoceric acid was much delayed (7-8 days). Electron microscopy indicated that by 6 days following hybridization, peroxisome structure and density in heterokaryons was comparable to normal control cells. The heterogenous biochemical response during peroxisome normalization could be due to several factors including a possible requirement for restoration of peroxisomal structural integrity for maximum activation of certain metabolic pathways.     

短链脂肪酸在宿主能量代谢方面的调节作用

肠道菌群数量庞大,对宿主多种生理活动具有重要调节作用。现有研究发现,肠道菌群主要通过调节其产生的不同代谢产物,参与宿主物质代谢反应,改变能量代谢水平,影响机体炎症反应。在诸多代谢产物中,短链脂肪酸(醋酸盐、丙酸盐、丁酸盐等)具有重要调节作用,对机体代谢功能方面具有深远影响。本文结合国内外相关研究文献,综述了短链脂肪酸在调节机体能量代谢方面的相关研究,以期为进一步阐明其在机体能量代谢方面的作用提供科学依据。     

Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox

The manner in which microorganisms utilize their metabolic processes can be predicted using constraint-based analysis of genome-scale metabolic networks. Herein, we present the constraint-based reconstruction and analysis toolbox, a software package running in the Matlab environment, which allows for quantitative prediction of cellular behavior using a constraint-based approach. Specifically, this software allows predictive computations of both steady-state and dynamic optimal growth behavior, the effects of gene deletions, comprehensive robustness analyses, sampling the range of possible cellular metabolic states and the determination of network modules. Functions enabling these calculations are included in the toolbox, allowing a user to input a genome-scale metabolic model distributed in Systems Biology Markup Language format and perform these calculations with just a few lines of code. The results are predictions of cellular behavior that have been verified as accurate in a growing body of research. After software installation, calculation time is minimal, allowing the user to focus on the interpretation of the computational results.     

Enantiopure five-membered cyclicdiamine derivatives as potent and selective inhibitors of factor Xa. Improving in vitro metabolic stability via core modifications

We previously reported a series of enantiopure cis-(1R,2S)-cyclopentyldiamine derivatives as potent and selective inhibitors of Factor Xa (FXa). Herein, we describe our approach to improve the metabolic stability of this series via core modifications. Multiple resulting series of compounds demonstrated similarly high FXa potency and improved metabolic stability in human liver microsomes compared with the cyclopentyldiamide 1. (3R,4S)-Pyrrolidinyldiamide 31 was the best overall compound with human FXa K(i) of 0.50 nM, PT EC(2x) of 2.1 microM in human plasma, bioavailability of 25% and t(1/2)of 2.7h in dogs. Further biochemical characterization of compound 31 is also presented.     

No apparent effect of an experimental narrow confinement on heart activity and cortisol in domestic pigs

The effects of continuing spatial restraint were examined in domestic pigs. For this purpose, the animals (German Landrace barrows) were housed individually in metabolic cages (12 animals) and, as controls, in single pens (six animals). In six replications with two experimental animals and one control animal, we collected saliva each morning (0730 h) for the cortisol analysis, recorded the behaviour and the heart beat for 3 h/day (0800 to 0900 h, 1100 to 1200 h, 1400 to 1500 h). Each replication consisted of 5 days of habituation to single housing and 8 experimental days during which the experimental animals lived continuously in the metabolic cages. Weight gain, cortisol, heart rate and heart rate variability were not significantly affected by experimental narrow confinement that only had a significant influence on the behaviours, locomotion and sitting. In conclusion, the experimental animals adapted very fast and did not show physiological indications of chronic stress. However, the absence of apparent stress does not exclude other, subtler, welfare impairments.     

The biochemistry of metabolic depression: a history of perceptions

Our interest in animals that 'turn off' dates back at least 300 years. This phenomenon has been reported in most of the major invertebrate phyla and in all vertebrate classes, and has implications for our understanding of a wide range of homeostasis and metabolic control issues. Surprisingly however, it took 20 years of biochemical research before the realization dawned that metabolic depression is the frontline strategy utilized by these animals to survive environmental stress. In this essay, the history of this research is treated in five stages, defined in terms of how the phenomenon now known as metabolic depression was perceived at the time. The two initial stages clearly show that the researchers involved were refractory to the concept of metabolic depression until about 1982 (stage 3). The two stages after 1982 reflect the impact of the acknowledgement of metabolic depression per se and show how research is now being directed towards both the mechanisms involved in, and the cellular targets of metabolic depression.     

Metabolomic profiling of amoebic and pyogenic liver abscesses: an in vitro NMR study

Pus samples obtained from 109 patients with liver abscess were examined by NMR spectroscopy. To our knowledge this is the first report on metabolic profiling of liver abscesses. Fifty metabolites were identified by combination of one (1D) and two-dimensional (2D) NMR spectra. Metabolic derangements were evaluated for differentiation between amoebic (ALA) and pyogenic liver abscess (PLA). The NMR results indicate that aspartate, asparagine and galactose, integral components of lipoproteophophoglycans (LPG) of the cell wall of Entamoeba histolytica are metabolic biomarkers of ALA. On the other hand, acetate, propionate, butyrate, succinate and formate, the fermentation products the facultative anaerobes are significantly prevalent in PLA. The NMR based metabolic profile of ALA and PLA are evaluated taking polymerase chain reaction (PCR) and bacterial culture as gold standard method. However, when NMR results were compared with culture and PCR methods, a correct diagnosis of 94.11% in ALA (n?=?85) and 100% in PLA (n?=?10) cases were observed. NMR spectroscopy in conjunction with PCR and culture can expedite in differentiating ALA from PLA.     

The promastigote surface protease of Leishmania

The infective forms o f several protozoan parasites are covered with a limited number o f major surface proteins. In this respect, Leishmania is no exception, and recent investigations have demonstrated on promostigotes the presence o f a single surface glycoprotein. In contrast to the major surface proteins o f other protozoans which have no known enzymatic activities, the surface protein of Leishmania. is a protease which is active on living cells. In this review, Clement Bordier presents the current structural, functional and immunological information concerning this intriguing and potentially important enzyme.     

Metabolic reconstruction and analysis for parasite genomes

With the completion of sequencing projects for several parasite genomes, efforts are ongoing to make sense of this mass of information in terms of the gene products encoded and their interactions in the growth, development and survival of parasites. The emerging science of systems biology aims to explain the complex relationship between genotype and phenotype by using network models. One area in which this approach has been particularly successful is in the modeling of metabolism. With an accurate picture of the set of metabolic reactions encoded in a genome, it is now possible to identify enzymes or transporters that might be viable targets for new drugs. Because these predictions greatly depend on the quality and completeness of the genome annotation, there are substantial efforts in the scientific community to increase the numbers of metabolic enzymes identified. In this review, we discuss the opportunities for using metabolic reconstruction and analysis tools in parasitology research, and their applications to protozoan parasites.     

The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity

Since the major approach in searching for potential anticancer agents over the last 50 years has been based on selective cytotoxic effects on mammalian cancer cell lines, cell-based methods for cytotoxicity are described and compared. The sulphorhodamine B (SRB) assay is described in detail as the preferred method and also a novel approach has been developed which is based on the hypothesis that, in some circumstances, the naturally occurring compounds act as prodrugs rather than active compounds in their own right. Consequently, extracts or compounds are pre-incubated with systems modelling metabolic processes in the body before being tested. The methods have been validated using known compounds and Iris tectorum extracts have been shown to be more cytotoxic after treatment with beta-glucosidase. In addition bioassays based on mammalian cells involving antioxidant and upregulation of some cellular self-defence mechanisms are discussed which are related to prevention as well as treatment of cancer. Extracts of Alpinia officinarum induced glutathione-S-transferase (GST) activity in cultured hepatocytes and this was traced to the phenylpropanoids present, especially 1'-acetoxychavicol acetate.     

Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia

Although significant variations in the metabolic profiles exist among different cells, little is understood in terms of genetic regulations of such cell type-specific metabolic phenotypes and nutrient requirements. While many cancer cells depend on exogenous glutamine for survival to justify the therapeutic targeting of glutamine metabolism, the mechanisms of glutamine dependence and likely response and resistance of such glutamine-targeting strategies among cancers are largely unknown. In this study, we have found a systematic variation in the glutamine dependence among breast tumor subtypes associated with mammary differentiation: basal- but not luminal-type breast cells are more glutamine-dependent and may be susceptible to glutamine-targeting therapeutics. Glutamine independence of luminal-type cells is associated mechanistically with lineage-specific expression of glutamine synthetase (GS). Luminal cells can also rescue basal cells in co-culture without glutamine, indicating a potential for glutamine symbiosis within breast ducts. The luminal-specific expression of GS is directly induced by GATA3 and represses glutaminase expression. Such distinct glutamine dependency and metabolic symbiosis is coupled with the acquisition of the GS and glutamine independence during the mammary differentiation program. Understanding the genetic circuitry governing distinct metabolic patterns is relevant to many symbiotic relationships among different cells and organisms. In addition, the ability of GS to predict patterns of glutamine metabolism and dependency among tumors is also crucial in the rational design and application of glutamine and other metabolic pathway targeted therapies.     

Metabolic flux analysis at ultra short time scale: isotopically non-stationary 13C labeling experiments

A novel approach to (13)C metabolic flux analysis (MFA) is presented using cytosolic metabolite pool sizes and their (13)C labeling data from an isotopically non-stationary (13)C labeling experiment (INST-CLE). The procedure is demonstrated with an E. coli wild type strain grown at fed batch conditions. The intra cellular labeling dynamics are excited by a sudden step increase of the (13)C portion in the substrate feed. Due to unchanged saturation of the substrate uptake system, the metabolic fluxes remain constant during the following sampling time period of only 16s, in which 20 samples are taken by an automated rapid sampling device immediately stopping metabolism by methanol quenching. Subsequent cell disruptive sample preparation and LC-MS/MS enabled simultaneous determination of pool sizes and mass isotopomers of intra cellular metabolites requiring detection limits in the nM range. Based on this data the new computational flux analysis tool 13CFLUX/INST is used to determine the intra cellular fluxes based on a complex carbon labeling network model. The measured data is in good agreement with the model predictions, thus proving the applicability of the new isotopically non-stationary (13)C metabolic flux analysis (INST-(13)C-MFA) concept. Moreover, it is shown that significant new information with respect to flux identifiability, non-measurable pool sizes, data consistency, or large storage pools can be taken from the novel kind of experimental data. This offers new insight into the biological operation of the metabolic network in vivo.     

Applications of mass spectrometry in metabolomic studies of animal model and invertebrate systems

Metabolomics provides rich datasets for systems biology. Massspectrometric (MS) techniques are rapidly gaining in importancefor untargeted metabolic profiling. In this review, we surveythe various techniques for sample preparation and analysis relatingto the various MS techniques and illustrate the potential ofthese techniques for both observing complete metabolomes anddetecting changes in the metabolism resulting from genetic mutationof other perturbations. The use of some of these techniquesin the study of model organisms including rodent and variousinvertebrate models is described. The invertebrate systems areof particular interest since such organisms have valuable mutantresources, such as RNAi panels directed against nearly all thegenes in the genome. The demonstration that they are readilycompatible with metabolomic approaches is particularly importantfor systems approaches to metabolic pathways.      

Anaerobic metabolism in aerobic mammalian cells: information from the ratio of calorimetric heat flux and respirometric oxygen flux

Calorimetric and respirometric studies of cultured cells show that both neoplastic and non-neoplastic cell types maintain an anaerobic contribution to their total heat flux. In many mammalian cells this can be explained quantitatively by lactate production observed under fully aerobic conditions. Uncoupling and enhanced futile substrate cycling increase the ratio of heat flux to oxygen flux, the calorimetric-respirometric (CR) ratio. The interpretation of calorimetric and respirometric measurements requires an energy balance approach in which experimentally measured CR ratios are compared with thermochemically derived oxycaloric equivalents. The oxycaloric equivalent is the enthalpy change per mole of oxygen consumed, and equals -470 kJ/mol O2 in the aerobic catabolism of glucose, assuming that catabolism is 100% dissipative (the net efficiency of metabolic heat transformation is zero). CR ratios more negative than -470 kJ/mol O2 have been reported in well-oxygenated cell cultures and are discussed in terms of integrated aerobic and anaerobic metabolism.