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At least 127 records · Page 7Linked to original sources
PubMed2004

Peroxide-utilizing biocatalysts: structural and functional diversity of heme-containing enzymes.

Heme-containing enzymes, such as peroxidases, catalase and peroxygenase P450 all utilize peroxides for their specific reactions. A variety of reactions catalyzed by such heme-containing enzymes involve a common, highly reactive intermediate, the so-called compound I (oxo-ferryl porphyrin pi-cation radical), which is generated via the reaction of peroxide with a ferric heme iron. However, the main reaction catalyzed by the heme-containing enzyme is determined by the accessibility of substrates to their active sites. Using the accumulated knowledge, we delineate a view, in which machineries of the heme-containing enzymes, especially the heme distal side structures, precisely regulate their functions in terms of sharing a common reactive intermediate. We also show the possibility that a hemoprotein of one functionality can be engineered to that with another functionality by modifying the heme distal side elements, on the basis of molecular-based mechanistic and structural data on these peroxide-utilizing enzymes.

Hemeproteins↗
PubMed2005

Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities.

The muscular dystrophies are a heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness. These disorders present a large clinical variability regarding age of onset, patterns of skeletal muscle involvement, heart damage, rate of progression and mode of inheritance. Difficulties in classification are often caused by the relatively common sporadic occurrence of autosomal recessive forms as well as by intrafamilial clinical variability. Furthermore recent discoveries, particularly regarding the proteins linking the sarcolemma to components of the extracellular matrix, have restricted the gap existing between limb girdle (LGMD) and congenital muscular dystrophies (CMD). Therefore a renewed definition of boundaries between these two groups is required. Molecular genetic studies have demonstrated different causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. These novel skeletal muscle genes encode highly diverse proteins with different localization within or at the surface of the skeletal muscle fibre, such as the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), the extracellular matrix (alpha2 laminin, collagen VI), the sarcomere (telethonin, myotilin, titin, nebulin and ZASP), the muscle cytosol (calpain-3, TRIM32), the nucleus (emerin, lamin A/C) and the glycosilation pathway enzymes (fukutin and fukutin related proteins). The accumulating knowledge about the role of these different proteins in muscle pathology has led to a profound change in the original phenotype-based classification and shed new light on the molecular pathogenesis of these disorders.

Animals↗
PubMed2005

Phylogenetic relationships and biodiversity in Hylids (Anura: Hylidae) from French Guiana.

We evaluated two biodiversity criteria, higher taxonomic diversity and phylogenetic diversity in French Guiana. For this, we used a recent assessment of the knowledge accumulated since 30 years of study on the amphibian species currently known in French Guiana. We focused on two well-represented genera, Hyla and Scinax, belonging to the subfamily Hylinae. We used partial sequences of two mitochondrial genes (16S rDNA and 12S rDNA, 813 bp) and two nuclear genes (tyrosinase and 18S rRNA, 1590 bp) covering a total of 2403 bp. According to the high bootstrap support in phylogenetic analysis of the complete dataset, the genus Scinax is a homophyletic clade formed by two species groups (rubra and rostrata) in French Guiana. The genus Hyla was confirmed to be a paraphyletic group formed by two species groups as well (30 chromosomes and the 'gladiator frogs'). We confirmed that these genera should be taxonomically reconsidered. Moreover, at the genus, subfamily and family levels, the use of only morphological characters or only molecular DNA markers would hamper estimations of biodiversity. Thus, we strongly advise the combined use of both morphology and molecular data (nuclear and mitochondrial markers).

Animals↗
PubMed2006

HTS technologies in biopharmaceutical discovery.

The concepts and philosophies of HTS can be productively applied to the discovery of new biopharmaceuticals. It is now possible, comprehensively and systematically, to enumerate, clone, produce and screen all secreted proteins, by building upon knowledge accumulated over the past two decades in HTS, genomics and parallel protein expression technologies. Each of the crucial operational components (comprehensive and high-quality cDNA library construction, proper protein-sequence classification, high-throughput protein production, medically relevant assays, state-of-the-art screening and data management) must be optimized to increase the chances of success. In this review, we draw comparisons between small-molecule and protein screening to illuminate common underlying principles as well as differences between the two operations.

Animals↗
PubMed2005

Chromosome translocations in sarcomas and the emergence of oncogenic transcription factors.

A subset of sarcomas is characterised by recurrent chromosome translocations that generate novel fusion oncoproteins. One or both of the genes involved in these translocations often encode transcription factors, and the resulting fusion proteins have aberrant transcriptional function compared to their wild-type counterparts. These fusion transcription factors disrupt multiple biological pathways by altering expression of target genes, and thereby result in a variety of altered cellular properties that contribute to the tumourigenic process. However, experimental data indicate that the fusion gene alone is not sufficient for transformation in primary cells (EWS-FLI1) or tumourigenesis in the mouse (PAX3-FKHR, FUS-CHOP), suggesting that additional collaborating genetic alterations are required. In addition to improving our understanding of the etiology of these tumours, this accumulating knowledge of the oncogenic properties of these fusion proteins, their downstream targets, and cooperating genetic alterations will permit the development of a variety of novel approaches to improve the therapy of these cancers.

Genetic Therapy↗
PubMed2005

JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species.

c-Jun N-terminal kinase (JNK), or stress-activated protein kinase, is an important member of the mitogen-activated protein kinase superfamily, the members of which are readily activated by many environmental stimuli. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important groups of free radicals that are capable of eliciting direct damaging effects or acting as critical intermediate signaling molecules, leading to oxidative and nitrosative stress and a series of biological consequences. Recently there has been an increasing amount of research interest focusing on the regulatory role of JNK activation in ROS-and RNS-induced cellular responses. In this review we will first summarize and discuss some recent findings regarding the signaling mechanisms of ROS-or RNS-mediated JNK activation. Second, we will talk about the role of JNK in ROS-or RNS-mediated cell death (both apoptosis and necrosis). Finally, we will analyze the emerging evidence for the involvement of ROS and RNS as mediators in tumor necrosis factor alpha-induced apoptosis. Taken together, the accumulating knowledge about the ROS/RNS-induced JNK signaling pathway has greatly advanced our understanding of the complex processes deciding the cellular responses to environmental stress.

Animals↗
PubMed2005

Interactions among multiple genomes: tsetse, its symbionts and trypanosomes.

Insect-borne diseases exact a high public health burden and have a devastating impact on livestock and agriculture. To date, control has proved to be exceedingly difficult. One such disease that has plagued sub-Saharan Africa is caused by the protozoan African trypanosomes (Trypanosoma species) and transmitted by tsetse flies (Diptera: Glossinidae). This presentation describes the biology of the tsetse fly and its interactions with trypanosomes as well as its symbionts. Tsetse can harbor up to three distinct microbial symbionts, including two enterics (Wigglesworthia glossinidia and Sodalis glossinidius) as well as facultative Wolbachia infections, which influence host physiology. Recent investigations into the genome of the obligate symbiont Wigglesworthia have revealed characteristics indicative of its long co-evolutionary history with the tsetse host species. Comparative analysis of the commensal-like Sodalis with free-living enterics provides examples of adaptations to the host environment (physiology and ecology), reflecting genomic tailoring events during the process of transitioning into a symbiotic lifestyle. From an applied perspective, the extensive knowledge accumulated on the genomic and developmental biology of the symbionts coupled with our ability to both express foreign genes in these microbes in vitro and repopulate tsetse midguts with these engineered microbes now provides a means to interfere with the host physiological traits which contribute to vector competence promising a novel tool for disease management.

Animals↗
PubMed2004

Transfection with different colloidal systems: comparison of solid lipid nanoparticles and liposomes.

Cationic solid lipid nanoparticles (SLN) for gene transfer are formulated using the same cationic lipids as for liposomal transfection agents. To investigate the differences and similarities in structure and performance between SLN and liposomes, a SLN preparation (S1), its counterpart formulation without matrix lipid (L1), a commercially available liposomal preparation (DLTR)--all based on the cationic lipid DOTAP--and a liposomal formulation that additionally contained the helper lipid dioleoylphosphatidylethanolamine (DOPE) (Escort) were compared. Photon correlation spectroscopy (PCS) showed that the SLN were smaller in diameter than the corresponding liposomes (88 vs. 148 nm) and atomic force microscopy (AFM) supported the expected structural differences. Desoxy ribonuclein acid (DNA) binding differed only marginally. Surprisingly, reporter gene expression was comparable between all DOTAP based formulations (S1, L1, DLTR), surpassed only by the DOPE containing liposomes (Escort). In conclusion, cationic lipid composition seems to be more dominant for in vitro transfection performance than the kind of colloidal structure it is arranged in. Hence, cationic SLN extend the range of highly potent non-viral transfection agents by one with favourable and distinct technological properties. Further SLN optimisation should be facilitated by the accumulated knowledge about cationic lipids in liposomal formulations.

Animals↗
PubMed2004

An allosteric model for transmembrane signaling in bacterial chemotaxis.

Bacteria are able to sense chemical gradients over a wide range of concentrations. However, calculations based on the known number of receptors do not predict such a range unless receptors interact with one another in a cooperative manner. A number of recent experiments support the notion that this remarkable sensitivity in chemotaxis is mediated by localized interactions or crosstalk between neighboring receptors. A number of simple, elegant models have proposed mechanisms for signal integration within receptor clusters. What is a lacking is a model, based on known molecular mechanisms and our accumulated knowledge of chemotaxis, that integrates data from multiple, heterogeneous sources. To address this question, we propose an allosteric mechanism for transmembrane signaling in bacterial chemotaxis based on the "trimer of dimers" model, where three receptor dimers form a stable complex with CheW and CheA. The mechanism is used to integrate a diverse set of experimental data in a consistent framework. The main predictions are: (1) trimers of receptor dimers form the building blocks for the signaling complexes; (2) receptor methylation increases the stability of the active state and retards the inhibition arising from ligand-bound receptors within the signaling complex; (3) trimer of dimer receptor complexes aggregate into clusters through their mutual interactions with CheA and CheW; (4) cooperativity arises from neighboring interaction within these clusters; and (5) cluster size is determined by the concentration of receptors, CheA, and CheW. The model is able to explain a number of seemingly contradictory experiments in a consistent manner and, in the process, explain how bacteria are able to sense chemical gradients over a wide range of concentrations by demonstrating how signals are integrated within the signaling complex.

Allosteric Regulation↗
PubMed2004

A similarity function to evaluate the orthodontic condition in patients with cleft lip and palate.

The objective of this work is the modeling of a similarity function adapted to the medical environment using the logical-combinatorial approach of pattern recognition theory, and its application to compare the orthodontic conditions of patients with cleft-primary palate and/or cleft-secondary palate congenital malformations. The variables in domains with no a priori algebraic or topological structure are objects whose similarity or difference is evaluated by comparison criteria functions. The range of these functions is an ordered set normalized into the unit interval, and they are designed to allow differentiation and non-uniform treatment of the object-variables. The analogy between objects is formalized as a similarity function that stresses the relations among the comparison criteria and evaluates the partial descriptions (partial similarity/difference) or total descriptions (total similarity/difference) of the objects. For the orthodontic problem we defined a set of 12 variables featuring the unilateral/bilateral fissures, the conditions of maxilla, premaxilla, mandible and patient's bite. The comparison criteria (logical for malocclusion, fuzzy for maxillary collapse unilateral/anteroposterior and for overbite, and Boolean for protrusive/retrusive premaxilla conditions) were assigned a relevance factor based on the orthodontist accumulated knowledge and experience. The modeling of the similarity function and its effectiveness in comparing orthodontic conditions in patients are illustrated by the study of four clinical cases with different clefts. The results through similarity are close to the expected ones. Moreover evaluated at different moments it allows to assess the effect of treatment in a single patient, hence providing valuable auxiliary criteria for medical decision making as to the patient's rehabilitation. We include the potential extension of the methodology to other medical disciplines such as speech therapy and reconstructive surgery.

Algorithms↗
PubMed2006

An obligatory caravanserai stop on the silk road to neural induction: inhibition of BMP/GDF signaling.

Work in Xenopus laevis produced the first molecular explanation for neural specification, the default model, where inactivation of the BMP pathway in ectodermal cells changes fates from epidermal to neural. This review covers the present status of our understanding of neural specification, with emphasis on Xenopus, but including relevant facts in other model systems. While recent experiments have increased the complexity of the molecular picture, they have also provided additional support for the default model and the central position of the BMP pathway. We conclude that synergy between accumulated knowledge and technical progress will maintain Xenopus at the forefront of research in neural development.

Animals↗
PubMed2000

Role of internal water molecules in bacteriorhodopsin.

Internal water molecules are considered to play a crucial role in the functional processes of proton pump proteins. They may participate in hydrogen-bonding networks inside proteins that constitute proton pathways. In addition, they could participate in the switch reaction by mediating an essential proton transfer at the active site. Nevertheless, little has been known about the structure and function of internal water molecules in such proteins. Recent progress in infrared spectroscopy and X-ray crystallography provided new information on water molecules inside bacteriorhodopsin, the light-driven proton pump. The accumulated knowledge on bacteriorhodopsin in the last decade of the 20th century will lead to a realistic picture of internal water molecules at work in the 21st century. In this review, I describe how the role of water molecules has been studied in bacteriorhodopsin, and what should be known about the role of water molecules in the future.

Bacteriorhodopsins↗
PubMed1993

Recent advances in cystic fibrosis research.

After the discovery of the gene, the next major landmark will be the elucidation of the basic defect of the disorder, which should lead to rational treatments. The accumulating knowledge of mutations and phenotypes allows more accurate testing and screening in selected populations. Considerable information is now available both on the pattern of gene and protein expression in the tissues involved in the disease and on the complex regulation and function of CFTR. In addition, an animal model with which to test therapeutic strategies has become available. Finally, two potential ways to cure the disease have emerged: that which exploits our knowledge of the normal and the mutant protein and their function, and that based on gene therapy. The latter approach is probably beginning to be tested on small groups of patients, and proof of its effectiveness is eagerly awaited.

Animals↗
PubMed1999

Does myasthenia gravis affect the brain?

Associations between myasthenia gravis (MG) and CNS functions have been made for over 80 years. An increased incidence of psychiatric disorders, epilepsy and multiple sclerosis as well as electroencephalographic (EEG) abnormalities and abnormal evoked responses have been noted in patients with MG. Descriptions of sleep and memory disturbances in MG patients appeared as knowledge accumulated about the role of brain cholinergic systems in sleep and memory. The inference of many of these studies has been that the alleged central cholinergic effects in MG were caused either by the anticholinesterases used to treat MG or by antibodies to muscle nicotinic acetylcholine receptor (nAchR) present in the serum and cerebrospinal fluid (CSF) of MG patients. The antigenic differences between muscle nAchR and neuronal nAchRs, together with the very low concentrations of muscle nAchR antibodies in the CSF, make highly unlikely the claims that CNS cholinergic systems are affected by these muscle antibodies in MG patients. Evoked response abnormalities, if indeed present, are more likely caused by peripheral than central mechanisms, and sleep abnormalities in MG also probably originate in the periphery rather than in the CNS, the result of hypoxia caused by oropharyngeal, intercostal and diaphragmatic muscle weakness which may worsen during sleep, especially during REM sleep. Such hypoxia may account for some of the EEG abnormalities noted in MG patients, but the association of MG with epilepsy appears to be either coincidental or the result of uncontrolled MG. Significant excessive daytime sleepiness resulting from sleep disturbances can also impair memory and the performance of MG patients on neuropsychological tests, as can the presence of mental depression. The psychological aspects of MG can be attributed to the expected consequences of a chronic but unpredictable neuromuscular disease involving weakness of breathing, swallowing, talking, limb and eye movement. Considering the number and variety of claims for direct CNS involvement in MG, the evidence for this is remarkably unconvincing. The quality of MG treatment, both physical and psychological, is a presently undefined variable which might help explain the diametrically opposed results which have been obtained in some of the studies reviewed. Adequate respiratory muscle strength during sleep is an often overlooked peripheral influence upon mental functioning and general well-being of MG patients.

Brain↗
PubMed1997

The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site.

The accumulated knowledge on the binding of estradiol (E2) and its analogs and the results of affinity-labeling studies have been reviewed and are used herein to derive a binding site model for the estrogen receptor (ER). Estradiol is nonpolar and hydrophobic, except at its molecular termini. Most of its skeletal flexibility resides in the B-ring, and it probably binds in a low-energy conformation. The phenolic OH group in the A-ring contributes about 1.9 kcal/mol to the binding free energy and probably acts primarily as a hydrogen bond donor. The 17 beta-hydroxyl group in the D-ring contributes approximately 0.6 kcal/mol to the binding and probably acts as a hydrogen bond acceptor, either directly or via a water molecule. There also seems to be a degree of flexibility in the region of the receptor that encompasses the D-ring. The aromatic ring contributes about 1.5 kcal/mol, probably through weak polar interactions with receptor residues that contact the beta-face of the steroid. The receptor seems to surround the ligand, so that all four rings contribute significantly to binding. Small hydrophobic substituents enhance binding affinity at positions 4, 12 beta, 14, and 16 alpha; whereas, larger hydrophobic substituents are tolerated at positions 7 alpha, 11 beta, and 17 alpha. In general, the ER is intolerant of polar substituents. Based on E2 analogs bearing affinity-labeling groups, cysteine residues might be present in the binding site in the area of C-4, C-17 alpha, and C-17 beta, and a lysine residue might be located near C-16. Models that represent the limits of deformability of the ligand binding site, the position of preformed pockets, and space occupied by the receptor are presented. The various elements in this model for the binding of steroidal estrogens by the estrogen receptor are consistent with evidence emerging from the crystal structures of related nuclear hormone receptor ligand complexes.

Amino Acid Sequence↗
PubMed1993

Surgery for complicated diverticulitis.

The surgical treatment of acute, complicated diverticulitis remains controversial. No randomized studies have been performed to clarify which operative procedure best fits each situation. As a result, the surgeon must use accumulated knowledge and judgment to make the correct decisions for an individual patient. The morbidity and mortality of patients with complicated diverticular disease in 1993 depend, not so much on the operative procedure, but on the severity of the disease and the associated comorbid conditions, namely the presence of fecal or purulent peritonitis, past medical problems, immune status, and nutritional status. However, adherence to the several principles detailed in this report will minimize morbidity and mortality. The surgeon should always attempt to convert the patient from an emergency to an urgent or elective operative status. In the absence of free perforation, this goal usually can be achieved. Rushing into surgery in patients with a normal immune system is generally ill advised. It is far preferable to stabilize the patient, percutaneously drain abscesses if possible, prepare the bowel before exploration, and thus keep the option of primary anastomosis open. A primary anastomosis done first thing in the morning is far preferable to an end-stoma created in the middle of the night in an emergency situation. The algorithm displayed in Figure 1 provides a useful guideline for treating patients with complicated diverticulitis.

Acute Disease↗
PubMed2006

Step out of the groove: epigenetic gene control systems and engineered transcription factors.

At the linear DNA level, gene activity is believed to be driven by binding of transcription factors, which subsequently recruit the RNA polymerase to the gene promoter region. However, it has become clear that transcriptional activation involves large complexes of many different proteins, which not only directly recruit components of the transcription machinery but also affect the DNA folding. Such proteins, including various chromatin-modifying enzymes, alter among other processes nucleosome positioning and histone modifications and are potentially involved in changing the overall structure of the chromatin and/or the position of chromatin in the nucleus. These epigenetic regulatory features are now known to control and regulate gene expression, although the molecular mechanisms still need to be clarified in more detail. Several diseases are characterized by aberrant gene-expression patterns. Many of these diseases are linked to dysregulation of epigenetic gene-regulatory systems. To interfere with aberrant gene expression, a novel approach is emerging as a disease therapy, involving engineered transcription factors. Engineered transcription factors are based on, for example, zinc-finger proteins (ZFP) that bind DNA in a sequence-specific manner. Engineered transcription factors based on ZFP are fused to effector domains that function to normalize disrupted gene-expression levels. Zinc-finger proteins most likely also influence epigenetic regulatory systems, such as the complex set of chemical histone and DNA modifications, which control chromatin compaction and nuclear organization. In this chapter, we review how epigenetic regulation systems acting at various levels of packaging the genome in the cell nucleus add to gene-expression control at the DNA level. Since an increasing number of diseases are described to have a clear link to epigenetic dysregulation, we here highlight 10 examples of such diseases. In the second part, we describe the different effector domains that have been fused to ZFPs and are capable of activating or silencing endogenous genes, and we illustrate how these effector domains influence epigenetic control mechanisms. Finally, we speculate how accumulating knowledge about epigenetics can be exploited to make such zinc-finger-transcription factors (ZF-TF) even more effective.

Animals↗
PubMed2001

Manipulation of tRNA properties by structure-based and combinatorial in vitro approaches.

The wide knowledge accumulated over the years on the structure and function of transfer RNAs (tRNAs) has allowed molecular biologists to decipher the rules underlying the function and the architecture of these molecules. These rules will be discussed and the implications for manipulating tRNA properties by structure-based and combinatorial in vitro approaches reviewed. Since most of the signals conferring function to tRNAs are located on the two distal extremities of their three-dimensional L shape, this implies that the structure of the RNA domain connecting these two extremities can be of different architecture and/or can be modified without disturbing individual functions. This concept is first supported by the existence in nature of RNAs of peculiar structures having tRNA properties, as well as by engineering experiments on natural tRNAs. The concept is further illustrated by examples of RNAs designed by combinatorial methods. The different procedures used to select RNAs or tRNA-mimics interacting with aminoacyl-tRNA synthetases or with elongation factors and to select tRNA-mimics aminoacylated by synthetases are presented, as well as the functional and structural characteristics of the selected molecules. Production and characteristics of aptameric RNAs fulfilling aminoacyl-tRNA synthetase functions and of RNAs selected to have affinities for amino acids are also described. Finally, properties of RNAs obtained by either the structure-based or the combinatorial methods are discussed in the light of the origin and evolution of the translation machinery, but also with a view to obtain new inhibitors targeting specific steps in translation.

Base Sequence↗