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At least 271 records · Page 15Linked to original sources

PubMed2001

Mitochondrial defects in neurodegenerative disease.

Over the past 12 years, a wide variety of neurodegenerative diseases has been linked to mutations in mitochondrial genes located in either the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). These disorders encompass an array of unorthodox inheritance patterns and a plethora of symptoms ranging from lethal neonatal multi-symptom disorders to later onset myopathies, cardiomyopathies, movement disorders, and dementias. The bases for the genetic and phenotypic variability of mitochondrial diseases lie in the multiplicity of the mitochondria genes dispersed across the human genome and the variety of cellular pathways and functions in which the mitochondria play a central role.

Aging↗

PubMed1989

Fluid shear and spin-echo images.

Because clinical studies have indicated that shear in fluids may be one of the major causes of magnetic resonance image artifacts, we imaged an apparatus that would separate the effects of shear from the plethora of other motion artifacts. The apparatus contained fluid between two concentric cylinders. To produce shear, we turned the outer cylinder. To produce motion without shear, we turned both cylinders as one. Shear rates near 200 s-1 (similar to those in large arteries) can cause pixel intensities either to increase 40% or decrease to background levels. Increases can occur when the velocities are nearly parallel to the phase-encoding gradient. Decreases can occur when velocities are in the direction of the frequency gradient. The decreases are similar to those predicted from phase dispersion within a "voxel" so long as the voxel's phase warp does not exceed 2 pi.

Body Fluids↗

PubMed2005

Plasticity of dendritic excitability.

Dendrites are equipped with a plethora of voltage-gated ion channels that greatly enrich the computational and storage capacity of neurons. The excitability of dendrites and dendritic function display plasticity under diverse circumstances such as neuromodulation, adaptation, learning and memory, trauma, or disorders. This adaptability arises from alterations in the biophysical properties or the expression levels of voltage-gated ion channels-induced by the activity of neurotransmitters, neuromodulators, and second-messenger cascades. In this review we discuss how this plasticity of dendritic excitability could alter information transfer and processing within dendrites, neurons, and neural networks under physiological and pathological conditions.

Adaptation, Physiological↗

PubMed2006

Automated analysis of behavior: a computer-controlled system for drug screening and the investigation of learning.

Efforts to understand cognition will be greatly facilitated by computerized systems that enable the automated analysis of animal behavior. A number of controversies in the invertebrate learning field have resulted from difficulties inherent in manual experiments. Driven by the necessity to overcome these problems during investigation of neural function in planarian flatworms and frog larvae, we designed and developed a prototype for an inexpensive, flexible system that enables automated control and analysis of behavior and learning. Applicable to a variety of small animals such as flatworms and zebrafish, this system allows automated analysis of innate behavior, as well as of learning and memory in a plethora of conditioning paradigms. We present here the schematics of a basic prototype, which overcomes experimenter effects and operator tedium, enabling a large number of animals to be analyzed with transparent on-line access to primary data. A scaled-up version of this technology represents an efficient methodology to screen pharmacological and genetic libraries for novel neuroactive reagents of basic and biomedical relevance.

Animals↗

PubMed2003

ECM homeostasis in renal diseases: a genomic approach.

Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor-beta, platelet-derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large-scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention.

Cytokines↗

PubMed2007

Epithelial-mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion.

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis during the wound healing process. As epithelial-mesenchymal interactions have been shown to regulate a plethora of genes in wound healing, we hypothesized that these interactions might have a role in modulating VEGF expression and angiogenesis. A two chamber co-culture model was used, wherein normal and keloid keratinocytes and fibroblasts were physically separated by membrane inserts while allowing cytokine diffusion. Cell lysates obtained from keratinocytes co-cultured with fibroblasts demonstrated increased expression of VEGF. An enzyme-linked immunosorbent assay (ELISA) showed significant increase in VEGF expression in co-culture conditioned media compared with controls. Additionally, the conditioned medium from keloid keratinocyte and fibroblast co-cultures increased proliferation and formation of complex three-dimensional capillary-like structures in human umbilical vein endothelial cells, emphasising the importance of epithelial-mesenchymal interactions in the angiogenic process. Immunostaining of keloid tissue localized VEGF in the basal layer of the epidermis and also demonstrated higher blood vessel density than normal skin. Keloid tissue extract also demonstrated increased expression of VEGF compared with normal skin. It is likely that epidermal VEGF exerts significant paracrine control over the dynamics and expression profile of underlying dermal fibroblasts. Addition of the inhibitors WP631, mitoxantrone, and Rapamycin to keloid keratinocyte and fibroblast co-cultures, downregulated secreted VEGF expression in a dose-dependent manner, suggesting therapeutic potential for these compounds in the treatment of keloid scars.

Antibiotics, Antineoplastic↗

PubMed2003

Can intensive three-day programmes improve nurses' communication skills in cancer care?

Effective communication is widely regarded as a crucial component of patient care that can determine patient satisfaction, compliance and recovery. The plethora of communication skills training programmes available to health professionals is also a testament to the importance of this element of care. However a review of studies evaluating the effectiveness of such training programmes concluded that little behavioural change in health professionals' communication skills was evident. This paper reports the findings of a programme offered to cancer/palliative care nurses (n=108) via eight condensed three-day workshops at various UK venues. Behavioural change was assessed through evaluation of audiotaped nursing assessments made pre- and six weeks post-course, scored along nine previously identified key communication areas. Mean overall scores rose by 6 points ( p<0.001) to 20 (out of 27) with statistically significant improvements on eight of the nine individual areas. Improvements in subjective levels of confidence in the areas of communication found difficult pre-course were observed immediately post-course ( p<0.001) and were still evident six weeks later. Similar improvements immediately post-course for teaching communication skills to colleagues ( p<0.001) were further improved six weeks post-course for seven of the eight areas assessed. These results suggest that three-day training courses can lead to clinically relevant behavioural change and improvements in perceived confidence in communication and dissemination of skills.

Adult↗

PubMed2005

Beyond chloride transport: CFTR in the 21st century-introductory remarks to a new state of the art series.

This new series of articles on cystic fibrosis provides an overview of the confusing plethora of problems that arise from the loss of function in a low abundance protein, the cystic fibrosis membrane conductance regulator CFTR. The references are designed to take the clinical reader into areas and journals that they might not normally read. In particular we have concentrated on recent advances that suggest CFTR has functions that do not relate to chloride transport alone. In forthcoming issues of the journal the topics covered range from prospects and difficulties in the translation of new therapies into clinical practice, the regulation of the defective gene (promoters, enhancers, silencers, etc.), regulation and interaction of the CFTR protein product with other proteins in the cell, to functional approaches using developmental and secretory paradigms. These themes have been chosen to bring controversies at the cutting edge of cystic fibrosis research to the practicing pulmonologist in order to stimulate lateral thinking, which we hope will ultimately benefit our patients.

Cystic Fibrosis↗

PubMed2004

A Shannon entropy-based filter detects high- quality profile-profile alignments in searches for remote homologues.

Detection of homologous proteins with low-sequence identity to a given target (remote homologues) is routinely performed with alignment algorithms that take advantage of sequence profile. In this article, we investigate the efficacy of different alignment procedures for the task at hand on a set of 185 protein pairs with similar structures but low-sequence similarity. Criteria based on the SCOP label detection and MaxSub scores are adopted to score the results. We investigate the efficacy of alignments based on sequence-sequence, sequence-profile, and profile-profile information. We confirm that with profile-profile alignments the results are better than with other procedures. In addition, we report, and this is novel, that the selection of the results of the profile-profile alignments can be improved by using Shannon entropy, indicating that this parameter is important to recognize good profile-profile alignments among a plethora of meaningless pairs. By this, we enhance the global search accuracy without losing sensitivity and filter out most of the erroneous alignments. We also show that when the entropy filtering is adopted, the quality of the resulting alignments is comparable to that computed for the target and template structures with CE, a structural alignment program.

Algorithms↗

PubMed2001

Cytochromes P450 of insects: the tip of the iceberg.

The cytochrome P450-dependent monooxygenases are an extremely important metabolic system involved in the metabolism of endogenous compounds and xenobiotics. Collectively, P450 monooxygenases can metabolize numerous substrates and carry out multiple oxidative reactions. The large number of substrates metabolized is due to the plethora of P450 isoforms and to the broad substrate specificity of some isoforms. Monooxygenases of insects have several functional roles, including growth, development, feeding and protection against xenobiotics, including resistance to pesticides and tolerance to plant toxins. This review begins with background information about P450s and their evolution, followed by a discussion of the extraordinary diversity of insect P450s. Given the enormous interest in studying individual P450s, we then provide a synopsis of the different methods that have been used in their isolation and the substrates that are known to be metabolized. We conclude by summarizing the lessons we have learned from the study of individual insect P450s, including their roles in insecticide resistance, plant-insect interactions and insect physiology. However, these studies are just the 'tip of the iceberg'. Our knowledge continues to expand at a rapid pace, suggesting that the next decade will outpace the last in terms of improving our understanding of the cytochromes P450 of insects.

Animals↗

PubMed2006

Bradykinin-related peptides from Phyllomedusa hypochondrialis azurea: Mass spectrometric structural characterisation and cloning of precursor cDNAs.

Amphibian skin secretions contain a plethora of bioactive compounds, many of which are understood to act to deter ingestion by predators. Bradykinins in particular are constitutively expressed in many amphibian skin secretions, mediating a variety of effects including hyperalgesia and contraction of gastric smooth muscle. Using a variety of proteomic techniques (high-performance liquid chromatography (HPLC) separation, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS), and quadrupole time-of-flight tandem mass spectrometry (Q-TOF-MS/MS)) the current study identified 13 bradykinin-like peptides in the skin secretions of Phyllomedusa hypochondrialis azurea, including several new C-terminally extended isoforms (VPPGFTPFRLT, VHypPGFTPFRQT) and a novel phyllokinin-like peptide (RPPGFTPFRVY). Identification of the cDNA sequences encoding these peptides led to the deduction that the peptides were derived from differential post-translational processing and modification of five different precursors. Such an event emphasises the metabolic efficiency of peptide production in amphibian venom, with multiple products perhaps selective to different receptors in a variety of predators generated from a single precursor. An unusual modification was also recognised in the present study, with several bradykinin-like peptides featuring hydroxyprolination of the first proline residue rather than the commonly targeted second. This alteration may be mediated by the structural organisation of N-terminal amino acids prior to precursor processing.

Amino Acid Sequence↗

PubMedDate not supplied

Selection bias in observational and experimental studies.

There has been a heightened awareness of the dangers of selection bias over the past two decades. Certainly coverage in statistical and 'statistics for medicine', and epidemiology textbooks have allocated pages to warn investigators and readers of investigations to be aware of its presence. The scientific community has not, however, yet accepted the necessity for critical assessment of the method of sample selection in the planning and execution of studies as a fundamental underpinning of observational and experimental studies. To wit, we are faced with a plethora of research studies receiving funding, being published in peer-reviewed journals and influencing future studies, that may be reporting entirely spurious associations. It is the intent of this paper to present examples of selection bias in a variety of areas which have resulted in misleading or entirely incorrect results. We hope to help make such research scientifically 'politically incorrect' to the degree that the scientific community 'just says no' to such studies, either proposed or reported.

Clinical Trials as Topic↗

PubMedDate not supplied

Embryologic concepts in the APUD system.

The amalgamation of the neural and endocrine physiologic mechanisms for functional homeostasis as a neuroendocrine system is brought into focus in this chapter on the embryologic concepts in the APUD system. The neuroendocrine system, now regarded as the third division of the nervous system, is a regulatory mechanism that links the functions of the autonomic nerves and the endocrine cells throughout the body. The current realization that both neural and endocrine actions are often involved in the clinical manifestations of many syndromes is clarified by the theories on the embryologic origin of the APUD system described here. Relevant historical developments, as well as cytochemical discoveries, have been gradually integrated into the evolving theories of the embryologic origin of the APUD system. These theories have not been without controversy, but new developments stimulate new concepts and, as new investigative tools have produced a plethora of new information that continues to push investigators, basic and clinical into new horizons, earlier theories have been modified and new theories have been developed. These theories are reviewed in chronological order in this chapter.

APUD Cells↗

PubMed2001

Formation and efficacy of vancomycin group glycopeptide antibiotic stereoisomers studied by capillary electrophoresis and bioaffinity mass spectrometry.

The conformational stability of vancomycin group antibiotics (i.e., vancomycin and avoparcin) in aqueous solution has been studied. These complex glycopeptide antibiotics contain many chiral centers allowing the potential formation of stereoisomers. Using capillary electrophoresis these stereoisomers could be separated and detected by UV and/or mass spectrometry. Fresh aqueous samples of both vancomycin and avoparcin already contained a plethora of stereoisomers. Thermal degradation of the antibiotics was studied as well. For vancomycin thermal degradation led primarily to the formation of CDP-I and aglycons. In the case of avoparcin thermal degradation led mainly to the interconversion between stereoisomers. These antibiotic stereoisomers may exhibit different antibacterial efficacy. Solution-phase association constants of fresh and heated samples of these antibiotics and their bacterial cell wall mimicking receptors were determined by bioaffinity mass spectrometry and revealed that the heated samples exhibited, in general, a lower affinity. Minimum inhibitory concentrations (Micrococcus flavus) were determined and confirmed the decrease in antibacterial efficacy upon heating.

Anti-Bacterial Agents↗

PubMed1998

Voluntary wheel running: a review and novel interpretation.

Voluntary wheel running by animals is an activity that has been observed and recorded in great detail for almost a century. This review shows that it is performed, often with startling intensity and coordination, by a wide variety of wild, laboratory and domestic species with diverse evolutionary histories. However, despite the plethora of published studies on wheel running, there is considerable disagreement between many findings, thus leading to a lack of consensus on explanations of the causality and function. In the initial part of this review, I discuss the internal and external factors that may be involved in the causality of this behaviour, with an emphasis on disparities in both the factual and theoretical development of the subject. I then address the various proposed functions of wheel running, again highlighting evidence to the contrary. This leads to the conclusion that any single theory on the basis of wheel running is likely to be simplistic with little generality. I then present a novel, behaviour-based interpretation in which it is argued that wheel running has no directly analogous naturally occurring behaviour, it is (sometimes) performed for its own sake per se rather than as a redirected or substitute activity, and studies on motivation show that wheel running is self-reinforcing and perceived by animals as 'important'. This review proposes that wheel running may be an artefact of captive environments or of the running-wheel itself, possibly resulting from feedback dysfunction. I also discuss the ubiquity and intensity of its performance, along with its great plasticity and maladaptiveness, all indicating that if it is an artefact, it is nevertheless one of great interest to behavioural science. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗

PubMed1996

MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP.

A plethora of signals induce the c-fos proto-oncogene via phosphorylation of the transcription factor Elk-1 by MAP kinase. We show that the coactivator CBP cooperates with Elk-1 to stimulate c-fos. Elk-1 physically interacts with CBP, which is dependent on the transactivation domain of Elk-1 but is independent of MAP kinase phosphorylation. However, functional cooperation between Elk-1 and CBP requires phosphorylation of Elk-1. Importantly, a carboxy-terminal transactivation domain of CBP itself is phosphorylated by MAP kinase, whereby the transactivation potential of CBP is enhanced. Thus, MAP kinase may not solely activate specific transcription factors but also the coactivator CBP, identifying a novel aspect of MAP kinase function. Thereby MAP kinase stimulation can pleiotropically affect activation of genes regulated by different transcription factors interacting with the same coactivator CBP.

Animals↗

PubMed1999

Apoptosis in human disease: a new skin for the old ceremony?

Naturally occurring cell death or apoptosis is essential for the maintenance of tissue homeostasis and serves to remove extraneous or dangerous cells in a swift and unobtrusive manner. Recent studies have indicated a role for apoptosis in a plethora of human diseases. Hence, dysregulation of apoptosis has been implicated in autoimmune disease, acquired immune deficiency syndrome, and other viral (and bacterial) infections, as well as in neurodegenerative disorders and cancer. Furthermore, dysregulated apoptosis signaling may impinge on other age-related disorders such as osteoporosis and atherosclerosis and perhaps on the process of aging itself. The present review provides an overview of human diseases, which are associated with defective or inadvertent apoptosis, with examples of pathological conditions in which putative apoptosis defects have been elucidated at the molecular level. Novel apoptosis-modulating therapeutic strategies are also discussed.

Apoptosis↗

PubMed2002

Evidence for "pre-recruitment" as a new mechanism of transcription activation in Escherichia coli: the large excess of SoxS binding sites per cell relative to the number of SoxS molecules per cell.

In response to the oxidative stress imposed by redox-cycling compounds like paraquat, Escherichia coli induces the synthesis of SoxS, which then activates the transcription of approximately 100 genes. The DNA binding site for SoxS-dependent transcription activation, the "soxbox," is highly degenerate, suggesting that the genome contains a large number of SoxS binding sites. To estimate the number of soxboxes in the cell, we searched the E. coli genome for SoxS binding sites using as query sequence the previously determined optimal SoxS binding sequence. We found approximately 12,500 sequences that match the optimal binding sequence under the conditions of our search; this agrees with our previous estimate, based on information theory, that a random sequence the size of the E. coli genome contains approximately 13,000 soxboxes. Thus, fast-growing cells with 4-6 genomes per cell have approximately 65,000 soxboxes. This large number of potential SoxS binding sites per cell raises the interesting question of how SoxS distinguishes between the functional soxboxes located within the promoters of target genes and the plethora of equivalent but nonfunctional binding sites scattered throughout the chromosome. To address this question, we treated cells with paraquat and used Western blot analysis to determine the kinetics of SoxS accumulation per cell; we also determined the kinetics of SoxS-activated gene expression. The abundance of SoxS reached a maximum of 2,500 molecules per cell 20 min after induction and gradually declined to approximately 500 molecules per cell over the next 1.5 h. Given that activation of target gene expression began almost immediately and given the large disparity between the number of SoxS molecules per cell, 2,500, and the number of SoxS binding sites per cell, 65,000, we infer that SoxS is not likely to activate transcription by the usual "recruitment" pathway, as this mechanism would require a number of SoxS molecules similar to the number of soxboxes. Instead, we propose that SoxS first interacts in solution with RNA polymerase and then the binary complex scans the chromosome for promoters that contain a soxbox properly positioned and oriented for transcription activation. We name this new pathway "pre-recruitment."

Bacterial Proteins↗