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Olfactory information is dramatically restructured as it makes its way through the brain. Recent work using a remarkable experimental preparation has revealed how this transformation is achieved.
BACKGROUND: Electronic availability of health care claims data maintained by health insurance companies today is higher than the availability of clinical patient record data. OBJECTIVE: To explore feasibility of automatically generated patient care summaries based on claims data and its benefit for health care professionals (HCP), when no shared electronic health record is available. METHODS: Based on an existing claims data model for German health insurance companies, a transformation and presentation algorithm was developed. To determine the utility of the resulting summaries, a focus group session comprising HCP and insurance representatives was arranged. Properties of an information system architecture capable of providing summaries to HCP were specified. RESULTS: A set of valuable healthcare information, in particular clinical pathways, medication, and anamnesis, can be derived from claims data that fits into the ASTM specification of a Continuity of Care Record. The focus group assessed the potential benefit of the summaries as high. Major issues are partial incompleteness and a lack of timeliness due to delayed reimbursement procedures as well as privacy-preserving and practicable access methods. The specified system architecture uses web services and a web interface to provide the summaries in HL7 CDA format. An important insight was that only a timely electronic reimbursement process will lead to precise, current, and reliable claims-based summaries. CONCLUSION: Generating patient care summaries based on claims data is feasible and produces valuable information for HCP, provided that the reimbursement process is conducted timely. Integration into a national health telematics platform will facilitate access to the summaries. Evaluation of algorithm and prototype system is underway to prove the benefit in clinical practice.
Monensin A and B were studied by electrospray ionisation tandem mass spectrometry (ESI-MS/MS) and the fragment ions were confirmed by accurate-mass measurements. Analyses were performed on both a quadrupole time-of-flight (QTOF) and a Fourier-transform ion cyclotron resonance (FTICR) mass spectrometer. The analysis revealed that fragment ions were produced by Grob-Wharton fragmentations and pericyclic rearrangements in addition to various simple neutral losses. A study of the protonated and sodiated sodium salt revealed different fragmentation pathways for these species, thus complementary structural information could be gained. A complete fragmentation pathway of monensin A and B protonated sodium salt [(M-H+Na)+H])+) and sodiated sodium salt [(M-H+Na)+Na](+) is proposed. MS(3) analysis confirmed the separate fragmentation pathways.
Transcriptomics provides the tool for deciphering gene expression networks, and proteomics links these networks to protein products. The third crucial partner is metabolomics, which defines the metabolic network(s) linked to gene expression. NMR and mass spectrometry enable the broad screen analysis of the metabolome and its transformation pathways, transcending classical targeted metabolic studies. These tools were combined to investigate the anticancer mechanisms of different selenium forms in human lung cancer cells. Using 2-D NMR and tandem-MS, we mapped perturbations of 13C labeling patterns in numerous metabolites induced by selenite and selenomethionine. This information was used to interpret selenite-induced changes in gene expression networks. Linking metabolic dysfunctions to altered gene expression profiles provided new insights into the regulatory network underlying the metabolic dysfunctions, enabled the assembly of discrete gene expression events into functional pathways, and revealed protein targets for proteomic analysis.
In bacterial D-amino acid transaminase, Lys-145, which binds the coenzyme pyridoxal 5'-phosphate in Schiff base linkage, was changed to Gln-145 by site-directed mutagenesis (K145Q). The mutant enzyme had 0.015% the activity of the wild-type enzyme and was capable of forming a Schiff base with D-alanine; this external aldimine was formed over a period of minutes depending upon the D-alanine concentration. The transformation of the pyridoxal-5'-phosphate form of the enzyme to the pyridoxamine-5'-phosphate form (i.e. the half-reaction of transamination) occurred over a period of hours with this mutant enzyme. Thus, information on these two steps in the reaction and on the factors that influence them can readily be obtained with this mutant enzyme. In contrast, these reactions with the wild-type enzyme occur at much faster rates and are not easily studied separately. The mutant enzyme shows distinct preference for D- over L-alanine as substrates but it does so about 50-fold less effectively than the wild-type enzyme. Thus, Lys-145 probably acts in concert with the coenzyme and other functional side chain(s) to lead to efficient and stereochemically precise transamination in the wild-type enzyme. The addition of exogenous amines, ethanolamine or methyl amine, increased the rate of external aldimine formation with D-alanine and the mutant enzyme but the subsequent transformation to the pyridoxamine-5'-phosphate form of the enzyme was unaffected by exogenous amines. The wild-type enzyme displayed a large negative trough in the circular dichroic spectrum at 420 nm, which was practically absent in the mutant enzyme. However, addition of D-alanine to the mutant enzyme generated this negative Cotton effect (due to formation of the external aldimine with D-alanine). This circular dichroism band gradually collapsed in parallel with the transformation to the pyridoxamine-5'-phosphate enzyme. Further studies on this mutant enzyme, which displays the characteristics of the wild-type enzyme but at attenuated rates, may yield information on the factors controlling the stereochemistry of the reaction as well as on the catalytic steps of the transaminase pathway.
Peripheral endocrine hormones and local paracrine and autocrine factors contribute, in a coordinated fashion, to the processes of recruitment, development or atresia, selection and ovulation of follicles. Among the local ovarian factors, there is growing evidence from genetic and experimental data that many members of the transforming growth factor (TGFbeta) superfamily have a biological role to play in folliculogenesis. These members include activin, inhibin, TGFbeta, BMP, GDF9 and perhaps MIS. In this review, we discuss the potential roles of the TGFbeta superfamily members, in particular activin, during folliculogenesis. Since the actions of these factors are determined by ligand availability, receptor expression and modulation of their signal transduction pathways, we also collate information on the expression of their signalling components in the follicle. We conclude that the TGFbeta superfamily signalling pathways, in particular activin's pathway, reside in the ovary. Furthermore, follistatin and beta-glycan-components of the accessory binding protein system that modifies activin action-are also present in follicles. In the post-natal rat ovary, the changes in receptor/Smad expression coincide with granulosa cell proliferation and antrum formation. We hypothesise that these pathway components are expressed in a temporal and cell-specific manner to meet the changing demands of cells during follicular development. The analysis of the components of the signal transduction pathways of the TGFbeta family members in populations of defined follicles and the identification of activated pathways in individually stimulated follicles should help clarify the roles of the TGFbeta members in folliculogenesis.
Methods are needed to obtain in situ information on the transformation rates of trichloroethene (TCE), the most commonly detected organic groundwater contaminant. The objective of this research was to investigate the potential for determining TCE transformation rates in groundwater by measuring the transformation rate of its fluorinated surrogate, trichlorofluoroethene (TCFE). To explore this hypothesis, the in situ transport behavior, transformation pathway, and transformation rate of injected TCFE were determined in TCE-contaminated groundwater using single-well, push-pull tests. Although transport behavior varied between wells, TCFE, dichlorofluoroethene (DCFE), and TCE were transported similarly to each other. In the shallow water-bearing zone, TCFE was reductively dechlorinated to cis-DCFE, trans-DCFE, and (E)-1-chloro-2-fluoroethene (CFE), while co-injected TCE was concurrently transformed to cis-dichloroethene (DCE), trans-DCE, 1,1-DCE, and a trace amount of chloroethene (CE). With added formate and the injected TCFE concentration being a factor of 20 higher than that of TCE, the TCFE transformation rate ranged from 0.053 to 0.30 mumol/L-day, while that of TCE ranged from 0.009 to 0.012 mumol/L-day. Without added formate, the TCFE transformation rate decreased to 0.036 mumol/L-day. In the deeper water-bearing zone, TCFE transformation occurred only after a lag time of 55 days with added formate. No TCFE transformation occurred in groundwater that had not previously been exposed to TCE. The potential applicability for TCFE as an in situ transport and transformation surrogate for TCE was demonstrated.
Post-natal growth of the skull vault occurs by the addition of new bone at the margins of individual calvarial bones. Continued growth depends on the maintenance of a proliferating osteogenic precursor cell population in the sutural membrane between the bones. Mutations in fibroblast growth factor receptors (FGFRs) have recently been detected as the cause of a number of human abnormalities characterized by premature sutural closure, i.e., craniosynostosis. These are activating mutations causing early differentiation of osteogenic precursor cells. Transforming growth factor-betas (TGF-Bs) are another family of developmentally important growth factors. In particular, they play important roles in bone differentiation and are known to be expressed in cranial sutures, and to be upregulated at the time of sutural fusion. It is therefore clear that the FGF and TGF-B signalling pathways interact co-operatively in calvarial bone growth and sutural fusion. The purpose of this study is to investigate this interaction. The long term aim of this work is to gain information that can be used to slow down the process of craniosynostosis after detection of this problem at birth.
The ability of mammals to discriminate thousands of structurally diverse odorants appears to derive from the existence of a multigene family that encodes approximately 1000 different odorant receptors. Recent studies have used this family to explore how the olfactory system organizes sensory information. These studies reveal striking patterns of organization suggesting that incoming sensory information is first broadly organized in the nose and is then transformed in the olfactory bulb into a stereotyped and highly organized spatial map.
The transcriptional Mediator (MED) is a multiprotein complex that transmits information from transcription factors to RNA polymerase II (PolII) to regulate transcription. At present, the role of distinct MED subunits in general transcription versus transcription stimulated by specific signaling pathways is unclear. By means of positional cloning, we reveal that the zebrafish mutant tennismatch is a hypomorphic allele of Med10, a conserved MED middle domain subunit. Using morpholino antisense oligonucleotides, we further demonstrate that reduction of Med10 levels led to an enhancement of the Wnt signaling pathway, while also suggesting a role for Med10 in mediating the Nodal signaling pathway. In contrast to the dual roles of Med10, reduction of Med12 and Med13 levels, two MED subunits in the regulatory domain, led to an enhancement of the Wnt signaling pathway but not the Nodal pathway, while reduction of Med15 levels, a MED subunit in the tail domain, suppressed the Nodal signaling pathway but not the Wnt signaling pathway. Thus, Med10 appears to be a unique MED subunit that differentially transduces information from distinct signaling pathways during zebrafish embryogenesis.
TGF-beta binds specifically and with high affinity to all cell types with few exceptions. The binding parameters vary because the dissociation constants range from 1 pM to 60 pM. There may be as few as 200 or as many as 100,000 receptors per cell, depending on the cell type. Several cell surface proteins that specifically bind TGF-beta 1 and TGF-beta 2 have been characterized as putative receptors and have been classified on the basis of their size. Type I receptors have an Mr of approximately 50,000, type II receptors an Mr of approximately 80,000. Both type I and II receptors are glycoproteins and TGF-beta-induced responses appear to be mediated by one or both types. The most abundant and largest of the cell surface TGF-beta binding proteins is a membrane-bound proteoglycan that is a dimer of subunits each with Mr of approximately 250,000 (beta-glycan). This protein is plentiful on primary cells of mesenchymal origin but absent on primary epithelial and endothelial cells. It does not appear to be associated with TGF-beta-mediated cell responses and its function remains unknown. There are multiple cellular responses to TGF-beta and accordingly there appear to be multiple pathways for signal transduction. A guanine nucleotide binding protein-dependent pathway is involved in transmission of the signal for at least one TGF-beta-induced response while there is evidence that other responses are mediated through an independent pathway. TGF-beta receptor purification and cloning efforts will be rewarded with valuable information on the mechanisms of signal transmission.
Cancer, including genitourinary malignancy, is a consequence of accumulated genetic aberrations in genes involved in crucial regulatory pathways. The result is a deregulation of cellular behaviour, leading to neoplastic transformation, uncontrolled cell proliferation and acquisition of metastatic ability. The development and perfection of techniques in the field of recombinant DNA technology, gene cloning, (differential) analysis of gene expression, and sequencing of genes and proteins have provided a wealth of information about the genetic aberrations associated with cancer development. This "recombinant DNA and gene cloning" technology and the recently developed DNA chip technology may provide new molecular diagnostic tools. Furthermore, the technology of gene cloning in combination with the progress in in vivo gene delivery techniques offers new treatment modalities, like gene therapy, additional to conventional therapies. This review is intended to provide a general introduction to the fundamentals or strategies of recombinant DNA and gene cloning techniques as a basis for understanding the rapidly expanding range of new diagnostic and therapeutic opportunities. Some illustrative examples are provided, addressing basic and biomedical research and possible clinical applications in genitourinary oncology.
The transforming growth factor-beta (TGF beta) polypeptides control a variety of cellular processes including organogenesis and cellular proliferation and differentiation. In the developing lung, TGF beta(1) treatment inhibits airway branching and expression of the genes for surfactant proteins (SP). Many effects of TGF beta are mediated at the level of gene transcription but there is limited information regarding signaling pathways and target transcription factors. In this study with human pulmonary adenocarcinoma H441 cells, we investigated TGF beta(1) effects on SP-B, a protein which is essential for normal function of pulmonary surfactant. TGF beta(1) (10 ng/ml) reduced SP-B mRNA content in a time-dependent fashion, and transient transfection studies localized responsiveness to the region of the SP-B promoter (-112/-72 bp) containing binding sites for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor 3 (HNF3), transcription factors that are important enhancers of SP gene expression. Using electrophoretic mobility shift assay and immunofluorescence, we demonstrated rapid accumulation of these transcription factors in the cytoplasm and subsequent loss from the nucleus on TGF beta(1) treatment of both adenocarcinoma cells and cultured human fetal lung. TGF beta(1) treatment caused intracellular translocation of protein kinase C and effects of TGF beta(1) were mostly abrogated in the presence of the protein kinase inhibitor calphostin C. We conclude that TGF beta(1), acting via protein phosphorylation, blocks nuclear translocation of TTF-1 and HNF3 which results in down-regulation of the SP-B gene and presumably other pulmonary genes which are transactivated by these factors.
Neural stem cells (NSC) are capable of differentiating toward neuronal, astrocytic, oligodendrocytic and glial lineages, depending on their spatial location within the central nervous system (CNS). Although, a lot of knowledge has been gained in the understanding of differentiation-specific signaling in hematopoietic (HSC) and mesenchymal (MSC) counterparts, the molecular mechanisms underlying lineage commitment in NSCs are just beginning to be understood. Furthermore, it is not well comprehended as to how the specification of one cell lineage can result in the suppression of parallel pathways in the NSCs. Thus, a thorough understanding of various signal transduction cascades activated via cytokines and growth factors, and the confounding effects of different CNS microenvironments are critically required to determine the full potential of NSCs. Our knowledge on the clonogenic ability, differentiation potential, and the inherent plasticity in both HSCs and MSCs may facilitate the understanding of lineage commitment in the NSCs as well. The information available from the marrow-derived stem cells may be extrapolated toward the similar signaling pathways in the neural precursors. From a number of previous studies, it is apparent that four distinctly different subsets of ligand-receptor superfamilies are involved in determining the fate of NSCs. These include 1) the transforming growth factor type-beta-1 (TGF-beta1) and bone morphogenetic protein (BMP) superfamily; 2) the platelet-derived and epidermal (PDGF/EGF) growth factors; 3) the interleukin-6, leukemia inhibitory factor, and ciliary neurotrophic factor (IL-6/LIF/CNTF) superfamily; and 4) the EGF-like Notch/Delta group of extracellular ligands. Ligand binding to the cell surface receptor activates the receptor's cytosolic catalytic domain and/or the receptor-associated protein-kinases, which in turn activate intracellular second messengers and different sets of transcription factors. Transcription factor oligomerization, nuclear localization, followed by their recognition of DNA elements, leads to the expression of lineage-specific genes. Association between different groups of transcription factors can also regulate their ability to transcriptionally activate different genes. The limited availability of coactivators and cosuppressors, which can sequester the transcription factor complexes toward or away from a specific gene locus, further adds to the complexity in the cross talk between different signaling cascades. Both concerted actions of temporally regulated signals and convergent effects of different signaling cascades can thus ultimately precipitate the phenotypic changes. It is beginning to be realized that in addition to the cytokines and growth factors, cell-to-cell and cell-to-extracellular matrix (ECM) interactions, are also important within the molecular scenario linked to both proliferation and differentiation of the stem cells. The cell surface molecules, which include cell adhesion molecules (CAMs), integrins, selectins, and the immunoglobulins, are well known to regulate HSC and MSC commitment within different tissue microenvironments and may have direct implications in understanding the NSC cell fate determination within different regions of the brain.
The integration of exteroceptive information in the flight control system of the locust was studied by determining the cellular basis of ocellar- (simple eye) mediated control of flight. Neural interactions that transform phase-independent sensory input into phase-specific motor output were characterized. Ocellar information about course deviations during flight was conveyed to the segmental thoracic ganglia by three pairs of large fast multimodal descending neurons. These made connections with thoracic motoneurons directly, via short-latency mono-or disynaptic pathways, and indirectly, via a population of intercalated thoracic interneurons. The synaptic potentials caused in the motoneurons by the direct pathway occurred at short latency and were adequate for summation with other types of sensory input. However, the strength of the synaptic effects of this pathway was weak compared with the central flight oscillator drive to the same motoneurons. In contrast, synaptic potentials evoked by the descending neurons in the thoracic interneurons were often large and brought these cells close to threshold. In turn, these interneurons always had stronger synaptic effects on postsynaptic flight motoneurons than did the descending neurons alone. We conclude that the indirect interneuronal pathway is more powerful in its effects on motoneurons than the direct pathway. Premotor thoracic interneurons, which received ocellar input appropriate for a role in correctional steering, were also rhythmically modulated during flight motor activity in phase with either depressor or elevator motoneurons. This phasic modulatory drive occurred in deafferented preparations, indicating that its source is the central oscillator for flight. Presentation of ocellar stimulation during flight motor activity showed that the central oscillatory modulation of the thoracic interneurons gated the transmission of sensory information through these interneurons. Ocellar-mediated postsynaptic potentials influenced the firing of thoracic interneurons only if they arrived during the proper phase of rhythmic drive. Thus the transmission of ocellar information from interneuron to motor neuron is possible only during appropriate phases of the flight cycle.
BACKGROUND: The p53 gene is one of a family of tumor suppressor genes that have been implicated in the genesis of a wide variety of malignant neoplasms including Bowen's disease. Its role in oncogenesis and tumor progression is thought to be of importance. Transforming growth factor beta (TGF-beta) is the most potent known inhibitor of the progression of normal epithelial cells through the cell cycle. p21(Waf1/Cip1) is thought to mediate p53 signaling induced by DNA-damaging agents to arrest the cell cycle. OBJECTIVE: The present study evaluates the expression of p53, p21(Waf1/Cip1) and TGF-beta(3) protein and speculates on their role in Bowen's disease. METHODS: Sixteen patients seen at our clinic between 1993 and 2000 were examined. We analyzed p21(Waf1/Cip1), p53 and TGF-beta(3) immunohistochemical staining in all specimens. RESULTS: In 7 of the Bowen's disease patients, overexpression of p53-positive cells was present in the middle and basal layers, and intense staining of p21(Waf1/Cip1) was observed in the upper spinous layers. In the other 9 Bowen's disease patients, we found positively stained cells for p21(Waf1/Cip1) but negative p53 immunostaining in the upper epidermal layer. Downregulated TGF-beta(3) expression was detected in all layers except the upper spinous layers. CONCLUSION: These observations suggest different roles for p21(Waf1/Cip1) and p53 within abnormal cells in Bowen's disease. p21(Waf1/Cip1) may induce terminal differentiation to the superficial layer in Bowen's disease via either a p53-independent or -dependent pathway. Moreover, downregualtion of TGF-beta(3) immunostaining provides relevant information concerning the pathogenesis of Bowen's disease.
Vocal communication between zebra finches includes the exchange of long calls (LCs) as well as song. By using this natural call behavior and quantifying the LCs emitted in response to playbacks of LCs of other birds, we have previously shown that adult male zebra finches have a categorical preference for the LCs of females over those of males. Female LCs are acoustically simpler than male LCs, which include complex acoustic features that are learned during development. Production of these male-typical features requires an intact nucleus RA, the sexually dimorphic source of the main telencephalic projection to brainstem vocal effectors. We have now made bilateral lesions of RA in 17 adult males and tested their discrimination behavior in the call response situation. Lesioned birds continue to call, but lose the male-typical preference for female LCs. The degree of loss is correlated with the extent of RA damage. Further, the simplified LCs of males with RA lesions have a variable duration that is correlated with stimulus features. In effect, the call response behavior of lesioned males becomes like that of females. Apparently, in the absence of RA, the remaining intact structures receive different call information than RA normally does, and/or process it differently. This suggests that the vocal motor nucleus RA could play a role in the transformation of a signal encoding the salience of stimulus parameters into a control signal that modulates the probability and strength of responding.
The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.