Writhe in the Stretch-Twist-Fold Dynamo

This is an Author's Original Manuscript of an article whose final and definitive form, the Version of Record, has been published in Geophysical and Astrophysical Fluid Dynamics (2008) Copyright © 2008 Taylor & Francis, available online at: http://www.tandfonline.com/10.1080/03091920802531791This article looks at the influence of writhe in the stretch-twist-fold dynamo. We consider a thin flux tube distorted by simple stretch, twist, and fold motions and calculate the helicity and energy spectra. The writhe number assists in the calculations, as it tells us how much the internal twist changes as the tube is distorted. In addition it provides a valuable diagnostic for the degree of distortion. Non mirror-symmetric dynamos typically generate magnetic helicity of one sign on large-scales and the opposite sign on small scales. The calculations presented here confirm the hypothesis that the large-scale helicity corresponds to writhe and the small scale corresponds to twist. In addition, the writhe helicity spectrum exhibits an interesting oscillatory behavior. The technique of calculating Fourier spectra for the writhe helicity may be useful in other areas of research, for example, the study of highly coiled molecules

Phenotypic and molecular assessment of seven patients with 6p25 deletion syndrome: Relevance to ocular dysgenesis and hearing impairment

BACKGROUND: Thirty-nine patients have been described with deletions involving chromosome 6p25. However, relatively few of these deletions have had molecular characterization. Common phenotypes of 6p25 deletion syndrome patients include hydrocephalus, hearing loss, and ocular, craniofacial, skeletal, cardiac, and renal malformations. Molecular characterization of deletions can identify genes that are responsible for these phenotypes. METHODS: We report the clinical phenotype of seven patients with terminal deletions of chromosome 6p25 and compare them to previously reported patients. Molecular characterization of the deletions was performed using polymorphic marker analysis to determine the extents of the deletions in these seven 6p25 deletion syndrome patients. RESULTS: Our results, and previous data, show that ocular dysgenesis and hearing impairment are the two most highly penetrant phenotypes of the 6p25 deletion syndrome. While deletion of the forkhead box C1 gene (FOXC1) probably underlies the ocular dysgenesis, no gene in this region is known to be involved in hearing impairment. CONCLUSIONS: Ocular dysgenesis and hearing impairment are the two most common phenotypes of 6p25 deletion syndrome. We conclude that a locus for dominant hearing loss is present at 6p25 and that this locus is restricted to a region distal to D6S1617. Molecular characterization of more 6p25 deletion patients will aid in refinement of this locus and the identification of a gene involved in dominant hearing loss

Clinical implications of the Royal College of Physicians three questions in routine asthma care: A real-life validation study

BACKGROUND: Annual recording of the Royal College of Physicians three questions (RCP3Q) morbidity score is rewarded within the UK 'pay-for-performance' Quality and Outcomes Framework. AIMS: To investigate the performance of the RCP3Qs for assessing control in real-life practice compared with the validated Asthma Control Questionnaire (ACQ) administered by self-completed questionnaire. METHODS: We compared the RCP3Q score extracted from a patient's computerised medical record with the ACQ self-completed after the consultation. The anonymous data were paired by practice, age, sex, and dates of completion. We calculated the sensitivity and specificity of the RCP3Q scale compared with the threshold for good/poor asthma control (ACQ greater than 1). RESULTS: Of 291 ACQ questionnaires returned from 12 participating practices, 129 could be paired with complete RCP3Q data. Twenty-five of 27 patients who scored zero on the RCP3Q were well controlled (ACQ less than 1). An RCP3Q score greater than 1 predicted inadequate control (ACQ greater than 1) with a sensitivity of 0.96 and specificity of 0.34. Comparable values for RCP3Q greater than 2 were sensitivity 0.50 and specificity 0.94. The intraclass correlation coefficient of 0.13 indicated substantial variability between practices. Exacerbations and use of reliever inhalers were moderately correlated with ACQ (Spearman's rho 0.3 and 0.35) and may reflect different aspects of control. CONCLUSIONS: In routine practice, an RCP3Q score of zero indicates good asthma control and a score of 2 or 3 indicates poor control. An RCP3Q score of 1 has good sensitivity but poor specificity for suboptimal control and should provoke further enquiry and consideration of other aspects of control such as exacerbations and use of reliever inhalers

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state

Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden.

Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology

Photometric redshifts for supernovae Ia in the Supernova Legacy Survey

We present a method using the SALT2 light curve fitter to determine the redshift of Type Ia supernovae in the Supernova Legacy Survey (SNLS) based on their photometry in g', r', i' and z'. On 289 supernovae of the first three years of SNLS data, we obtain a precision $\sigma_{\Delta z/(1+z)} = 0.022$ on average up to a redshift of 1.0, with a higher precision of 0.016 for z<0.45 and a lower one of 0.025 for z>0.45. The rate of events with $|\Delta z|/(1+z)>0.15$ (catastrophic errors) is 1.4%. Both the precision and the rate of catastrophic errors are better than what can be currently obtained using host galaxy photometric redshifts. Photometric redshifts of this precision may be useful for future experiments which aim to discover up to millions of supernovae Ia but without spectroscopy for most of them.Comment: 7 pages, 9 figures, published in Astronomy and Astrophysic

Characterization of an Nmr Homolog That Modulates GATA Factor-Mediated Nitrogen Metabolite Repression in Cryptococcus neoformans

Nitrogen source utilization plays a critical role in fungal development, secondary metabolite production and pathogenesis. In both the Ascomycota and Basidiomycota, GATA transcription factors globally activate the expression of catabolic enzyme-encoding genes required to degrade complex nitrogenous compounds. However, in the presence of preferred nitrogen sources such as ammonium, GATA factor activity is inhibited in some species through interaction with co-repressor Nmr proteins. This regulatory phenomenon, nitrogen metabolite repression, enables preferential utilization of readily assimilated nitrogen sources. In the basidiomycete pathogen Cryptococcus neoformans, the GATA factor Gat1/Are1 has been co-opted into regulating multiple key virulence traits in addition to nitrogen catabolism. Here, we further characterize Gat1/Are1 function and investigate the regulatory role of the predicted Nmr homolog Tar1. While GAT1/ARE1 expression is induced during nitrogen limitation, TAR1 transcription is unaffected by nitrogen availability. Deletion of TAR1 leads to inappropriate derepression of non-preferred nitrogen catabolic pathways in the simultaneous presence of favoured sources. In addition to exhibiting its evolutionary conserved role of inhibiting GATA factor activity under repressing conditions, Tar1 also positively regulates GAT1/ARE1 transcription under non-repressing conditions. The molecular mechanism by which Tar1 modulates nitrogen metabolite repression, however, remains open to speculation. Interaction between Tar1 and Gat1/Are1 was undetectable in a yeast two-hybrid assay, consistent with Tar1 and Gat1/Are1 each lacking the conserved C-terminus regions present in ascomycete Nmr proteins and GATA factors that are known to interact with each other. Importantly, both Tar1 and Gat1/Are1 are suppressors of C. neoformans virulence, reiterating and highlighting the paradigm of nitrogen regulation of pathogenesis

The prevalence of vertebral fracture amongst patients presenting with non-vertebral fractures

INTRODUCTION: Despite vertebral fracture being a significant risk factor for further fracture, vertebral fractures are often unrecognised. A study was therefore conducted to determine the proportion of patients presenting with a non-vertebral fracture who also have an unrecognised vertebral fracture. METHODS: Prospective study of patients presenting with a non-vertebral fracture in South Glasgow who underwent DXA evaluation with vertebral morphometry (MXA) from DV5/6 to LV4/5. Vertebral deformities (consistent with fracture) were identified by direct visualisation using the Genant semi-quantitative grading scale. RESULTS: Data were available for 337 patients presenting with low trauma non-vertebral fracture; 261 were female. Of all patients, 10.4% were aged 50–64 years, 53.2% were aged 65–74 years and 36.2% were aged 75 years or over. According to WHO definitions, 35.0% of patients had normal lumbar spine BMD (T-score −1 or above), 37.4% were osteopenic (T-score −1.1 to −2.4) and 27.6% osteoporotic (T-score −2.5 or lower). Humerus (n=103, 31%), radius–ulna (n=90, 27%) and hand/foot (n=53, 16%) were the most common fractures. For 72% of patients (n=241) the presenting fracture was the first low trauma fracture to come to clinical attention. The overall prevalence of vertebral deformity established by MXA was 25% (n=83); 45% (n=37) of patients with vertebral deformity had deformities of more than one vertebra. Of the patients with vertebral deformity and readable scans for grading, 72.5% (58/80) had deformities of grade 2 or 3. Patients presenting with hip fracture, or spine T-score ≤−2.5, or low BMI, or with more than one prior non-vertebral fracture were all significantly more likely to have evidence of a prevalent vertebral deformity (p<0.05). However, 19.8% of patients with an osteopenic T-score had a vertebral deformity (48% of which were multiple), and 16.1% of patients with a normal T-score had a vertebral deformity (26.3% of which were multiple). Following non-vertebral fracture, some guidelines suggest that anti-resorptive therapy should be reserved for patients with DXA-proven osteoporosis. However, patients who have one or more prior vertebral fractures (prevalent at the time of their non-vertebral fracture) would also become candidates for anti-resorptive therapy—which would have not been the case had their vertebral fracture status not been known. Overall in this study, 8.9% of patients are likely to have had a change in management by virtue of their underlying vertebral deformity status. In other words, 11 patients who present with a non-vertebral fracture would need to undergo vertebral morphometry in order to identify one patient who ought to be managed differently. CONCLUSIONS: Our results support the recommendation to perform vertebral morphometry in patients who are referred for DXA after experiencing a non-vertebral fracture. Treatment decisions will then better reflect any given patient’s future absolute fracture risk. The 'Number Needed to Screen' if vertebral morphometry is used in this way would be seven to identify one patient with vertebral deformity, and 14 to identify one patient with two or more vertebral deformities. Although carrying out MXA will increase radiation exposure for the patient, this increased exposure is significantly less than would be obtained if X-rays of the dorso-lumbar spine were obtained

Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine