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At least 1,531 records · Page 85Linked to original sources
PubMed2003

Endocytosis of adenovirus and adenovirus capsid proteins.

Key proteins of the icosahedral-shaped adenovirus (Ad) capsid mediate infection, and interact with cellular proteins to coordinate stepwise events of cell entry that produce successful gene transfer. Infection is mediated predominantly by the penton and fiber capsid proteins. The fiber initiates cell binding while the penton binds integrin coreceptors, triggering integrin-mediated endocytosis. Penton integrin signaling precedes viral escape from the endosomal vesicle. After cell binding, the virus undergoes stepwise disassembly of the capsid, shedding proteins during cell entry. Intracellular trafficking of the remaining capsid shell is mediated by the interaction of naked particles with the cytoskeleton. The capsid translocates toward the nucleus, with the majority of capsid proteins accumulating at the nuclear periphery, while viral DNA and associated protein VII are extruded through the nuclear pore. This discussion will encompass the current knowledge on Ad cell entry and trafficking, with an emphasis on the contribution of Ad capsid proteins to these processes. A greater understanding of the highly effective Ad cell entry pathway may lend itself to the development of safer drug and gene delivery alternatives utilizing similar pathways.

Adenoviridae↗
PubMed2004

Multistep and multifactorial carcinogenesis: when does a contributing factor become a carcinogen?

Our greatest successes in fighting cancer derive from the identification and removal or inactivation of carcinogenic substances, and from the identification and removal of pre-malignant lesions. In comparison, our successes at treating already formed malignancies have been minimal. Therefore, emphasis should be put in identifying and removing pre-malignant lesions, and in the identification and removal of those agents that cause or contribute to cancer development. It is important to target initiators, co-carcinogens and promoters, since by removing any one of them, tumor growth may be prevented. Identification of these agents is difficult. Epidemiological studies largely study cancer after it has occurred. It would be preferable to identify potential carcinogenic substances at an earlier stage before they have caused a large number of malignancies and thus become identifiable by epidemiology. During the past three decades, we have accumulated an impressive amount of evidence concerning molecular pathways that when altered contribute to malignant growth. It is time that we start applying this knowledge to the identification of human carcinogens. Here, we review the molecular changes that are required for carcinogenesis and propose some criteria that, in the absence of epidemiological evidence, can be used to identify agents that cause or contribute to human cancer development. In the absence of epidemiological evidence, a given agent should be considered a human carcinogen when: (1) the agent causes or contributes to the development of tumors in animals that are of the same type as those tumors associated with exposure to the agent in humans; (2) the agent transforms or contributes to the transformation of human cells in culture and these cells are of the same type from which associated human malignancies arise; (3) there is molecular evidence that the agent interferes with one or more key molecular pathways in human cells which leads to the formation of human cancer.

Animals↗
PubMed2003

Capillary electrophoresis-based profiling and quantitation of total salicylic acid and related phenolics for analysis of early signaling in Arabidopsis disease resistance.

A capillary electrophoresis-based method for quantitation of total salicylic acid levels in Arabidopsis leaves was developed. Direct comparison to previous high-performance liquid chromatography (HPLC)-based measurements showed similar levels of salicylic acid. Simultaneous quantitation of trans-cinnamic acid, benzoic acid, sinapic acid, and an internal recovery standard was achieved. A rapid, streamlined protocol with requirements for plant tissue reduced relative to those of HPLC-based protocols is presented. Complicated, multiparameter experiments were thus possible despite the labor-intensive nature of inoculating plants with bacterial pathogens. As an example of this sort of experiment, detailed time course studies of total salicylic acid accumulation by wild-type Arabidopsis and two lines with mutations affecting salicylic acid accumulation in response to either of two avirulent bacterial strains were performed. Accumulation in the first 12h was biphasic. The first phase was partially SID2 and NDR1 dependent with both bacterial strains. The second phase was largely independent of both genes with bacteria carrying avrB, but dependent upon both genes with bacteria carrying avrRpt2. Virulent bacteria did not elicit salicylic acid accumulation at these time points. Application of this method to various Arabidopsis pathosystems and the wealth of available disease resistance signaling mutants will refine knowledge of disease resistance and associated signal transduction.

Arabidopsis↗
PubMed1998

Cancer cells exhibit a mutator phenotype.

This review analyzes the concept and evidence in support of a mutator phenotype in human cancer. The large number of mutations reported in tumor cells cannot be accounted for by the low mutation rates observed in normal somatic cells; rather, it must be a manifestation of a mutator phenotype present early during the tumorigenic process. The interaction between increased mutagenesis and clonal selection provides a mechanism for the selection of cells with increased proliferative advantage. The concept of a mutator phenotype in cancer has gained considerable support from the findings of enormous numbers of somatic mutations in repetitive sequences in human tumors. Moreover, cell lines exhibiting microsatellite instability demonstrate an increased mutation frequency in expressed genes. A knowledge of mechanisms that generate multiple mutations in cancer cells has important implications for prevention. For many tumors, a delay in the rate of accumulation of mutations by a factor of two could drastically reduce the death rates from these tumors.

Animals↗
PubMed2002

Allelic imbalance of 14q32 in esophageal carcinoma.

It has been demonstrated that the accumulation of alterations in several oncogenes and tumor suppressor genes plays a role in the initiation and progression of esophageal carcinoma. However, to our knowledge, very few studies have described the molecular genetic changes of chromosome arm 14q in esophageal carcinoma. In this study, we examined 35 primary esophageal carcinomas for allelic imbalance on 14q32. Analysis of four polymorphic microsatellite markers identified 13 (37%) tumors exhibiting allelic imbalance on 14q32 in at least one locus. In particular, the allelic imbalance of the D14S267 marker that has been reported in various tumors as having a high frequency of deletion was observed in 10 of 26 informative cases (38.5%). The commonly deleted regions were delineated by markers D14S65 and D14S250 on 14q32. In regard to the macroscopic features of tumor, the 14q allelic imbalance rate of protruding type tumors was higher than that of the ulcerative type. These data suggest that potential suppressor loci on 14q32 are related to the development and progression of esophageal carcinoma.

Allelic Imbalance↗
PubMed1998

Uncontrolled pearls, controlled evidence, meta-analysis and the individual patient.

Medicine has been dominated by uncontrolled data, often of unproven validity and insufficient to answer clinically important questions pertaining to individual patients. Controlled clinical trials, when designed and conducted rigorously, offer advantages over uncontrolled data, but they cannot be done for everything and often cater to the interests of sponsors rather than medical knowledge. With such sparse evidence, clinical research is doomed to look at main effects across populations rather than diversity of effects among individuals. By accumulating data from a large number of studies, meta-analysis provides a unique opportunity to address individual- and study-level heterogeneity. Diversity may be due to biases or may be real. Both sources must be scrutinized and meta-analysis may find a prime role in dissecting these components of diversity. Concurrent progress in basic sciences revolutionizing our predictive power for disease outcomes will heighten the importance of considering individual heterogeneity.

Bias↗
PubMed2001

Parameters related to lipid metabolism as markers of myelination in mouse brain.

Myelination, during both normal development and with respect to disorders of myelination, is commonly studied by morphological and/or biochemical techniques that assay as their end-points the extent of myelination. The rate of myelination is potentially a more useful parameter, but it is difficult and time-consuming to establish, requiring a complete developmental study with labor-intensive methodology. We report herein development of methodology to assay the absolute rate of myelination at any desired time during development. This involves intraperitoneal injection of (3)H(2)O to label body water pools, followed by determination of label in the myelin-specific lipid, cerebroside. The absolute amount of cerebroside synthesized can then be calculated from the specific radioactivity of body water and knowledge of the number of hydrogens from water incorporated into cerebroside. During development, the rate of cerebroside synthesis correlated well with the rate of accumulation of the myelin-specific components, myelin basic protein and cerebroside. For purposes of control, we also tested other putative, albeit less quantitative, indices of the rate of myelination. Levels of mRNA for ceramide galactosyltransferase (rate-limiting enzyme in cerebroside synthesis) and for myelin basic protein did not closely correlate with myelination at all times. Cholesterol synthesis closely matched the rate of cholesterol accumulation but did not track well with myelination. Synthesis of fatty acids did not correlate well with accumulation of either fatty acids (phospholipids) or myelin markers. We conclude that measurement of cerebroside synthesis rates provides a good measure of the rate of myelination. This approach may be useful as an additional parameter for examining the effects of environmental or genetic alterations on the rate of myelination.

Aging↗
PubMed2004

Extracting knowledge from the World Wide Web.

The World Wide Web provides a unprecedented opportunity to automatically analyze a large sample of interests and activity in the world. We discuss methods for extracting knowledge from the web by randomly sampling and analyzing hosts and pages, and by analyzing the link structure of the web and how links accumulate over time. A variety of interesting and valuable information can be extracted, such as the distribution of web pages over domains, the distribution of interest in different areas, communities related to different topics, the nature of competition in different categories of sites, and the degree of communication between different communities or countries.

Artificial Intelligence↗
PubMed1993

Endoplasmic reticulum-through-Golgi transport assay based on O-glycosylation of native glycophorin in permeabilized erythroleukemia cells: role for Gi3.

An assay for endoplasmic reticulum (ER)-through-Golgi transport has been developed in streptolysin O-permeabilized murine erythroleukemia (MEL) cells. The reporter proteins are metabolically labeled native murine glycophorins, which display a distinctive shift in electrophoretic mobility after acquisition of O-linked oligosaccharides. The O-linked sugars are acquired at a site distal to a brefeldin A block, presumably in a cis Golgi compartment, and sialylation occurs in middle and/or trans Golgi compartments. In permeabilized cells supplemented with cytosolic proteins and an ATP-generating system, 20-50% of the radiolabeled precursor glycophorins can be converted to the mature, sialylated form. This maturation process is ATP- and cytosol-dependent and is blocked by guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]). Electron microscopy of permeabilized MEL cells shows retention of ER elements, stacked Golgi cisternae, free polysomes, and other subcellular components. In the presence of GTP[gamma S], dilated vesicles accumulate around the Golgi stacks. Antisera to the carboxyl terminus of the Golgi resident alpha subunit of Gi3 inhibit maturation of glycophorin. To our knowledge, a transport assay utilizing O-glycosylation of an endogenous protein as a monitor of ER-through-Golgi traffic in permeabilized cells has not been reported previously. Furthermore, the data provide evidence for heterotrimeric GTP-binding protein involvement in Golgi function.

Adenosine Triphosphate↗
PubMed2004

Neurodegeneration caused by proteins with an aberrant carboxyl-terminus.

In recent years, 2 groups of hereditary neurodegenerative diseases have been recognized in which different genetic defects lead to the accumulation of proteins that contain a carboxyl-terminus that is abnormal in length and primary sequence. In this paper, we review the current knowledge on the molecular basis of diseases from these 2 groups. The first group includes familial British and Danish dementias, in which the molecular genetic defect resides in the BRI2 gene located on chromosome 13. In this group, carboxyl-terminal proteolytic products of the mutant BRI2 proteins aggregate in the extracellular space of the brain and in blood vessels. The second group includes 2 recently described ferritinopathies, in which the molecular genetic defect resides in the ferritin light polypeptide gene located on chromosome 19. In this group, full-length ferritin polypeptides aggregate intracellularly. The study of these conditions has led to the discovery of the BRI2 gene and to the finding of an unsuspected role for ferritin in neurodegeneration. These diseases provide new models in which to study the relationship between abnormal protein aggregation, neuronal cell death, and dementia.

Amino Acid Sequence↗
PubMed2005

Somatic mutations in human cancer: insights from resequencing the protein kinase gene family.

All cancers arise due to the accumulation of mutations in critical target genes that, when altered, give rise to selective advantage in the cell and its progeny that harbor them. Knowledge of these mutations is key in understanding the biology of cancer initiation and progression, as well as the development of more targeted therapeutic strategies. We have undertaken a systematic screen of all annotated protein kinases in the human genome for mutations in a series of cancers including breast, non-small-cell lung, and testicular cancer. Our results show a wide diversity in mutation prevalence within and between tumor types. We have identified a mutator phenotype in human breast previously undescribed. The results presented from sequencing the same 1.3 million base pairs through several tumor types suggest that most of the observed mutations are likely to be passenger events rather than causally implicated in oncogenesis. However, this work does provide evidence for the likely existence of multiple, infrequently mutated kinases.

Breast Neoplasms↗
PubMed2003

Arabidopsis hot mutants define multiple functions required for acclimation to high temperatures.

Plants acquire thermotolerance to lethal high temperatures if first exposed to moderately high temperature or if temperature is increased gradually to an otherwise lethal temperature. We have taken a genetic approach to dissecting acquired thermotolerance by characterizing loss-of-function thermotolerance mutants in Arabidopsis. In previous work, we identified single recessive alleles of four loci required for thermotolerance of hypocotyl elongation, hot1-1, hot2-1, hot3-1, and hot4-1. Completed screening of M2 progeny from approximately 2500 M1 plants has now identified new alleles of three of these original loci, along with three new loci. The low mutant frequency suggests that a relatively small number of genes make a major contribution to this phenotype or that other thermotolerance genes encode essential or redundant functions. Further analysis of the original four loci was performed to define the nature of their thermotolerance defects. Although the HOT1 locus was shown previously to encode a major heat shock protein (Hsp), Hsp101, chromosomal map positions indicate that HOT2, 3, and 4 do not correspond to major Hsp or heat shock transcription factor genes. Measurement of thermotolerance at different growth stages reveals that the mutants have growth stage-specific heat sensitivity. Analysis of Hsp accumulation shows that hot2 and hot4 produce normal levels of Hsps, whereas hot3 shows reduced accumulation. Thermotolerance of luciferase activity and of ion leakage also varies in the mutants. These data provide the first direct genetic evidence, to our knowledge, that distinct functions, independent of Hsp synthesis, are required for thermotolerance, including protection of membrane integrity and recovery of protein activity/synthesis.

Acclimatization↗
PubMed1993

Pathophysiological mechanisms for restenosis following coronary angioplasty: possible preventive alternatives.

Restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) remains an unsolved medical problem. The search for the underlying pathophysiological mechanisms have identified intimal proliferation of smooth muscle cells (SMC) to be the prevailing cause of late restenosis, with endothelial cells (EC) and platelets being important participators in the process. According to the most accepted present theory, SMC would be stimulated to migrate and proliferate shortly after the angioplasty by the release of growth factors from injured EC and accumulated platelets. However, clinical trials of agents interfering with these mechanisms have not significantly diminished the rate of restenosis, which suggest both that our knowledge of the process is incomplete, and that new ways of administering the agents may be required.

Angioplasty, Balloon, Coronary↗
PubMed2004

How molecular microscopy revealed new insights into the dynamics of hepatic endothelial fenestrae in the past decade.

This review discusses the current state of knowledge about the ultrastructure of hepatic endothelial fenestrae. The application of different high-resolution correlative microscopic methods during the past decade facilitated the accumulation of new insights in the morpho-functional and structural organization of the liver sieve. The data gathered unambiguously show the involvement of special domains in de novo formation and disappearance of fenestrae, and focuses future research into the (supra)molecular structure of the fenestrae-forming center, defenestration center and fenestrae-associated cytoskeleton ring by using cryo-electron microscopic tomography.

Animals↗
PubMed2005

Biological transmission of arboviruses: reexamination of and new insights into components, mechanisms, and unique traits as well as their evolutionary trends.

Among animal viruses, arboviruses are unique in that they depend on arthropod vectors for transmission. Field research and laboratory investigations related to the three components of this unique mode of transmission, virus, vector, and vertebrate host, have produced an enormous amount of valuable information that may be found in numerous publications. However, despite many reviews on specific viruses, diseases, or interests, a systematic approach to organizing the available information on all facets of biological transmission and then to interpret it in the context of the evolutionary process has not been attempted before. Such an attempt in this review clearly demonstrates tremendous progress made worldwide to characterize the viruses, to comprehend disease transmission and pathogenesis, and to understand the biology of vectors and their role in transmission. The rapid progress in molecular biologic techniques also helped resolve many virologic puzzles and yielded highly valuable data hitherto unavailable, such as characterization of virus receptors, the genetic basis of vertebrate resistance to viral infection, and phylogenetic evidence of the history of host range shifts in arboviruses. However, glaring gaps in knowledge of many critical subjects, such as the mechanism of viral persistence and the existence of vertebrate reservoirs, are still evident. Furthermore, with the accumulated data, new questions were raised, such as evolutionary directions of virus virulence and of host range. Although many fundamental questions on the evolution of this unique mode of transmission remained unresolved in the absence of a fossil record, available observations for arboviruses and the information derived from studies in other fields of the biological sciences suggested convergent evolution as a plausible process. Overall, discussion of the diverse range of theories proposed and observations made by many investigators was found to be highly valuable for sorting out the possible mechanism(s) of the emergence of arboviral diseases.

Animals↗
PubMed1995

Local control of veins: biomechanical, metabolic, and humoral aspects.

The incidence of vein diseases (varicosity, thrombophlebitis, phlebosclerosis, orthostatic intolerance) is extremely high. In several countries it may exceed that of the arterial pathology by an order of magnitude. In the last decades, this recognition and the rapid accumulation of experimental data have resulted in a progressive reevaluation of the physiological significance of the venous system, which had been rather neglected earlier by scientists. The major aim of this review is to provide a critical survey of recent selected literature related to different physiological functions of the venous system as well as to biomechanical, metabolic, and humoral (ionic, hormonal) aspects of the local venous control. Local neural control mechanisms, including effects of catecholamines and other transmitters, are regarded to be beyond the scope of this work. At present, the synthesis of information available in the literature meets certain difficulties, because occasionally poorly defined methodological techniques and physiological parameters have been applied. On the other hand, a significant part of works dealing with venous physiology is excellent and inspirational. We have good reason to believe that the fast accumulation of reliable scientific data on this very important field will soon reach a new critical level, then an even more effective integration of knowledge will be possible.

Animals↗
PubMed1995

Animals models for the development of human sexuality: a critical evaluation.

Biological explanations of human homosexuality build upon a theoretical framework developed from the study of animals, especially that of rodents. Researchers have constructed a physiological model to explain the origin and development of "masculine" and "feminine" behavior. According to this model hormones acting at critical stages in early development organize cells in key areas of the brain. After puberty these hormonally organized brain regions are purportedly capable of activation by post-pubertally produced circulating hormones. This model of sexual development, called the organizational-activational (O/A) model, has framed research on sexual behavior in animals and animal-based account of human behavior for more than 30 years. However, evidence from a variety of sources has slowly accumulated, requiring modification after modification of the original premise. Continuing to use the organizational-activational model now interferes with the acquisition of new knowledge. I sketch the outlines of an alternative bio-social program for research on the development of sexual behavior in animals.

Adolescent↗
PubMed2006

Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer.

BACKGROUND: Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs. METHODS AND FINDINGS: Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. CONCLUSIONS: This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.

Adenocarcinoma↗