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PubMed2005

Volatile anesthetics disrupt frontal-posterior recurrent information transfer at gamma frequencies in rat.

We seek to understand neural correlates of anesthetic-induced unconsciousness. We hypothesize that cortical integration of sensory information may underlie conscious perception and may be disrupted by anesthetics. A critical role in frontal-posterior interactions has been proposed, and gamma (20-60 Hz) oscillations have also been assigned an essential role in consciousness. Here we investigated whether general anesthetics may interfere with the exchange of information encoded in gamma oscillations between frontal and posterior cortices. Bipolar electrodes for recording of event-related potentials (ERP) were chronically implanted in the primary visual cortex, parietal association and frontal association cortices of six rats. Sixty light flashes were presented every 5s, and ERPs were recorded at increasing concentrations of halothane or isoflurane (0-2%). Information exchange was estimated by transfer entropy, a novel measure of directional information transfer. Transfer entropy was calculated from 1-s wavelet-transformed ERPs. We found that (1) feedforward transfer entropy (FF-TE) and feedback transfer entropy (FB-TE) were balanced in conscious-sedated state; (2) anesthetics at concentrations producing unconsciousness augmented both FF-TE and FB-TE at 30 Hz but reduced them at 50 Hz; (3) reduction at 50 Hz was more pronounced for FB-TE, especially between frontal and posterior regions; (4) at high concentrations, both FF-TE and FB-TE at all frequencies were at or below conscious-sedated baseline. Our findings suggest that inhalational anesthetics preferentially impair frontal-posterior FB information transfer at high gamma frequencies consistent with the postulated role of frontal-posterior interactions in consciousness.

Anesthetics, Inhalation↗

PubMed2002

Separable neuronal circuitries for manipulable and non-manipulable objects in working memory.

Previous work using single-cell recordings in monkeys and neuro-imaging studies in humans has shown that perceiving an object or imaging the action associated with the object recruits the same brain regions in the ventral premotor cortex as performing an action with the object. We used functional magnetic resonance imaging (fMRI) for examining whether similar brain regions are also activated while maintaining information about manipulable objects in working memory. Holding information about manipulable objects in working memory activated the left ventral premotor cortex and the left inferior frontal gyrus (Broca's area). Conversely, non-manipulable objects to be held in working memory co-activated Broca's area and the left angular gyrus. When contrasted directly, manipulable relative to non-manipulable objects activated the left ventral premotor cortex and the anterior intraparietal sulcus, a circuitry that is assumed to mediate the transformation of movement-relevant object properties into hand actions. These results indicate that visual working memory for manipulable objects is based on motor programmes associated with their use. Similar to speech motor programmes in verbal memory tasks, hand motor programmes may allow the maintenance of objects in working memory over short intervals.

Adult↗

PubMed1995

Location of N2,N2-dimethylguanosine-specific tRNA methyltransferase.

Most steps in the maturation of nuclear coded tRNAs occur in the nucleus in eukaryotic cells, but little is known as to the intranuclear location of this RNA maturation pathway. Indirect immunofluorescence experiments using antibody to N2,N2 dimethylguanosine-specific tRNA methyltransferase, a tRNA processing enzyme, and to Nup1p, a nuclear pore protein, show that both locate to the nuclear periphery in wild type cells. Staining of the nuclear membrane is more uniform with anti-Trm1p than the punctate staining observed with antibodies recognizing Nup1p. Biochemical fractionation experiments comparing fractionation of Trm1p with Nup1p, tRNA splicing ligase, and tRNA splicing endonuclease show that Trm1p behaves more like the known peripheral nuclear membrane proteins, Nup1p and tRNA splicing ligase, than like the integral membrane protein, tRNA splicing endonuclease. Cells overproducing Trm1p also concentrate it to the nuclear periphery. Thus, the site(s) of interaction of Trm1p are not easily saturable and are likely to be in excess to Trm1p. Trm1p is shared by mitochondria and the nucleus. Cells transformed with a gene coding Trm1p with a mutant nuclear targeting signal display cytoplasmic staining and an enzyme with increased solubility when compared to the solubility of wild type enzyme. Thus, mutations that prevent the enzyme from entering the nucleus result in an increase in its cytosolic but not mitochondrial concentration suggesting that the mitochondrial/nuclear distribution of Trm1p is not due solely to competition of mitochondrial and nuclear targeting information.

Amino Acid Sequence↗

PubMed1998

Cell signaling in growth and development: the 11th Annual CABM Symposium, October 8-9, 1997.

While many topics were discussed during this symposium, several common themes emerged from the presentations. First, it is increasingly evident that regulation of ligand-receptor interactions is complex and can occur at nearly every conceivable step, including protein processing for release from or tethering to the cell surface, diffusibility through tissues, binding to soluble inhibitors, and competition with antagonists for receptor binding. In particular, the availability of these regulatory steps allows for a range of potential mechanisms by which ligand signaling can be modulated by other protein factors, such as in the case of fringe and its effects on signaling through the Notch receptor. Secondly, a major area of effort in the signaling field will increasingly focus on how cells integrate the signals received from different pathways to coordinate specific developmental responses. For example, as McMahon pointed out, the major signaling pathways that govern the anterior-posterior, dorsal-ventral, and proximal-distal axes of the developing limb bud have now been identified, yet it is completely unclear how these pathways interact to produce positional information in three dimensions. Thirdly, biochemical and structural investigations are now providing insights into the nature of the feedback mechanisms that regulate the strength and duration of activated signals, and how in some cases, these feedback loops can also provide a 'memory' of the signaling response, such as in the case of the adaptation found in bacterial chemotaxis. Finally, the structural analyses of signal transducing molecules remind us of the necessity to understand the mechanistic details of how active and inactive states are maintained, particularly since distant protein modifications can lead to global conformational changes that alter protein activity. These and other general insights underscore the value of broad-based meetings that cut across a range of disciplines and methodologies, such as this CABM symposium, and provide ideas for future directions of investigation.

Animals↗

PubMed2006

Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway--a report of the Tumour Angiogenesis Research Group.

PURPOSE: Lactate dehydrogenase 5 (LDH-5) regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition. Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors. The clinical significance of tissue LDH-5, however, remains largely unexplored. PATIENTS AND METHODS: We investigated the immunohistochemical expression of LDH-5 in a series of 128 stage II/III colorectal adenocarcinomas treated with surgery alone. In addition, markers of tumor hypoxia (hypoxia-inducible factor 1 alpha [HIF1alpha]), angiogenesis (vascular endothelial growth factor [VEGF] and phosporylated kinase domain receptor [pKDR]/flk-1 receptor) and the tumor vascular density (CD31 positive standard vascular density [sVD] and pKDR positive activated vascular density [aVD]) were assessed. RESULTS: The expression of LDH-5, together with that of HIF1alpha and pKDR, was both nuclear and cytoplasmic. Assessment, with minimal interobserver variability, was achieved using a previously described scoring system. LDH-5 was significantly associated with HIF1alpha (P = .01), aVD (P = .001) and, particularly, with pKDR expression in cancer cells (P = .0001). Tissue LDH-5 expression was linked with elevated serum LDH levels, but serum levels failed to reflect tissue expression in 71% of LDH-5 positive cases. In univariate analysis tissue LDH-5 was associated with poor survival (P = .0003, HR 15.1), whereas in multivariate analysis this isoenzyme was the strongest independent prognostic factor (P = .0009). VEGF, pKDR, aVD, sVD and vascular invasion were all significantly related to unfavorable prognosis. CONCLUSION: The immunohistochemical assessment of tissue LDH-5 and pKDR provides important prognostic information in operable colorectal cancer. The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor therapy.

Adenocarcinoma↗

PubMed1980

Origins of metabolic diversity: substitution of homologous sequences into genes for enzymes with different catalytic activities.

Similar amino acid sequences were found in portions of bacterial enzymes that mediate different biochemical transformations. Reaction catalyzed by the enzymes include oxygenation, decarboxylation, isomerization, and hydrolysis. The proteins share a common evolutionary history because they participate in an overall catabolic process known as the beta-ketoadipate pathway. One interpretation of the sequence similarities might be that duplication of a single gene gave rise to ancestral genes for the enzymes with different catalytic activities. According to this view, homologous sequences from the ancestral gene were conserved as the proteins diverged to assume different functions. This hypothesis is vitiated by comparison of the NH2-terminal amino acid sequences of sets of enzymes that mediate identical or analogous metabolic reactions within an organism. Gene duplications giving rise to the enzymes within each set must have followed duplication of a putative ancestral gene for all the sets. Yet the amino acid sequences of the proteins within each set have diverged widely, and against this background of divergence the conservation of sequences from an ancestor common to all the enzymes is unlikely. Rather, it appears that most regions of sequence similarity shared by enzymes from different sets were acquired subsequent to their divergence from any common ancestor. In some cases it appears that relatively short regions of sequence homology were achieved by mutations causing the transfer of sequence information from one set of structural genes to structural genes in another set. Alignment of homologous amino acid sequences within any single set requires the introduction of few gaps. Because gaps are required to align sequences that have been altered by the insertion of genetic material, the evidence indicates that copies of oligonucleotides were exchanged by genetic substitution among different structural genes as they coevolved.

Acinetobacter↗

PubMed2000

Signaling from E-cadherins to the MAPK pathway by the recruitment and activation of epidermal growth factor receptors upon cell-cell contact formation.

E-cadherins are well characterized cell surface molecules expressed in epithelial cells, which play a major role in cell adhesion through the establishment of calcium-dependent homophilic interactions at sites of cell-cell contacts. They are also integral components of morphogenetic programs controlling the maintenance of the structural and functional integrity of epithelia. Accumulated evidence indicates that the E-cadherin-mediated cell adhesion system is highly regulated from inside the cells by a number of intracellular signaling pathways. Recently available information suggests that E-cadherins may also play a role in the transduction of signals from the outside of the cell to the cytoplasm. However, the nature of the biochemical routes regulated by E-cadherins is still largely unknown. In this study, we set out to explore the possibility that E-cadherins may regulate the activity of MAPK, a key signaling pathway involved in cell fate decisions, upon the formation of cell-cell contacts among neighboring cells. By using an immortalized non-tumorigenic keratinocyte cell line, HaCat, as a model system, we provide evidence that the assembly of calcium-dependent adherens junctions leads to a rapid and remarkable increase in the state of activation of MAPK and that this event is mediated by E-cadherins. Furthermore, we found that E-cadherins stimulate the MAPK pathway through the ligand-independent activation of epidermal growth factor receptors and the consequent activation of a biochemical route leading to the stimulation of MAPKs. These findings suggest that E-cadherins can initiate outside-in signal transducing pathways through the engagement of tyrosine kinase receptors for epidermal growth factor, thus providing a novel molecular mechanism whereby these cell adhesion molecules may ultimately control the fate of normal and transformed epithelial cells.

Cadherins↗

PubMedDate not supplied

Superoxide dismutase in hepatocellular carcinoma affects patient prognosis.

BACKGROUND/AIMS: The free radicals play an important role in the pathogenesis of neoplastic transformation of the tissues. Superoxide dismutase is a metalloenzyme, protecting the cells from oxygen radical insult. The superoxide dismutase activity may therefore alter the cellular signaling pathways against the insults derived from oxidative stress especially in the tumor tissues. Therefore, it is considered that superoxide dismutase activity is crucial in affecting the survival of the cancer bearing patients. This study aims to investigate the level of superoxide dismutase activity in hepatocellular carcinoma tissues and correlate this with patients' survival after surgery for hepatocellular carcinoma. METHODOLOGY: Thirty-six patients who had hepatectomy for hepatocellular carcinoma at the National Taiwan University Hospital from 1992 to 1993 were included in this study. Superoxide dismutase activity of the tumor tissues was determined. The results were correlated with the patients' survival. The patients were grouped based on their postoperative survival time. Those patients who were deceased less then one year after surgery were in group I. Group II included patients who survived more than one year but less than 3 years after operation. Group III patients survived more than 3 years but less than 5 years. Ten patients who survived longer than 5 years after surgical intervention were in group IV. Data were expressed as mean and analyzed with ANOVA. RESULTS: The demographic and clinical information of patients, such as age, gender, plasma albumin, globulin, alpha-fetoprotein levels, and hepatitis markers were comparable among these groups. The superoxide dismutase levels in the hepatocellular carcinoma were significantly higher in group IV than the other three groups (P < 0.05). Similarly, the superoxide dismutase levels of the hepatocellular carcinoma tissues from group III patients were significantly greater than those tissues from patients of either group I or group II. Tumor superoxide dismutase levels tended to be higher in group II than in group I, although it did not reach a statistical significance. CONCLUSIONS: Patients with higher superoxide dismutase levels in the hepatocellular carcinoma survived longer after hepatectomy. The superoxide dismutase levels of the tumor tissue may influence the malignancy and the outcome of the patients. It serves as prognostic factor for patients after hepatocellular carcinoma operation.

Aged↗

PubMed2000

Some transformations of color information from lateral geniculate nucleus to striate cortex.

We have recorded the responses of single cells in the lateral geniculate nucleus (LGN) and striate cortex of the macaque monkey. The response characteristics of neurons at these successive visual processing levels were examined with isoluminant gratings, cone-isolating gratings, and luminance-varying gratings. The main findings were: (i) Whereas almost all parvo- and konio-cellular LGN cells are of just two opponent-cell types, either differencing the L and M cones (L(o) and M(o) cells), or the S vs. L + M cones (S(o) cells), relatively few striate cortex simple cells show chromatic responses along these two cardinal LGN axes. Rather, most are shifted away from these LGN chromatic axes as a result of combining the outputs (or the transformed outputs) of S(o) with those of L(o) and/or M(o) cells. (ii) LGN cells on average process color information linearly, exhibiting sinusoidal changes in firing rate to isoluminant stimuli that vary sinusoidally in cone contrast as a function of color angle. Some striate cortex simple cells also give linear responses, but most show an expansive response nonlinearity, resulting in narrower chromatic tuning on average at this level. (iii) There are many more +S(o) than -S(o) LGN cells, but at the striate cortex level -S(o) input to simple cells is as common as +S(o) input. (iv) Overall, the contribution of the S-opponent path is doubled at the level of the striate cortex, relative to that at the LGN.

Animals↗

PubMed1997

Alterations in the Chlamydomonas plastocyanin transit peptide have distinct effects on in vitro import and in vivo protein accumulation.

Nucleus-encoded chloroplast proteins that reside in the thylakoid lumen are synthesized as precursors with bipartite transit peptides that contain information for uptake and intra-chloroplast localization. We have begun to apply the superb molecular and genetic attributes of Chlamydomonas to study chloroplast protein import by creating a series of deletions in the transit peptide of plastocyanin and determining their effects on translocation into isolated Chlamydomonas chloroplasts. Most N-terminal mutations dramatically inhibited in vitro import, whereas replacement with a transit peptide from the gamma-subunit of chloroplast ATPase restored uptake. Thus, the N-terminal region has stroma-targeting function. Deletions within the C-terminal portion of the transit peptide resulted in the appearance of import intermediates, suggesting that this region is required for lumen translocation and processing. Thus, despite its short length and predicted structural differences, the Chlamydomonas plastocyanin transit peptide has functional domains similar to those of vascular plants. Similar mutations have been analyzed in vivo by transforming altered genes into a mutant defective at the plastocyanin locus (K. L. Kindle, manuscript in preparation). Most mutations affected in vitro import more severely than plastocyanin accumulation in vivo. One exception was a deletion that removed residues 2-8, which nearly eliminated in vivo accumulation but had a modest effect in vitro. We suggest that this mutant precursor may not compete successfully with other proteins for the translocation pathway in vivo. Apparently, in vivo and in vitro analyses reveal different aspects of chloroplast protein biogenesis.

Adenosine Triphosphate↗

PubMed1998

Mitochondria as regulators of apoptosis: doubt no more.

Scientific revolution [1] implies a transformation of the world view in which a dominant paradigm is substituted by a new one, one which furnishes an ameliorated comprehension of facts, as well as an advantage for the design of informative experiments. Apoptosis research has recently experienced a change from a paradigm in which the nucleus determined the apoptotic process to a paradigm in which mitochondria constitute the center of death control. Several pieces of evidence imply mitochondria in the process of apoptosis. Kinetic data indicate that mitochondria undergo major changes in membrane integrity before classical signs of apoptosis become manifest. These changes concern both the inner and the outer mitochondrial membranes, leading to a disruption of the inner transmembrane potential (DeltaPsim) and the release of intermembrane proteins through the outer membrane. Cell-free systems of apoptosis demonstrate that mitochondrial products are rate limiting for the activation of caspases and endonucleases in cell extracts. Functional studies indicate that drug-enforced opening or closing of the mitochondrial megachannel (also called permeability transition pore) can induce or prevent apoptosis. The anti-apoptotic oncoprotein Bcl-2 acts on mitochondria to stabilize membrane integrity and to prevent opening of the megachannel. These observations are compatible with a three-step model of apoptosis: a premitochondrial phase during which signal transduction cascades or damage pathways are activated; a mitochondrial phase, during which mitochondrial membrane function is lost; and a post-mitochondrial phase, during which proteins released from mitochondria cause the activation of catabolic proteases and nucleases. The implication of mitochondria in apoptosis has important consequences for the understanding of the normal physiology of apoptosis, its deregulation in cancer and degenerative diseases, and the development of novel cytotoxic and cytoprotective drugs.

Animals↗

PubMed2004

Global gene expression profile of nasopharyngeal carcinoma by laser capture microdissection and complementary DNA microarrays.

A number of genetic and epigenetic changes underlying the development of nasopharyngeal carcinomas have recently been identified. However, there is still limited information on the nature of the genes and gene products whose aberrant expression and activity promote the malignant conversion of nasopharyngeal epithelium. Here, we have performed a genome-wide transcriptome analysis by probing cDNA microarrays with fluorescent-labeled amplified RNA derived from laser capture microdissected cells procured from normal nasopharyngeal epithelium and areas of metaplasia-dysplasia and carcinoma from EBV-associated nasopharyngeal carcinomas. This approach enabled the identification of genes differentially expressed in each cell population, as well as numerous genes whose expression can help explain the aggressive clinical nature of this tumor type. For example, genes indicating cell cycle aberrations (cyclin D2, cyclin B1, activator of S-phase kinase, and the cell cycle checkpoint kinase, CHK1) and invasive-metastatic potential (matrix metalloproteinase 11, v-Ral, and integrin beta(4)) were highly expressed in tumor cells. In contrast, genes underexpressed in tumors included genes involved in apoptosis (B-cell CLL/lymphoma 6, secretory leukocyte protease inhibitor, and calpastatin), cell structure (keratin 7 and carcinoembryonic antigen-related cell adhesion molecule 6), and putative tumor suppressor genes (H-Ras-like suppressor 3, retinoic acid receptor responder 1, and growth arrested specific 8) among others. Gene expression patterns also suggested alterations in the Wnt/beta-catenin and transforming growth factor beta pathways in nasopharyngeal carcinoma. Thus, expression profiles indicate that aberrant expression of growth, survival, and invasion-promoting genes may contribute to the molecular pathogenesis of nasopharyngeal carcinoma. Ultimately, this approach may facilitate the identification of clinical useful markers of disease progression and novel potential therapeutic targets for nasopharyngeal carcinoma.

Carcinoma↗

PubMed1994

The role of sensory information in the guidance of voluntary movement: reflections on a symposium held at the 22nd annual meeting of the Society for Neuroscience.

This article reviews a symposium on the sensory control of movement held at the 22nd annual meeting of the Society for Neuroscience. Four speakers addressed a large audience on the proposition that "one can only control what one senses." Charles Vierck supported the notion with a description of the severe motor deficits caused by lesions of the spinal dorsal columns (DCs) in monkeys. In the discussion of Vierck's presentation, Robert Forget described the difficulties experienced by deafferented patients in tasks of daily life. Next, John Brooke showed that sensorimotor transformations vary greatly with task, anticipation, and uncertainty. In light of this, he questioned the simplifications inherent in servo and equilibrium-point theories of motor control. Paul Cordo then showed that in a rapid throwing task, proprioceptive information is used to control the moment of release (contradicting the idea that sensory feedback is too delayed for ballistic movements). Dick Burgess, like Brooke, criticized equilibrium-point models; he argued that a subject's sense of effort is a measure of the internal motor command, which should correspond to specific equilibrium points. However, his experimental data were inconsistent with this interpretation. He suggested instead that motor output is adjusted by comparing incoming afferent information to an expected "afferent template." Anatol Feldman and Mark Latash disagreed, saying that a constant sense of effort does not imply a constant equilibrium-point command. The equilibrium-point debate was not resolved, but the symposium ended with a consensus that in most motor tasks, one can control only what one senses.

Afferent Pathways↗

PubMed1997

Developmental expression of morphoregulatory genes in the mouse embryo: an analytical approach using a novel technology.

The molecular techniques of in situ transcription and antisense RNA amplification (IST/aRNA) have allowed for the monitoring of coordinate changes in the expression of multiple genes simultaneously. However, the analysis of their concurrent behavior during murine embryogenesis has been problematic. Studies involving the investigation of temporal and spatial gene expression during embryogenesis have focused solely on the analysis of isolated, single gene events. Such an approach has failed to provide an integrative picture of genetic control over the varied and complicated cellular processes governing embryogenesis. In order to interpret the enormous amount of gene expression data generated by these procedures, we have attempted to develop an analytical framework by employing the statistical concepts of principal components analysis (PCA). For the current study, we performed IST/aRNA on neural tubes dissected from the highly inbred LM/Bc murine strain collected during four gestational time periods. A subset of these genes, representing a partial signaling pathway in the developing neuroepithelium, was then subjected to PCA. Here, we report that PCA highlighted the transcriptional interplay among the genes p53, wee-1, Tgf beta-2, and bcl-2 such that the combined reciprocal regulation of their gene products is suggestive of a predominant proliferative state for the developing neuroepithelium. The application of PCA to the gene expression data has elucidated previously unknown interrelationships among cell cycle genes, growth, and transcription factors on a transcriptional level during critical stages of neurulation. The information gleaned from this analysis, while not definitive, suggests distinct hypotheses to guide future research.

Analysis of Variance↗

PubMed1998

The bone morphogenetic protein family: multifunctional cellular regulators in the embryo and adult.

Originally identified as the active components within osteoinductive extracts derived from bone, the BMPs now are known to include a large family of proteins within the TGF-beta superfamily of growth and differentiation factors. Members of the BMP family have been determined to be key signaling molecules in embryogenesis, in species ranging from Drosophila to humans. They are involved in delivering positional information, the development of hard tissues (both bones and teeth), as well as soft tissue types. When implanted into adult animals, several of the BMPs have been shown to initiate the complex cellular process resulting in the induction of bone through both the endochondral and intramembranous bone formation pathways. Preclinical studies have shown the ability of these factors to induce bone and heal large bony defects in a variety of models relevant to clinical problems in orthopedics, as well as the oral and maxillofacial/dental areas. For example, implantation of recombinant human BMP-2 (rhBMP-2) has been shown to augment the alveolar ridge in several animal models, and when placed in a periodontal environment to restore not only new bone, but also the attachment tissues. Results from ongoing clinical studies support the ability of rhBMP-2 implants to induce physiologic bone.

Adult↗

PubMed1987

In vitro mutagenesis of trypsinogen: role of the amino terminus in intracellular protein targeting to secretory granules.

The mouse anterior pituitary tumor cell line, AtT-20, targets secretory proteins into two distinct intracellular pathways. When the DNA that encodes trypsinogen is introduced into AtT-20 cells, the protein is sorted into the regulated secretory pathway as efficiently as the endogenous peptide hormone ACTH. In this study we have used double-label immunoelectron microscopy to demonstrate that trypsinogen colocalizes in the same secretory granules as ACTH. In vitro mutagenesis was used to test whether the information for targeting trypsinogen to the secretory granules resides at the amino (NH2) terminus of the protein. Mutations were made in the DNA that encodes trypsinogen, and the mutant proteins were expressed in AtT-20 cells to determine whether intracellular targeting could be altered. Replacing the trypsinogen signal peptide with that of the kappa-immunoglobulin light chain, a constitutively secreted protein, does not alter targeting to the regulated secretory pathway. In addition, deletion of the NH2-terminal "pro" sequence of trypsinogen has virtually no effect on protein targeting. However, this deletion does affect the signal peptidase cleavage site, and as a result the enzymatic activity of the truncated trypsin protein is abolished. We conclude that neither the signal peptide nor the 12 NH2-terminal amino acids of trypsinogen are essential for sorting to the regulated secretory pathway of AtT-20 cells.

Adrenocorticotropic Hormone↗

PubMed2001

Butyrate induces glutathione S-transferase in human colon cells and protects from genetic damage by 4-hydroxy-2-nonenal.

Butyrate, one of the major products of gut fermentation, is known to inhibit proliferation, induce apoptosis and differentiation, and increase phase II enzyme activities in tumor cells, whereas little information is available on protective effects in less-transformed colon cells. The aim of this study was to investigate whether the chemoprotective mechanism of glutathione S-transferase (GST) induction by butyrate could also play a role in earlier stages of colon carcinogenesis and whether chemoresistance of cells toward the endogenous genotoxic risk factor 4-hydroxy-2-nonenal (HNE) could be a consequence of butyrate treatment. As cell models, we used the human tumor cell lines HT29 and HT29 clone 19A, a differentiated subclone with properties resembling primary colon cells. We determined the expression of GSTP1 protein (enzyme-linked immunosorbent assay), the major GST in HT29, GSTP1 mRNA (Northern blotting), GST activity, intracellular glutathione, and total protein. The genotoxic impact of HNE (100-200 microM) was compared in butyrate-treated and nontreated cells using single-cell microgel electrophoresis. Our results show that GSTP1 mRNA, GSTP1 protein, GST activity, and total protein were increased (1.2- to 2.5-fold) and glutathione levels were maintained after 24-72 h of incubation with 4 mM butyrate. Moreover, a marked reduction of HNE-induced genotoxicity was caused by preincubation with butyrate. Butyrate also induced the phosphorylation of extracellular signal-regulated kinases (ERK1/2, Western blotting) after 5-30 min, which indicates a regulation of GST expression by this signal pathway. Most effects were greater in HT29 parent cells than in clone cells. In conclusion, butyrate enhances expression of GST and other proteins in both cell lines, which leads to an enhanced chemoprotection, reducing the impact of HNE genotoxicity. Thus butyrate could play a role in early and later stages of cancer prevention by reducing exposure to relevant risk factors.

Aldehydes↗

PubMedDate not supplied

Predicting neuronal responses during natural vision.

A model that fully describes the response properties of visual neurons must be able to predict their activity during natural vision. While many models have been proposed for the visual system, few have ever been tested against this criterion. To address this issue, we have developed a general framework for fitting and validating nonlinear models of visual neurons using natural visual stimuli. Our approach derives from linear spatiotemporal receptive field (STRF) analysis, which has frequently been used to study the visual system. However, prior to the linear filtering stage typical of STRFs, a linearizing transformation is applied to the stimulus to account for nonlinear response properties. We used this approach to compare two models for neurons in primary visual cortex: a nonlinear Fourier power model, which accounts for spatial phase invariant tuning, and a traditional linear model. We characterized prediction accuracy in terms of the total explainable variance, given intrinsic experimental noise. On average, Fourier power STRFs predicted 40% of explainable variance while linear STRFs were able to predict only 21% of explainable variance. The performance of the Fourier power model provides a benchmark for evaluating more sophisticated models in the future.

Animals↗