ABSTRACT
The neutron flux distribution within the pool of the SLOWPOKE-2 reactor at the RMC has been characterized using neutron activation measurements as well as MCNP simulations. Westcott equivalent thermal neutron flux values were calculated from measured activities of solutions of Co, Au, and Cd-shielded Au at several reactor flux settings and compared to tabulated fluxes from MCNP simulations. Good agreement was found between the simulated and experimental thermal flux values, while larger uncertainties were highlighted in higher energy neutron fluxes.
ABSTRACT
Recently, a significant epigenetic component in the pathology of suicide has been realized. Here we investigate candidate functional SNPs in epigenetic-regulatory genes, DNMT1 and DNMT3B, for association with suicide attempt (SA) among patients with co-existing psychiatric illness. In addition, global DNA methylation levels [5-methyl cytosine (5-mC%)] between SA and psychiatric controls were quantified using the Methylflash Methylated DNA Quantification Kit. DNA was obtained from blood of 79 suicide attempters and 80 non-attempters, assessed for DSM-IV Axis I disorders. Functional SNPs were selected for each gene (DNMT1; n = 7, DNMT3B; n = 10), and genotyped. A SNP (rs2424932) residing in the 3' UTR of the DNMT3B gene was associated with SA compared with a non-attempter control group (P = 0.001; Chi-squared test, Bonferroni adjusted P value = 0.02). Moreover, haplotype analysis identified a DNMT3B haplotype which differed between cases and controls, however this association did not hold after Bonferroni correction (P = 0.01, Bonferroni adjusted P value = 0.56). Global methylation analysis showed that psychiatric patients with a history of SA had significantly higher levels of global DNA methylation compared with controls (P = 0.018, Student's t-test). In conclusion, this is the first report investigating polymorphisms in DNMT genes and global DNA methylation quantification in SA risk. Preliminary findings suggest that allelic variability in DNMT3B may be relevant to the underlying diathesis for suicidal acts and our findings support the hypothesis that aberrant DNA methylation profiles may contribute to the biology of suicidal acts. Thus, analysis of global DNA hypermethylation in blood may represent a biomarker for increased SA risk in psychiatric patients.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methylation , Genetic Variation , Mental Disorders/genetics , Suicide, Attempted , Adult , Case-Control Studies , Female , Genome, Human , Haplotypes , Humans , Male , Polymorphism, Single Nucleotide , DNA Methyltransferase 3BABSTRACT
A reporter molecule consisting of a synthetic oligonucleotide is being characterised for a novel damage detection scenario for its potential use as a field-deployable, personal deoxyribonucleic acid (DNA) dosemeter for radiation detection. This dosemeter is devoid of any biological properties other than being naked DNA and therefore has no DNA repair capabilities. It supports biodosimetry techniques, which require lengthy analysis of cells from irradiated individuals, and improves upon inorganic dosimetry, thereby providing for a more relevant means of measuring the accumulated dose from a potentially mixed-radiation field. Radiation-induced single strand breaks (SSBs) within the DNA result in a quantifiable fluorescent signal. Proof of concept has been achieved over 250 mGy-10 Gy dose range in radiation fields from 6°Co, with similar results seen using a linear accelerator X-ray source. Further refinements to both the molecule and the exposure/detection platform are expected to lead to enhanced levels of detection for mixed-field radiological events.
Subject(s)
Biological Assay/instrumentation , Biosensing Techniques/instrumentation , DNA/radiation effects , Occupational Exposure/analysis , Radiation Monitoring/instrumentation , Spectrometry, Fluorescence/instrumentation , DNA/chemistry , Equipment Design , Equipment Failure Analysis , Radiation Dosage , Reproducibility of Results , Sensitivity and Specificity , Staining and LabelingSubject(s)
Wastewater , Organization and Administration , 32465 , Rural Population , Urban Population , Water Quality , Health , Agribusiness , Climate ChangeSubject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Gene Expression Regulation/physiology , Transcription, Genetic/physiology , Animals , Calcium-Calmodulin-Dependent Protein Kinase Kinase , Calcium-Calmodulin-Dependent Protein Kinases/physiology , Cells, Cultured , Humans , Protein Serine-Threonine Kinases/metabolismABSTRACT
SCH 56592 (posaconazole), a new triazole antifungal agent, was tested in vitro, and its activity was compared to that of itraconazole against 39 Aspergillus strains and to that of fluconazole against 275 Candida and 9 Cryptococcus strains. The SCH 56592 MICs for Aspergillus ranged from =0.002 to 0.5 microg/ml, and those of itraconazole ranged from =0.008 to 1 microg/ml. The SCH 56592 MICs for Candida and Cryptococcus strains ranged from =0. 004 to 16 microg/ml, and those of fluconazole ranged from =0.062 to >64 microg/ml. SCH 56592 showed excellent activity against Aspergillus fumigatus and Aspergillus flavus in a pulmonary mouse infection model. When administered therapeutically, the 50% protective doses (PD(50)s) of SCH 56592 ranged from 3.6 to 29.9 mg/kg of body weight, while the PD(50)s of SCH 56592 administered prophylactically ranged from 0.9 to 9.0 mg/kg; itraconazole administered prophylactically was ineffective (PD(50)s, >75 mg/kg). SCH 56592 was also very efficacious against fluconazole-susceptible, -susceptible dose-dependent, or -resistant Candida albicans strains in immunocompetent or immunocompromised mouse models of systemic infection. The PD(50)s of SCH 56592 administered therapeutically ranged from 0.04 to 15.6 mg/kg, while the PD(50)s of SCH 56592 administered prophylactically ranged from 1.5 to 19.4 mg/kg. SCH 56592 has excellent potential for therapy against serious Aspergillus or Candida infections.
Subject(s)
Antifungal Agents/pharmacology , Aspergillus/drug effects , Candida/drug effects , Triazoles/pharmacology , Animals , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillosis/mortality , Aspergillosis/prevention & control , Candidiasis/drug therapy , Candidiasis/microbiology , Candidiasis/mortality , Candidiasis/prevention & control , Disease Models, Animal , Lung Diseases, Fungal/drug therapy , Lung Diseases, Fungal/microbiology , Lung Diseases, Fungal/mortality , Lung Diseases, Fungal/prevention & control , Male , Mice , Microbial Sensitivity Tests , Treatment Outcome , Triazoles/therapeutic useSubject(s)
Chest Pain/etiology , Emergency Treatment/methods , Hematoma, Epidural, Cranial/etiology , Laminectomy/adverse effects , Neck Pain/etiology , Chest Pain/diagnosis , Decompression, Surgical , Emergency Nursing/methods , Emergency Treatment/nursing , Hematoma, Epidural, Cranial/diagnosis , Hematoma, Epidural, Cranial/surgery , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neck Pain/diagnosis , Neck Pain/surgery , Nursing Assessment/methods , Spinal Cord Compression/etiologyABSTRACT
Rational protein design is an emerging approach for testing general theories of structure and function. The ability to manipulate function rationally also offers the possibility of creating new proteins of biotechnological value. Here we use the design approach to test the current understanding of the structural principles of allosteric interactions in proteins and demonstrate how a simple allosteric system can form the basis for the construction of a generic biosensor molecular engineering system. We have identified regions in Escherichia coli maltose-binding protein that are predicted to be allosterically linked to its maltose-binding site. Environmentally sensitive fluorophores were covalently attached to unique thiols introduced by cysteine mutations at specific sites within these regions. The fluorescence of such conjugates changes cooperatively with respect to maltose binding, as predicted. Spatial separation of the binding site and reporter groups allows the intrinsic properties of each to be manipulated independently. Provided allosteric linkage is maintained, ligand binding can therefore be altered without affecting transduction of the binding event by fluorescence. To demonstrate applicability to biosensor technology, we have introduced a series of point mutations in the maltose-binding site that lower the affinity of the protein for its ligand. These mutant proteins have been combined in a composite biosensor capable of measuring substrate concentration within 5% accuracy over a concentration range spanning five orders of magnitude.