Two-photon imaging of dendritic spine development in the mouse cortex

Dendritic spines are the postsynaptic sites of most excitatory synapses in the mammalian brain. With the advent of two-photon microscopy and transgenic mice expressing fluorescent proteins, dendritic spines can now be imaged in the living cerebral cortex over time scales ranging from seconds to years. Recent studies with this in vivo imaging approach have begun to provide important insights into the development and plasticity of dendritic spines in the intact brain. Here, we review these studies and discuss technical requirements for image acquisition. We envision that intravital two-photon imaging at the level of individual synapses will greatly expand our current understandings of how neuronal networks are assembled and modified throughout life.     

Application of ITC in foods: A powerful tool for understanding the gastrointestinal fate of lipophilic compounds

BackgroundIsothermal titration calorimetry (ITC) is a biophysical technique widely used to study molecular interactions in biological and non-biological systems. It can provide important information about molecular interactions (such as binding constant, number of binding sites, free energy, enthalpy, and entropy) simply by measuring the heat absorbed or released during an interaction between two liquid solutions.Scope of the reviewIn this review, we present an overview of ITC applications in food science, with particular focus on understanding the fate of lipids within the human gastrointestinal tract. In this area, ITC can be used to study micellization of bile salts, inclusion complex formation, the interaction of surface-active molecules with proteins, carbohydrates and lipids, and the interactions of lipid droplets.Major conclusionsITC is an extremely powerful tool for measuring molecular interactions in food systems, and can provide valuable information about many types of interactions involving food components such as proteins, carbohydrates, lipids, surfactants, and minerals. For systems at equilibrium, ITC can provide fundamental thermodynamic parameters that can be used to establish the physiochemical origin of molecular interactions.General significanceIt is expected that ITC will continue to be utilized as a means of providing fundamental information about complex materials such as those found in foods. This knowledge may be used to create functional foods designed to behave in the gastrointestinal tract in a manner that will improve human health and well-being. This article is part of a Special Issue entitled Microcalorimetry in the BioSciences — Principles and Applications, edited by Fadi Bou-Abdallah.     

Molecularly imprinted polymers for the recognition of proteins: the state of the art

Molecular imprinting has proved to be an effective technique for the creation of recognition sites on a polymer scaffold. Protein imprinting has been a focus for many chemists working in the area of molecular recognition, since the creation of synthetic polymers that can specifically recognise proteins is a very challenging but potentially extremely rewarding objective. It is expected that molecularly imprinted polymers (MIPs) with specificity for proteins will find application in medicine, diagnostics, proteomics, environmental analysis, sensors and drug delivery. In this review, the authors provide an overview of the progress achieved in the decade between 1994 and 2005, with respect to the challenging area of MIPs for protein recognition. The discussion furnishes a comparative analysis of different approaches developed, underlining their relative advantages and disadvantages and highlighting trends and possible future directions.     

Multiscale simulations of heterogeneous model membranes

This review will focus on computer modeling aimed at providing insights into the existence, structure, size, and thermodynamic stability of localized domains in membranes of heterogeneous composition. Modeling the lateral organization within a membrane is problematic due to the relatively slow lateral diffusion rate for lipid molecules so that microsecond or longer time scales are needed to fully model the formation and stability of a raft in a membrane. Although atomistic simulations currently are not able to reach this scale, they can provide data on the intermolecular forces and correlations that are involved in lateral organization. These data can be used to define coarse grained models that are capable of predictions of lateral organization in membranes. In this paper, we review modeling efforts that use interaction data from MD simulations to construct coarse grained models for heterogeneous bilayers. In this review we will discuss MD simulations done with the aim of gaining the information needed to build accurate coarse-grained models. We will then review some of the coarse-graining work, emphasizing modeling that has resulted from or has a basis in atomistic simulations.     

Cancer and the web

The applications of functional genomics, proteomics and informatics to cancer research have yielded a tremendous amount of information, which is growing all the time. Much of this information is available publicly on the Internet and ranges from general information about different cancers from a patient or clinical viewpoint, through to databases suitable for cancer researchers of all backgrounds, to very specific sites dedicated to individual genes or molecules. A simple search for 'cancer' from a typical Web browser search engine yields more than half a million hits; an even more specific search for 'leukaemia' (>40 000 hits) or 'p53' (>5700 hits) yields far too many hits to allow one to identify particular sites of interest. This review aims to provide a brief guide to some of the resources and databases that can be used as springboards to home in rapidly on information relevant to many fields of cancer research. As such, this article will not focus on a single website but hopes to illustrate some of the ways that postgenomic biology is revolutionizing cancer research. It will cover genomics and proteomics approaches that have been applied to studying global expression patterns in cancers, in addition to providing links ranging from general information about cancer to specific cancer gene mutation databases.     

Modulation of NMDA receptor responsiveness by neurotransmitters, drugs and chemical modification

The NMDA receptor is intimately involved an a wide range of pathophysiological processes in the mammalian brain, including epilepsy and ischemia-induced neurodegeneration. The widespread distribution of NMDA receptors places almost every area of the brain at risk from NMDA receptor over-activity. However, it is clear that the central nervous system can function effectively without imminent danger of self-destruction. The focus of this review is the processes that control NMDA receptor responsiveness in vivo. The review will cover the modulation of the receptor by Mg2+, glycine, Zn2+ and polyamines that is believed to occur by virtue of interaction with distinct ligand binding sites on the NMDA receptor complex. Studies suggesting a role for receptor phosphorylation and for redox modulation will be discussed. Finally, some evidence for indirect regulation of cellular responses to NMDA receptor activation by other neurotransmitters will be presented.     

The role of multiscale computational approaches for rational design of conventional and nanoparticle oral drug delivery systems

Multiscale computational modeling of drug delivery systems (DDS) is poised to provide predictive capabilities for the rational design of targeted drug delivery systems, including multi-functional nanoparticles. Realistic, mechanistic models can provide a framework for understanding the fundamental physico-chemical interactions between drug, delivery system, and patient. Multiscale computational modeling, however, is in its infancy even for conventional drug delivery. The wide range of emerging nanotechnology systems for targeted delivery further increases the need for reliable in silico predictions. This review will present existing computational approaches at different scales in the design of traditional oral drug delivery systems. Subsequently, a multiscale framework for integrating continuum, stochastic, and computational chemistry models will be proposed and a case study will be presented for conventional DDS. The extension of this framework to emerging nanotechnology delivery systems will be discussed along with future directions. While oral delivery is the focus of the review, the outlined computational approaches can be applied to other drug delivery systems as well.     

Immunoglobulin A

Although immunoglobulin (Ig) A is commonly recognized as the most prevalent antibody subclass at mucosal sites with an important role in mucosal defense, its potential as a therapeutic monoclonal antibody is less well known. However, IgA has multifaceted anti-, non-, and pro-inflammatory functions that can be exploited for different immunotherapeutical strategies, which will be the focus of this review.     

Multiscale simulations of heterogeneous model membranes

This review will focus on computer modeling aimed at providing insights into the existence, structure, size, and thermodynamic stability of localized domains in membranes of heterogeneous composition. Modeling the lateral organization within a membrane is problematic due to the relatively slow lateral diffusion rate for lipid molecules so that microsecond or longer time scales are needed to fully model the formation and stability of a raft in a membrane. Although atomistic simulations currently are not able to reach this scale, they can provide data on the intermolecular forces and correlations that are involved in lateral organization. These data can be used to define coarse grained models that are capable of predictions of lateral organization in membranes. In this paper, we review modeling efforts that use interaction data from MD simulations to construct coarse grained models for heterogeneous bilayers. In this review we will discuss MD simulations done with the aim of gaining the information needed to build accurate coarse-grained models. We will then review some of the coarse-graining work, emphasizing modeling that has resulted from or has a basis in atomistic simulations.     

Phenobabelomics--mouse phenotype data resources.

An essential aspect to understanding the functional significance of individual genes in the mouse genome is an understanding of the phenotypic consequences of gene mutations. A wide variety of online sites exist that provide different types of phenotypic information on the laboratory mouse. In this review, we describe the major resources that are currently available and discuss some of the bioinformatics requirements that will be necessary to make more seamless searching, comparison and analysis of these various data types possible.     

Cell surface adhesion molecules and adhesion-initiated signaling: understanding of anoikis resistance mechanisms and therapeutic opportunities

Cells express various cell surface adhesion molecules (receptors) that not only mechanically serve as contacting sites between the cell and extracellular matrix (ECM) or adjacent cells, but also initiate intracellular signaling pathways modulating important cellular events including survival and proliferation. Normal cells undergo apoptosis when lacking ECM attachment. This type of cell death has been termed anoikis. Anoikis can be viewed as a normal process which ensures tissue homeostasis and failure to execute the anoikis program or resistance to anoikis could result in adherent cells surviving under suspension condition and proliferating at ectopic sites where the matrix proteins are different from those the cells originally contact. Resistance to anoikis is emerging as a hallmark of metastatic cancers which enables cancer cells to disseminate to distant organs through systemic circulation. In this review, we will discuss the molecular basis of adhesion-initiated signaling, the impact of loss of cell-ECM adhesion on normal cell survival, the role of cancer cell aggregate formation via intercellular adhesion under non-adherent condition, and mechanisms of anoikis resistance developed in metastatic cancer cells. Understanding of these aspects will provide opportunities to find new potential molecular targets, and therapeutic strategies based on these findings will likely prove to be more specific and effective.     

Molecular mechanisms for the recognition of damaged DNA regions by peptides and proteins

DNA damages can lead to drastic perturbations of living cell cycle (e.g., in carcinogenesis) by inducing mutations in the genetic information. Therefore DNA repair processes play an important role during cell life by eliminating DNA damages before mutation fixation. Different repair processes are briefly presented in this review. Two probes were used to provide information on the mechanisms involved in the specific recognition of damaged DNA by proteins and enzymes of the DNA repair machinery. It will be shown that a simple tripeptide Lys-Trp-Lys is able to mimic two repair systems, namely, the photosensitized splitting of pyrimidine dimers and the cleavage of phosphodiester bonds at apurinic sites.     

Foraging height and landscape context predict the relative abundance of bird species in urban vegetation patches

In Australian urban environments, revegetation and vegetation restoration are increasingly utilized conservation actions. Simple methods that help assess the utility of urban vegetation for bird species will help direct this effort for bird conservation purposes. We therefore examine whether ecological principles can be used to predict, a priori, the relative abundance of different bird species in urban vegetation. Our model proposes that a bird species will be in greater abundance where vegetation structure better reflects its foraging height requirements, and this relationship will be moderated by the landscape context of the patch. To quantify and test this model, we created an index to rank existing and revegetated urban vegetation sites in order of greatest expected abundance for each of 30 bird species. We tested this model, alongside two simpler models which consider landscape context and foraging height preferences alone, using bird abundance data from 20 woodland remnants and 20 revegetated sites in Brisbane, Australia. From these bird abundance data, we calculated the relative abundance of each species between the top‐ranking sites and lowest‐ranking sites. The model which incorporated both foraging height requirements and landscape context made predictions that were positively correlated with the data for 77% of species in remnant vegetation and 67% in revegetation. The results varied across species groups; for example, we achieved lower predictive success for canopy foraging species in the less mature revegetation sites. Overall, this model provided a reasonable level of predictive accuracy despite the diversity of factors which can influence species occurrence in urban landscapes. The model is generic and, subject to further testing, can be used to examine the effect of manipulating vegetation structure and landscape context on the abundance of different bird species in urban vegetation. This could provide a cost‐effective tool for directing urban restoration and revegetation efforts.     

In vivo relevance of citrullinated proteins and the challenges in their detection

Citrullination is a posttranslational modification of arginine. It plays both a physiological role, for instance during apoptosis and epigenetics, and a pathological role in cancer or diseases of the central nervous system. Most research on citrullination to date focuses on its role in auto-immune diseases such as multiple sclerosis and rheumatoid arthritis. In this context, the exact knowledge of citrullination sites in a protein can provide invaluable information about the etiological importance of these citrullinated proteins. However, few techniques exist that can accurately detect citrullination on the peptide level. This review aims to give an overview of the different methods available to date for the detection of citrullinated proteins and peptides. These include 2D-SDS-PAGE and immunodetection, as well as specific mass spectrometry (MS) approaches, both labeled and unlabeled. These MS approaches have been developed to pinpoint the exact location of citrullination on the peptide level. Improving the currently existing detection strategies while focusing on the role of citrullinated proteins will be invaluable to elucidate the importance of this posttranslational modification in vivo.     

The regulation of cancer cell death and metabolism by extracellular matrix attachment

The metastasis of cancer cells to distant sites is responsible for the vast majority of cancer mortalities yet the molecular mechanisms underlying this extraordinarily complicated process have yet to be sufficiently elucidated. Recently, it has become clear that cancer cells need to inhibit anoikis, a cell death program induced by loss of attachment to the extracellular matrix (ECM), in order to successfully metastasize. These studies have motivated additional research into the relationship between ECM-detachment and cell viability, much of which reveals integral connections between ECM-detachment and cell metabolism. This review serves to thoroughly discuss the signaling pathways and metabolic changes that are induced by ECM-detachment. In addition, the molecular mechanisms by which cancer cells can alter signaling and metabolism to survive in the absence of ECM-attachment will be highlighted. Furthermore, cell death mechanisms that have been observed or implicated in cells detached from the ECM will also be examined. In aggregate, the studies discussed in this review reveal that ECM-detachment can regulate cancer cell metabolism in a variety of distinct cell types and suggest that interfering with metabolism in ECM-detached cells may be a novel and effective chemotherapeutic approach to selectively inhibit tumor progression.     

抗菌药物治疗疾病的新靶位——丙氨酸消旋酶

丙氨酸消旋酶是以磷酸吡哆醛为辅酶,催化L-丙氨酸与D-丙氨酸相互转化的一种酶,它广泛分布在低等生物,而不存在于人类等高等真核生物中.来自不同物种的丙氨酸消旋酶一级结构同源性较高,其大多功能单位为同源二聚体,拥有2个相同的活性中心,每个活性中心均是由来自不同亚基的2个保守残基共同组成.丙氨酸消旋酶催化生成的产物D-丙氨酸是合成细菌细胞壁肽聚糖的重要成分,也是调节细菌孢子萌芽的关键因子.因而丙氨酸消旋酶与由细菌引起的肺结核、炭疽热、中耳炎等疾病密切相关.近年来丙氨酸消旋酶已成为设计抗菌药物的又一理想靶位.本文从丙氨酸消旋酶的结构、功能、作用机理、抑制剂以及其与疾病的关系等方面进行了阐述.     

Revisiting the seed and soil in cancer metastasis

Metastasis remains the overwhelming cause of death for cancer patients. During metastasis, cancer cells will leave the primary tumor, intravasate into the bloodstream, arrest at a distant organ, and eventually develop into gross lesions at the secondary sites. This intricate process is influenced by innumerable factors and complex cellular interactions described in 1889 by Stephen Paget as the seed and soil hypothesis. In this review, we revisit this seed and soil hypothesis with an emerging understanding of the cancer cell (i.e. seed) and its microenvironment (i.e. soil). We will provide background to suggest that a critical outcome of the seed–soil interaction is resistance of the stresses that would otherwise impede metastasis.     

Dendritic Spine Loss and Synaptic Alterations in Alzheimer’s Disease

Dendritic spines are tiny protrusions along dendrites, which constitute major postsynaptic sites for excitatory synaptic transmission. These spines are highly motile and can undergo remodeling even in the adult nervous system. Spine remodeling and the formation of new synapses are activity-dependent processes that provide a basis for memory formation. A loss or alteration of these structures has been described in patients with neurodegenerative disorders such as Alzheimer's disease (AD), and in mouse models for these disorders. Such alteration is thought to be responsible for cognitive deficits long before or even in the absence of neuronal loss, but the underlying mechanisms are poorly understood. This review will describe recent findings and discoveries on the loss or alteration of dendritic spines induced by the amyloid beta (Abeta) peptide in the context of AD.     

Artificial enzymes, “Chemzymes”: current state and perspectives

Enzymes have fascinated scientists since their discovery and, over some decades, one aim in organic chemistry has been the creation of molecules that mimic the active sites of enzymes and promote catalysis. Nevertheless, even today, there are relatively few examples of enzyme models that successfully perform Michaelis–Menten catalysis under enzymatic conditions (i.e., aqueous medium, neutral pH, ambient temperature) and for those that do, very high rate accelerations are seldomly seen. This review will provide a brief summary of the recent developments in artificial enzymes, so called “Chemzymes”, based on cyclodextrins and other molecules. Only the chemzymes that have shown enzyme-like activity that has been quantified by different methods will be mentioned. This review will summarize the work done in the field of artificial glycosidases, oxidases, epoxidases, and esterases, as well as chemzymes that catalyze conjugate additions, cycloadditions, and self-replicating processes. The focus will be mainly on cyclodextrin-based chemzymes since they have shown to be good candidate structures to base an enzyme model skeleton on. In addition hereto, other molecules that encompass binding properties will also be presented.