Photoaffinity labeling of P-glycoprotein in multidrug-resistant cells.
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
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Ethical challenges in community-based research.
Investigators in population-based studies confront unique ethical challenges due to the community context of their research, their methods of inquiry, and the implications of their findings for social groups. Issues surrounding requirements for informed consent, the protection of privacy and confidentiality, and relationships between investigators and participants take on greater complexity and have significance beyond the individual research subject. In this paper, ethical challenges associated with community-based epidemiological research are briefly examined. We argue that ethically responsible population-based studies must seriously consider community needs and priorities and that researchers should work collaboratively with local populations to implement study goals. Strategies that promote respect for populations in community-based studies are outlined. These include community participation in research development, implementation and interpretation; adequate provision of information about study objectives to community members; and systematic feedback of study results.
Bioethical Issues↗
Developing community capacity and improving health in African American communities.
Community-based programs have produced mixed results. Community capacity is thought to be a major determinant of program effectiveness. Thus, enhancing community capacity may increase the beneficial effects of existing programs and enhance future program effectiveness. This highlights the need to focus on understanding the components of capacity and the methods of enhancing capacity. Although we are just beginning to examine and understand key concepts, community capacity is probably influenced by both relatively nonmodifiable characteristics (such as demographic factors, institutional resources, and social structures) and relatively modifiable characteristics (such as knowledge, skills, and the ability and willingness of members and agencies to work collaboratively). In their relationships with community members and agencies, academicians and public health practitioners may help acquire categorical funding to enhance opportunities to build community capacity and their own capacity as well. The relationship between academicians/practitioners and community members/agencies probably is influenced by a host of characteristics which determine the degree to which capacity can be built. This paper discusses: the key components of capacity; the factors that influence building capacity through collaborations; a community health advisor (CHA) model which both builds on sociocultural aspects of African American culture and is consistent with methods for building community capacity; and how modifications to this model allow it to be compatible with categorically funded projects.
Black or African American↗
Bogalusa Heart Study: a long-term community study of a rural biracial (Black/White) population.
The Bogalusa Heart Study, a long-term population study with a continued relationship with a community, addresses the problem of capacity building in minority health research. The study was originally funded as a Specialized Center of Research-Arteriosclerosis (SCOR-A) by the National Heart Lung and Blood Institute (NHLBI). These centers were to conduct research on atherosclerosis, coronary artery disease (CAD), hypertension, diabetes mellitus, and complications of cardiovascular-renal disease as the major causes of deaths in the United States. From earlier research on atherosclerosis, we became interested in the underlying characteristics in early life that would eventually lead to clinical morbidity and mortality from heart disease. An observation at autopsy showed the degree of atherosclerotic involvement in human aortas, from young to older individuals (Figure 1). For example, at age 40 years, marked individual variability occurred in the severity and involvement with atherosclerotic disease. Some individuals showed very little disease, while almost 70% of the surface was diseased in others. Further studies on arterial wall matrix showed aortas from young individuals varied with the extent of disease and its chemical composition. This background stimulated an interest in studying children for early clinical evidence of major adult heart diseases. The Bogalusa Heart Study was begun in 1972 as an epidemiology study of cardiovascular risk factors in children and adolescents; it eventually evolved into observations of young adults. Bogalusa, LA, is a biracial (black/white) rural community 70 miles north of New Orleans, comparable to many other communities in southeastern United States.
Adolescent↗
Using live FRET imaging to reveal early protein-protein interactions during T cell activation.
The emerging challenge for proteomics in general and lymphocyte biology in particular is to understand protein-protein interactions in the dynamic context of the living cell. Particularly interesting are the molecular dynamics of the T cell receptor-CD3 complex and other immunoreceptors in immune synapses. Fluorescence (or Förster) resonance energy transfer (FRET) is one of the few techniques that are capable of giving dynamic information about the nanometer-range proximity between molecules, as opposed to simply the subcellular co-localization that is provided by fluorescence microscopy. Spectral changes in fluorescence intensity and down modulation of donor lifetime are the basis for rapidly developing approaches to real-time FRET imaging. With two-photon excitation, FRET can now be extended to in vivo imaging.
Animals↗
Fine-needle aspiration cytology of tongue swellings: a study of 75 cases.
Tongue swellings and growths are traditionally evaluated by surgical biopsy. Most of them, however, are easily accessible by fine-needle aspiration (FNA). We reviewed 75 lesions presenting as tongue swellings, which were examined by fine-needle aspiration cytology (FNAC) in our institutions over a period of 11 yr. The lesions included 17 malignant tumors: 12 cases of squamous carcinoma (SQC), 2 metastases, and 3 non-Hodgkin's lymphomas (NHL). In addition, 15 benign tumors and 43 nonneoplastic benign conditions were found. Thirteen of the 17 malignant lesions were diagnosed cytologically as malignant, 3 as suspicious for malignancy, and 1 as atypical, with biopsy recommended. There were no false-positive diagnoses. There were no clinical complications resulting from FNA. We conclude that FNAC of the tongue permits rapid and reliable diagnosis, and we recommend this method as the first diagnostic step in the evaluation of tongue swellings.
Adolescent↗
Sequence analysis or rat integrin alphaE1 and alphaE2 subunits: tissue expression reveals phenotypic similarities between intraepithelial lymphocytes and dendritic cells in lymph.
The integrin alphaOX-62 subunit is defined by the OX-62 monoclonal antibody that was raised against rat dendritic cells in lymph (veiled cells) and shows properties similar to those of human alphaE that is predominantly expressed on intraepithelial lymphocytes. To clone alphaOX-62, rat probes generated using primers specific for the human alphaE sequence were used to screen rat T cell cDNA libraries. cDNA clones encoding two similar but not identical alpha subunits that are closely related but distinct from human alphaE were isolated. alphaE1 is predicted to be the rat homolog of mouse alphaM290 and alphaE2 corresponds to rat alphaOX-62. Immunofluorescence analysis revealed that mouse alphaE1 and rat alphaE2 are expressed in dendritic epidermal T cells in the skin, intraepithelial lymphocytes in the small intestine and in cells with a dendritic morphology present at sites where gammadelta T cells occur in lymphoid organs. Unexpectedly, in veiled cells alphaE2 is co-expressed with intracellular CD3-delta and a 33-kDa CD3 chain but not the T cell receptor. These findings suggest that veiled cells may be derived from a lymphoid precursor. Furthermore, veiled cells show phenotypic similarities to intraepithelial lymphocytes.
Amino Acid Sequence↗
Erratum: Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome.
Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular matrix, is due to mutations in fibrillin-1 (FBN1) gene. Investigations carried out in the last decade, unveiled the unpredictability of the site of the mutation, which could be anywhere in the gene. FBN1 mutations have been reported in a spectrum of diseases related to MFS, with no clear evidence for a phenotype-genotype correlation. In this paper we analysed 10 British patients affected by MFS and we were able to characterise five novel missense mutations (C474W, C1402Y, G1987R, C2153Y, G2536R), one novel frameshift mutation (7926delC), one already described mutation (P1424A) and one FBN1 variant (P1148A) classified as a polymorphism in the Asian population. Four out of the five novel missense mutations involved either cysteines or an amino acid conserved in the domain structure. The mutation yield in this study is calculated at 80.0% (8/10), thus indicating that SSCA is a reliable and cost-effective technique for the screening of such a large gene. Our results suggest that this method is reliable to search for FBN1 mutations and that FBN1 screening could be a helpful tool to confirm and possibly anticipate the clinical diagnosis in familial cases.
Adult↗
Erratum: Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment.
Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22-q31 and encodes a chloride-iodide transport protein. Mutations in this gene are also a cause of non-syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five novel mutations (X781W, T132I, IVS2-2A>G, Y556H and 406del5).
Alleles↗
Cattaneo models for chemosensitive movement: numerical solution and pattern formation.
We derive models for chemosensitive movement based on Cattaneo's law of heat propagation with finite speed. We apply the model to pattern formation as observed in experiments with Dictyostelium discoideum, with Salmonella typhimurium and with Escherichia coli. For Salmonella typhimurium we make predictions on pattern formation which can be tested in experiments. We discuss the relations of the Cattaneo models to classical models and we develop an effective numerical scheme.
Animals↗
A fluorometric assay of peroxidase activity utilizing 2',7'-dichlorofluorescein with thiocyanate: application to the study of salivary secretion.
A sensitive assay for secretory peroxidase activity has been developed utilizing the fluorogenic substrate 2',7'-dichlorofluorescin in the presence of thiocyanate. The assay has been characterized using bovine lactoperoxidase and used to determine the peroxidase activities of salivas and extracts obtained from rat submandibular glands. Comparison of the 2',7'-dichlorofluorescin-thiocyanate assay and the commonly used 2,2'-azinobis(3-ethylbenzthiazoline-6-sulphonic acid) colorimetric assay indicates that the new assay is approx. 50-fold more sensitive. This has enabled measurement of peroxidase activities present in parasympathetic saliva samples which were beyond the detection limit of the colorimetric assay. Despite great differences in the peroxidase activities and protein concentrations of parasympathetic and sympathetic salivas and tissue extracts, the activities per unit protein were very similar. Unlike most other published methods, prior dialysis of samples to remove interference by endogenous thiocyanate is not required. The assay is therefore convenient and will be particularly useful for applications in which sample volume or peroxidase activity is low.
Animals↗
Improving generalisation skills in a neural network on the basis of neurophysiological data.
The distribution of striate cortex cells exhibits a maximum number of cells tuned to vertical and horizontal orientations (Mansfield, 1974). This was interpreted as an adaptation of the visual system to the presence in the visual environment of greater amounts of vertical and horizontal information compared to information from other orientations (Keil & Cristobal, 2000). The present research confirms that vertical and horizontal orientations are, indeed, present in greater number in natural scenes. After normalization of the amount of information across all orientations, vertical information appeared to be better for bottom-up categorization. We demonstrate this using a connectionist autoassociator model of categorization used elsewhere in simulations of early infant categorization.
Neural Networks, Computer↗
Erratum to "Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans" [Mech. Ageing Dev. 127 (5) (2006) 458-472].
The longevity of the Caenorhabditis elegans diapausal dauer larva greatly exceeds that of the adult. Dauer formation and adult ageing are both regulated by insulin/IGF-1 signalling (IIS). Reduced IIS, e.g. by mutation of the daf-2 insulin/IGF-1 receptor gene, increases adult lifespan. This may reflect mis-expression in the adult of dauer longevity-assurance processes. Since IIS plays a central role in the regulation of metabolism, metabolic alterations shared by dauer larvae and daf-2 adults represent candidate mechanisms for lifespan determination. We have conducted a detailed comparison of transcript profile data from dauers and daf-2 mutant adults, focusing on expression of metabolic pathway genes. Our results imply up-regulation in both dauers and daf-2 mutant adults of gluconeogenesis, glyoxylate pathway activity, and trehalose biosynthesis. Down-regulation of the citric acid cycle and mitochondrial respiratory chain occurs in dauers, but not daf-2 adults. However, the F1 ATPase inhibitor was up-regulated in both, implying enhanced homeostasis in conditions where mitochondria are stressed. Overall, the data implies increased conversion of fat to carbohydrate, and conservation of ATP stocks in daf-2 mutant adults, suggesting a state of increased energy availability. We postulate that this fuels increased somatic maintenance activity, as suggested by the disposable soma theory.
Animals↗
Peptidergic sensory and parasympathetic fiber sprouting in the mucosa of the rat urinary bladder in a chronic model of cyclophosphamide-induced cystitis.
In this study, we used a well-established animal model to investigate changes in the peptidergic and parasympathetic innervation of the bladder following chronic bladder inflammation. Adult female Sprague-Dawley rats were injected with either 70 mg/kg cyclophosphamide diluted in saline, i.p., once every 3 days or saline. After 10 days, all animals were tested for urinary frequency and number of low volume voids, as well as symptoms of spontaneous pain. At the end of 12 days, all animals were perfused with histological fixatives and the urinary bladders processed for immunofluorescence using antibodies against calcitonin gene-related peptide and the vesicular acetylcholine transporter as markers, respectively, of peptidergic primary afferent fibers and parasympathetic efferent fibers. We show that animals treated with cyclophosphamide had inflamed bladders and displayed high urinary frequency as well as some indicators of spontaneous pain, such as piloerection and a rounded-back posture. Furthermore, they had a significant increase in the density of both parasympathetic and peptidergic sensory fibers in the bladder mucosa and an increase in peptidergic sensory fibers in the detrusor muscle. Based on these results, we suggest that peripheral sprouting of parasympathetic and peptidergic fibers could be a mechanism responsible for sensitization of the bladder, leading to urinary symptoms. Since we observed that the parasympathetic and peptidergic fibers often wrapped around one another and that their varicosities were very close, these two fiber populations may be interacting with each other to lead to and maintain sensitization. Future studies are required to establish the role of this fiber sprouting in bladder symptoms.
Afferent Pathways↗
Dietary nucleotides and human immune cells. II. Modulation of PBMC growth and cytokine secretion.
OBJECTIVE: The immune system is dependent on purines and pyrimidines as building blocks for DNA and RNA synthesis to enable rapid cell proliferation and protein synthesis. Emerging evidence suggests that dietary nucleotides optimize immune function. We investigated whether growth and function of human immune cells were affected by an exogenous source of nucleotides during specific antigen challenge. METHODS: Peripheral blood mononuclear cells from healthy individuals (n = 10) were stimulated with influenza virus antigen and either DNA sodium from fish soft roe (DNA), RNA from bakers yeast (Saccharomyces cerevisiae) (RNA), 2' deoxyadenosine 5'-monophosphate sodium (dAMP), 2' deoxycytidine 5'-monophosphate sodium (dCMP), 2' deoxyguanosine 5'-monophosphate sodium (dGMP), 2' deoxyuridine 5'-monophosphate sodium (dUMP) or thymidine sodium (TMP). Growth effects were ascertained by measuring the amount of tritium-labeled thymidine, incorporated into cell DNA. Cell function was measured by detection of IFN-gamma, TNF-alpha and IL-10 production. RESULTS: Specific nucleotide derivatives alone did not affect the growth of healthy peripheral blood mononuclear cells. However, the nucleotide derivatives influenced immune cell growth and cytokine secretion when cocultured with specific antigen. DNA, RNA, dAMP, dCMP and dUMP increased influenza virus antigen induced immune cell proliferation. In contrast dGMP and TMP inhibited the antigen-induced growth response. RNA and dAMP cocultured with virus antigen significantly increased peripheral blood mononuclear cell secretion of IFN-gamma, IL-10 and TNF-alpha. DNA increased virus antigen-induced immune cell secretion of IFN-gamma only, whereas dUMP significantly increased secretion of IL-10 only. dGMP completely inhibited virus-triggered IFN-gamma secretion, whereas TMP did not change the virus induced secretion pattern of measured cytokines. CONCLUSION: Nucleotide derivatives affect growth and function of specific virus antigen-stimulated human immune cells in vitro.
Antigens, Viral↗
Evidence for the monophyletic evolution of benzylisoquinoline alkaloid biosynthesis in angiosperms.
Benzylisoquinoline alkaloids (BIAs) consist of more than 2500 diverse structures largely restricted to the order Ranunculales and the eumagnoliids. However, BIAs also occur in the Rutaceae, Lauraceae, Cornaceae and Nelumbonaceae, and sporadically throughout the order Piperales. Several of these alkaloids function in the defense of plants against herbivores and pathogens--thus the capacity for BIA biosynthesis is expected to play an important role in the reproductive fitness of certain plants. Biochemical and molecular phylogenetic approaches were used to investigate the evolution of BIA biosynthesis in basal angiosperms. The occurrence of (S)-norcoclaurine synthase (NCS; EC 4.2.1.78) activity in 90 diverse plant species was compared to the distribution of BIAs superimposed onto a molecular phylogeny. These results support the monophyletic origin of BIA biosynthesis prior to the emergence of the eudicots. Phylogenetic analysis of NCS, berberine bridge enzyme and several O-methyltransferases suggest a latent molecular fingerprint for BIA biosynthesis in angiosperms not known to accumulate such alkaloids. The limited occurrence of BIAs outside the Ranunculales and eumagnoliids suggests the requirement for a highly specialized, yet evolutionarily unstable cellular platform to accommodate or reactivate the pathway in divergent taxa. The molecular cloning and functional characterization of NCS from opium poppy (Papaver somniferum L.) is also reported. Pathogenesis--related (PR)10 and Bet v 1 major allergen proteins share homology with NCS, but recombinant polypeptides were devoid of NCS activity.
Alkaloids↗
Mother rats bar-press for pups: effects of lesions of the mpoa and limbic sites on maternal behavior and operant responding for pup-reinforcement.
This series of studies explored the operant response rates for pup-reinforcement of female Sprague Dawley rats that were either postpartum or cycling and sustained lesions of the medial preoptic area (mpoa), the lateral amygdala, the nucleus accumbens, or sham lesions. The last experiment tested the effects on operant responding of preventing direct access to pups in mpoa and sham-lesioned postpartum mothers. All animals were trained prior to mating on an FR-1 bar-press schedule to criterion (50 presses in 30 min) for a food (Froot Loops) reward in an operant chamber. At the end of pregnancy animals that were to be tested postpartum were provided in their home cages with six newborn foster pups; mother-litter interactions were observed on the last 3 days of pregnancy and throughout the postpartum period. On each of these same days after a period of separation from pups, females were tested in the operant box for delivery of rat pups. With each bar-press response, a rat pup rather than a Fruit Loop was delivered down a gentle shoot into the hopper. Non-postpartum, but maternal, multiparous animals who were showing estrous cycles were tested using the same procedures. The first and second studies showed that animals (both postpartum and as cycling multiparous animals) with mpoa lesions exhibited a significant reduction in bar-press rate for pup reinforcement in the operant box. In postpartum animals, amygdala lesions also produced a bar-press deficit, whereas nucleus accumbens lesions did not. All lesioned groups showed deficits in maternal responding in the home cage and deficits in retrieval in the operant box. These results indicate that systems associated with the mpoa mediate both the stereotypical maternal behaviors and pup-reinforcement. In contrast, the expression of home cage maternal behavior is dependent on the integrity of both the amygdala and nucleus accumbens, whereas operant responding need not be. These results indicate a dissociation of mechanisms mediating expression of the species-typical maternal behavior and pup-reinforcement.
Amygdala↗
An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei.
Ascofuranone, a prenylphenol antibiotic isolated from a phytopathogenic fungus, Ascochyta visiae, strongly inhibited both glucose-dependent cellular respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption of long slender bloodstream forms of Trypanosoma brucei brucei. This inhibition was suggested to be due to inhibition of the mitochondrial electron-transport system, composed of glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) and plant-like alternative oxidase. Ascofuranone noncompetitively inhibited the reduced coenzyme Q1-dependent O2 uptake of the mitochondria with respect to ubiquinol (Ki = 2.38 nM). Therefore, the susceptible site is deduced to be the ubiquinone redox machinery which links the two enzyme activities. Further, ascofuranone in combination with glycerol completely blocked energy production, and potently inhibited the in vitro growth of the parasite. Our findings suggest that ascofuranone might be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.
Animals↗