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PubMed1996

Mental transformations in the motor cortex.

The behavioral and neural correlates of processing of motor directional information are described for two visuomotor tasks: mental rotation and context-recall. Psychological studies with human subjects suggested that these two tasks involve different time-consuming processes of directional information. Analyses of the activity of single cells and neuronal populations in the motor cortex of behaving monkeys performing in the same tasks provided direct insight into the neural mechanisms involved and confirmed their different nature. In the mental rotation task the patterns of neuronal activity revealed a rotation of the intended direction of movement. In contrast, in the context-recall task the patterns of neural activity identified a switching process of the intended direction of movement.

Cues↗

PubMed2026

Deficient arsenic methylation and global proteomic reprogramming in human keratinocytes during arsenic-induced skin carcinogenesis.

Chronic inorganic arsenic (iAs) exposure affects > 220 million people worldwide and skin cancer is a hallmark of long-term iAs exposure. Limited information exists regarding arsenic methylation by human keratinocytes and how methylation influences skin carcinogenesis. Inorganic arsenite (iAsIII) and its methylated metabolites disrupt diverse zinc finger proteins, leading to differential toxicity patterns. We examined arsenic methylation capacity in non-malignant human keratinocytes and interrogated proteomic remodeling across three stages of iAsIII induced malignant transformation using the well-established preclinical HaCaT model. Arsenic methylation was assessed by hydride generation cryotrapping inductively coupled-mass spectrometry and global proteomic changes were analyzed by tandem-mass tagging liquid chromatography-tandem mass spectrometry. Primary, hTERT-immortalized and HaCaT human keratinocytes exhibited negligible arsenic methylation, with iAsIII comprising at least 98.5% of total intracellular arsenic, attributable to minimal expression of arsenite methyltransferase. Proteomic profiling identified over 275 differentially expressed proteins at each stage of transformation, including multiple zinc finger proteins implicated in cell cycle control, RNA metabolism, and genome stability. Ingenuity® Pathway Analysis revealed progressive, coordinated disruption of cancer-associated pathways and regulatory networks over the transformation timeline, including zinc-coordinating upstream regulators that may explain widespread pathway dysregulation. Collectively, our findings suggest that iAsIII promotes skin carcinogenesis by disrupting C3H1- and C4-type zinc finger protein-centered regulatory networks that coordinate cancer-associated signaling and metabolic pathways in human keratinocytes, highlighting key candidates for future mechanistic studies.

Arsenic↗

PubMed2002

Signaling on telomerase: a master switch in cell aging and immortalization.

Cell aging involves damages and losses of genetic materials including the gradual shortening of telomeres. Telomeres, the ends of chromosomes, have a variety of functions, and the most notable ones include those involved in retaining genome integrity and stability and in regulating cell lifespan. Early loss or damage of telomeres causes premature aging, whereas excessive gain of telomeres confers immortality upon some cancer cells. However, the opposing changes in telomere structures and their associated cellular effects on aging and immortalization are forcefully regulated by the enzyme telomerase. Telomerase is a large protein-RNA complex that has telomeric DNA reverse transcriptase activity. Although a wealthy body of information has been obtained on the involvement of telomerase in tumorigenesis, its structure of the holoenzyme, the mode of its action, its cellular function in aging, and the pathways of its regulatory mechanisms have not been entirely understood. Recent research on telomerase has become an increasing investigative effort to uncover the molecular mechanisms of aging and aging-related diseases. This article will briefly review now telomerase may impact aging, what potential in vivo significance the regulation of telomerase may have on aging, how signals are transduced from telomerase and telomere to different cellular effects, and how telomerase itself is controlled in mammalian cells.

Animals↗

PubMed2004

Cell cycle checkpoint control mechanisms that can be disrupted in cancer.

Maintenance of genomic integrity is essential to avoid cellular transformation, neoplasia, or cell death. DNA synthesis, mitosis, and cytokinesis are important cellular processes required for cell division and the maintenance of cellular homeostasis; they are governed by many extra- and intra-cellular stimuli. Progression of normal cell division depends on cyclin interaction with cyclin-dependent kinases (Cdk) and the degradation of cyclins before chromosomal segregation through ubiquitination. Multiple checkpoints exist and are conserved in the cell cycle in higher eukaryotes to ensure that if one fails, others will take care of genomic integrity and cell survival. Many genes act as either positive or negative regulators of checkpoint function through different kinase cascades, delaying cell cycle progression to repair the DNA lesions and breaks, and assuring equal segregation of chromosomes to daughter cells. Understanding the checkpoint pathways and genes involved in the cellular response to DNA damage and cell division events in normal and cancer cells, provides information about cancer predisposition, and suggests design of small molecules and other strategies for cancer therapy.

Cell Cycle↗

PubMed1985

Growth factors and cancer.

Recent advances in protein chemistry and genetic engineering have revealed new information about the molecular lesions involved in the induction and maintenance of cancer cells. It is now known that a single base change in the DNA of human cells leads to cancer. The normal pathway of proliferation and differentiation is perturbed by changes to molecules involved in the intracellular biochemical pathways controlled by growth factors. Some cancer cells appear to produce their own growth factor, others have higher concentrations of growth factor receptors on their surface and others have mutated versions of the intracellular proteins linked to the growth factor receptors. This increased understanding of growth control in normal and neoplastic cell populations is gradually providing a foundation for new approaches to cancer therapy.

Animals↗

PubMed2002

Pancreatitis as a risk for pancreatic cancer.

Chronic pancreatitis clearly predisposes to pancreatic cancer, with early onset-long duration chronic pancreatitis from cystic fibrosis, TP, and HP conferring the highest risk. Chronic pancreatitis is not a critical step, however, but rather one of several conditions that accelerate the accumulation of critical genetic mutations and chromosomal losses necessary for carcinogenesis. Indeed, other germline mutations, environmental factors such as tobacco smoking and alcohol consumption, or dietary factors may also accelerate the pathway to carcinogenesis, and may be synergistic with the conditions created by chronic pancreatitis. Because patients with chronic pancreatitis are at high risk of pancreatic cancer, the physician is faced with decisions on how to manage this risk. Discontinuing smoking and alcohol consumption, and perhaps dietary modification are obvious recommendations for risk reduction. If, however, the patient is older and already in a very high-risk category (e.g., long-standing HP), then screening for cancers must be considered. Inclusion in multicenter trials is recommended, and information on ongoing studies can be obtained through the office of Dr. Whitcomb, or as posted on www.pancreas.org.

Cell Transformation, Neoplastic↗

PubMed2006

Metabolism of mono- and dihalogenated C1 and C2 compounds by Xanthobacter autotrophicus growing on 1,2-dichloroethane.

The conversion of and toxic effects exerted by several mono- and dihalogenated C1 and C2 compounds on cultures of Xanthobacter autotrophicus GJ10 growing on 1,2-dichloroethane were investigated. Bromochloromethane, dibromomethane and 1-bromo-2-chloroethane were utilized by strain GJ10 in batch culture as a cosubstrate and sole carbon source. The rate of degradation of dihalomethanes by whole cells was lower than that of 1,2-dichloroethane, but a significant increase of the rate of dihalomethane biodegradation was observed when methanol or ethanol were added as a cosubstrate. Products of the degradation of several tested compounds by haloalkane dehalogenase were analyzed and a new metabolic pathway based on hydrolytic conversion to formaldehyde was proposed for the dihalomethanes. Strain GJ10 growing on 1,2-dichloroethane converted 2-fluoroethanol and 1-chloro-2-fluoroethane to 2-fluoroacetate, which was tolerated up to a concentration of 2.5 mM. On the basis of the results from batch cultures an inert (dichloromethane), a growth-supporting (dibromomethane) and a toxic (1,2-dibromoethane) compound were selected for testing their effects on a continuous culture of strain GJ10 growing on 1,2-dichloroethane. The compounds were added as pulses to a steady-state chemostat and the response of the culture was followed. The effects varied from a temporary decrease in cell density for dibromomethane to severe toxicity and culture washout with 1,2-dibromoethane. Our results extend the spectrum of halogenated C1 and C2 compounds that are known to be degraded by strain GJ10 and provide information on toxic effects and transformation of compounds not serving as a carbon source for this bacterium.

Culture Media↗

PubMed2026

Crosstalk between the Wnt pathway and other signaling pathways.

The Wnt/β-catenin signaling pathway is a deeply conserved regulatory network that governs embryonic development, stem cell maintenance, and tissue homeostasis. Aberrant activation of the Wingless/Integrated protein (Wnt) signaling is a hallmark of numerous human diseases, most prominently in colorectal cancer, where it cooperates with additional oncogenic pathways to drive tumor initiation, progression, and therapeutic resistance (See Supplementary Table 1 for a list of the abbreviations used in this manuscript and their definitions.). Increasing evidence indicates that Wnt signaling does not function as an isolated linear cascade but rather as an integrative signaling hub that dynamically interfaces with major signaling pathways, including the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways. Rat Sarcoma protein (RAS)- Rapidly Accelerated Fibrosarcoma protein (RAF)- Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K)- Ak strain transforming protein (AKT)- Mechanistic Target of Rapamycin (mTOR) pathways. These interactions occur at multiple molecular levels, encompassing shared kinases, transcriptional regulators, metabolic nodes, and cytoskeletal components, thereby coordinating proliferative, metabolic, and migratory programs. In this review, we synthesize current mechanistic and clinical insights into the crosstalk between Wnt signaling and the RAS-RAF-MAPK and PI3K-AKT-mTOR pathways, with particular emphasis on colorectal cancer. We discuss how these signaling networks converge to regulate β-catenin stability, transcriptional activity, cell adhesion, and metabolic reprogramming, thereby generating oncogenic phenotypes that cannot be explained by activation of individual pathways alone. To illustrate the evolutionary conservation and biological significance of these interactions, we integrate developmental paradigms from early Xenopus embryogenesis, where Wnt signaling governs zygotic genome activation, body axis formation, and the regulation of cell growth, protein stability, and biomass accumulation. Finally, we examine how an improved understanding of Wnt-centered signaling networks is informing emerging therapeutic strategies, including combinatorial pathway inhibition and nanoparticle-based drug delivery. Collectively, this review highlights Wnt signaling as a central integrator of developmental and oncogenic programs, providing a conceptual framework for understanding signaling network crosstalk and identifying new therapeutic opportunities in cancer.

Humans↗

PubMed1995

Excess copper and ceruloplasmin biosynthesis in long-term cultured hepatocytes from Long-Evans Cinnamon (LEC) rats, a model of Wilson disease.

Immortalized hepatic cell lines obtained from laboratory animals or patients with defects in copper metabolism in the liver provide new approaches to examine related metabolism and toxicity. We established a series of hepatic cell lines from the liver of Long-Evans Cinnamon (LEC) rats, using recombinant adenovirus which expresses SV40 large T. Cells from the LEC rats were cultured and accumulated larger amounts of copper than did control cells, when the concentrations of copper in the culture medium exceeded 5 microM. The secretion of ceruloplasmin (CP) from the cultured cells was not reduced in hepatocytes from LEC cells, as compared with the control cells. As accumulation of copper did not affect CP secretion, CP production was not likely to be affected by the accumulation of copper in LEC rat hepatocytes. The production of holo-CP was further investigated by transfection of human CP cDNA and detection of human holo-CP by immunological procedures and use of a monoclonal antibody (mAb CP60) which recognizes human holo-CP but not human apo-CP and rat CP. Hepatocytes from the LEC rats processed and secreted holo-CP into the medium, even with excess copper present in the medium. These observations suggest that the genetic defect in LEC rats did not alter biosynthetic and secretory pathways of CP and that the intracellular copper concentration did not regulate the synthesis and processing of CP in the cultured hepatocytes. Low ceruloplasmin levels are observed in most, but not all, patients with Wilson disease, as well as in LEC rats. Our results do suggest that the copper transporting ATPase encoded in the Wilson disease gene is not a integral part of the biochemical mechanism of copper incorporation into apoprotein. The cell lines and immunological procedures we used are expected to add to information on biologically important process related to copper metabolism and to CP biosynthesis.

Adenoviruses, Human↗

PubMed2001

Modeling Huntington's disease in cells, flies, and mice.

A milestone in Huntington's disease (HD) research is represented by the identification of the causative gene. With the genetics at hand, a series of transgenic cellular and animal models has been developed, which has greatly contributed to understanding of HD. All these models are described in this review, and are compared to each other, along with the information they have generated. Although the mechanism by which progressive loss of striatal neurons occurs in HD remains uncertain, hypotheses on mutant huntingtin toxicity involve impaired vescicular trafficking, transcriptional dysregulation, and/or activation of apoptotic pathways. The development of inducible HD mice has shown that neurodegeneration in HD may be at least partially blocked. Although traditionally considered a "gain-of-function" disease, the recent finding that normal huntingtin has an important role in neuronal survival suggests that loss of function of the normal protein might contribute to HD as well, also discloseing new perspectives on the therapeutical approach to the pathology.

Animals↗

PubMed1979

The object of the sensory cortex.

The phenomenon of "transfer" is used to draw attention to the point that whereas the brain stem animal can solve a variety of individual problem ad hoc, only the intact animal appears to be able to use the result of one problem to solve a closely related problem. It is suggested that this is because information is organized in the cortex as objects and concepts, rather than as a set of more or less elaborate features. The shortcomings of a hierarchical system of feature detectors as a model of cortical organization are examined, and compared with a distributive model. It is pointed out that our ways of thinking about complex tones--e.g. their pitch and harmonic structure--is related to the fact that sound suffers a Fourier transform at the cochlea, and it is this transform which is represented in the brain stem. It is suggested that an analogous integral transform may equally naturally represent the data as "objects" in the cortex. The resistance of such transforms to degradation by ablation, and the implication for single neurone behaviour are discussed.

Acoustic Stimulation↗

PubMed2005

Phylogenetic conservation of the regulatory and functional properties of the Vav oncoprotein family.

Vav proteins are phosphorylation-dependent GDP/GTP exchange factors for Rho/Rac GTPases. Despite intense characterization of mammalian Vav proteins both biochemically and genetically, there is little information regarding the conservation of their biological properties in lower organisms. To approach this issue, we have performed a characterization of the regulatory, catalytic, and functional properties of the single Vav family member of Drosophila melanogaster. These analyses have shown that the intramolecular mechanisms controlling the enzyme activity of mammalian Vav proteins are already present in Drosophila, suggesting that such properties have been set up before the divergence between protostomes and deuterostomes during evolution. We also show that Drosophila and mammalian Vav proteins have similar catalytic specificities. As a consequence, Drosophila Vav can trigger oncogenic transformation, morphological change, and enhanced cell motility in mammalian cells. Gain-of-function studies using transgenic flies support the implication of this protein in cytoskeletal-dependent processes such as embryonic dorsal closure, myoblast fusion, tracheal development, and the migration/guidance of different cell types. These results highlight the important roles of Vav proteins in the signal transduction pathways regulating cytoskeletal dynamics. Moreover, they indicate that the foundations for the regulatory and enzymatic activities of this protein family have been set up very early during evolution.

Amino Acid Sequence↗

PubMed2003

Detection and characterization of methionine oxidation in peptides by collision-induced dissociation and electron capture dissociation.

Electron capture dissociation (ECD) and collision-induced dissociation (CID), the two complementary fragmentation techniques, are demonstrated to be effective in the detection and localization of the methionine sulfoxide [Met(O)] residues in peptides using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. The presence of Met(O) can be easily recognized in the low-energy CID spectrum showing the characteristic loss of methanesulfenic acid (CH(3)SOH, 64 Da) from the side chain of Met(O). The position of Met(O) can then be localized by ECD which is capable of providing extensive peptide backbone fragmentation without detaching the labile Met(O) side chain. We studied CID and ECD of several Met(O)-containing peptides that included the 44-residue human growth hormone-releasing factor (GRF) and the human atrial natriuretic peptide (ANP). The distinction and complementarity of the two fragmentation techniques were particularly remarkable in their effects on ANP, a disulfide bond-containing peptide. While the predominant fragmentation pathway in CID of ANP was the loss of CH(3)SOH (64 Da) from the molecular ion, ECD of ANP resulted in many sequence-informative products, including those from cleavages within the disulfide-bonded cyclic structure, to allow for the direct localization of Met(O) without the typical procedures for disulfide bond reduction followed by [bond]SH alkylation.

Adrenocorticotropic Hormone↗

PubMed2001

Development of a genetic system for Geobacter sulfurreducens.

Members of the genus Geobacter are the dominant metal-reducing microorganisms in a variety of anaerobic subsurface environments and have been shown to be involved in the bioremediation of both organic and metal contaminants. To facilitate the study of the physiology of these organisms, a genetic system was developed for Geobacter sulfurreducens. The antibiotic sensitivity of this organism was characterized, and optimal conditions for plating it at high efficiency were established. A protocol for the introduction of foreign DNA into G. sulfurreducens by electroporation was also developed. Two classes of broad-host-range vectors, IncQ and pBBR1, were found to be capable of replication in G. sulfurreducens. In particular, the IncQ plasmid pCD342 was found to be a suitable expression vector for this organism. When the information and novel methods described above were utilized, the nifD gene of G. sulfurreducens was disrupted by the single-step gene replacement method. Insertional mutagenesis of this key gene in the nitrogen fixation pathway impaired the ability of G. sulfurreducens to grow in medium lacking a source of fixed nitrogen. Expression of the nifD gene in trans complemented this phenotype. This paper constitutes the first report of genetic manipulation of a member of the Geobacter genus.

Anti-Bacterial Agents↗

PubMedDate not supplied

Frequency analysis of electromyographically measured covert speech behavior.

Eleven subjects were asked to silently read slides of the letters "P" and "T," and to view meaningless control slides similarly as they were presented visually. One-eighth-second electromyographic excerpts were sampled from the baseline and response periods. The data were then transformed into the frequency domain for inferential analyses. The mean power spectral frequencies for the response period were significantly lower than those for the base-line in the overall analysis. There were, however, no significant changes from baseline as a function of kind of stimulus (T, P, or Control) or muscle activated (lips or tongue). It was concluded that there was a generalized responding, not unique to the processing of the specific stimuli studied. Frequency analysis of EMG measures of covert behavior holds some promise of yielding unique information not available through traditional analysis procedures, but more sensitive methods than those used here would be required to demonstrate this.

Afferent Pathways↗

PubMed2002

Contextual influences on visual processing.

The visual image formed on the retina represents an amalgam of visual scene properties, including the reflectances of surfaces, their relative positions, and the type of illumination. The challenge facing the visual system is to extract the "meaning" of the image by decomposing it into its environmental causes. For each local region of the image, that extraction of meaning is only possible if information from other regions is taken into account. Of particular importance is a set of image cues revealing surface occlusion and/or lighting conditions. These information-rich cues direct the perceptual interpretation of other more ambiguous image regions. This context-dependent transformation from image to perception has profound-but frequently under-appreciated-implications for neurophysiological studies of visual processing: To demonstrate that neuronal responses are correlated with perception of visual scene properties, rather than visual image features, neuronal sensitivity must be assessed in varied contexts that differentially influence perceptual interpretation. We review a number of recent studies that have used this context-based approach to explore the neuronal bases of visual scene perception.

Animals↗

PubMedDate not supplied

Adenovirus: from foe to friend.

Human adenoviruses (HAdVs) can cause mild respiratory, gastrointestinal, urogenital and ocular disease. Knowledge about HAdVs has been expanding for more than five decades putting them amongst the most-studied viruses. This continued interest stems, to a great extent, from the fact that these double-stranded DNA viruses have proven to be a versatile tool to probe the basic phenomena of eukaryotic cells. HAdV research has led to the discovery of, for instance, RNA splicing and greatly contributed to our knowledge of processes as fundamental as replication, transcription and translation. Moreover, the transformation of rodent cells by HAdVs has provided a system to unravel the molecular pathways that control cell proliferation. As a result, the genetic organisation of these agents is known in great detail allowing the straightforward manipulation of their genomes. In addition, the virus itself became renowned for its ability to produce large amounts of progeny and to efficiently infect mammalian cells regardless of their cell cycle status. These features contributed to the broad use of recombinant HAdVs as gene carriers particularly in in vivo settings where the vast majority of target cells are post-mitotic. The most advanced type of HAdV vectors can accommodate up to 37 kb of foreign DNA and are devoid of viral genes. With the aid of these high-capacity HAdV vectors large physiologically responsive transcriptional elements and/or genes can be efficiently introduced into target cells while minimising adaptive immune responses against the transduced cells. This article provides information on HAdV especially on the aspects pertinent to the design, production and performance of its recombinant forms. The development and characteristics of the main HAdV-based vector types are also briefly reviewed.

Adenoviridae↗

PubMed2005

Recent insight on the control of enzymes involved in estrogen formation and transformation in human breast cancer.

The great majority of breast cancers are in their early stage hormone-dependent and it is well accepted that estradiol (E2) plays an important role in the genesis and evolution of this tumor. Human breast cancer tissues contain all the enzymes: estrone sulfatase, 17beta-hydroxysteroid dehydrogenase, aromatase involved in the last steps of E2 bioformation. Sulfotransferases which convert estrogens into the biologically inactive estrogen sulfates are also present in this tissue. Quantitative data show that the 'sulfatase pathway', which transforms estrogen sulfates into the bioactive unconjugated E2, is 100-500 times higher than the 'aromatase pathway', which converts androgens into estrogens. The treatment of breast cancer patients with anti-aromatases is largely developed with very positive results. However, the formation of E2 via the 'sulfatase pathway' is very important in the breast cancer tissue. In recent years it was found that antiestrogens (e.g. tamoxifen, 4-hydroxytamoxifen), various progestins (e.g. promegestone, nomegestrol acetate, medrogestone, dydrogesterone, norelgestromin), tibolone and its metabolites, as well as other steroidal (e.g. sulfamates) and non-steroidal compounds, are potent sulfatase inhibitors. In another series of studies, it was found that E2 itself has a strong anti-sulfatase action. This paradoxical effect of E2 adds a new biological response of this hormone and could be related to estrogen replacement therapy in which it was observed to have either no effect or to decrease breast cancer mortality in postmenopausal women. Interesting information is that high expression of steroid sulfatase mRNA predicts a poor prognosis in patients with +ER. These progestins, as well as tibolone, can also block the conversion of estrone to estradiol by the inhibition of the 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD-1). High expressison of 17beta-HSD-1 can be an indicator of adverse prognosis in ER-positive patients. It was shown that nomegestrol acetate, medrogestone, promegestone or tibolone, could stimulate the sulfotransferase activity for the local production of estrogen sulfates. This is an important point in the physiopathology of this disease, as it is well known that estrogen sulfates are biologically inactive. A possible correlation between this stimulatory effect on sulfotransferase activity and breast cancer cell proliferation is presented. In agreement with all this information, we have proposed the concept of selective estrogen enzyme modulators (SEEM). In conclusion, the blockage in the formation of estradiol via sulfatase, or the stimulatory effect on sulfotransferase activity in combination with anti-aromatases can open interesting and new possibilities in clinical applications in breast cancer.

17-Hydroxysteroid Dehydrogenases↗