CPMG Experiments for Protein Minor Conformer Structure Determination

CPMG relaxation dispersion NMR experiments have emerged as a powerful method to characterize protein minor states that are in exchange with a visible dominant conformation, and have lifetimes between ~0.5 and 5 milliseconds (ms) and populations greater than 0.5%. The structure of the minor state can, in favorable cases, be determined from the parameters provided by the CPMG relaxation dispersion experiments. Here, we go through the intricacies of setting up these powerful CPMG experiments

UBC-Nepal Expedition: Acute alterations in sympathetic nervous activity do not influence brachial artery endothelial function at sea-level and high-altitude.

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high-altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g. shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that: 1) at rest, SNA would be elevated and FMD would be reduced at HA compared to sea-level (SL); and 2) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344m) and HA (5050m) in 14 participants during mild lower-body negative pressure (LBNP; -10 mmHg) and lower-body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrodcardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants (n=5). Our findings were: 1) at rest, SNA was elevated (P<0.01), and absolute FMD was reduced (P=0.024), but relative FMD remained unaltered (P=0.061), at HA compared to SL, and 2) despite significantly altering SNA with LBNP (+60.3±25.5%) and LBPP (-37.2±12.7%) (P<0.01), FMD was unaltered at SL (P=0.448), and HA (P=0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA

UBC-Nepal Expedition: Acute alterations in sympathetic nervous activity do not influence brachial artery endothelial function at sea-level and high-altitude.

Evidence indicates that increases in sympathetic nervous activity (SNA), and acclimatization to high-altitude (HA), may reduce endothelial function as assessed by brachial artery flow-mediated dilatation (FMD); however, it is unclear whether such changes in FMD are due to direct vascular constraint, or consequential altered hemodynamics (e.g. shear stress) associated with increased SNA as a consequence of exposure to HA. We hypothesized that: 1) at rest, SNA would be elevated and FMD would be reduced at HA compared to sea-level (SL); and 2) at SL and HA, FMD would be reduced when SNA was acutely increased, and elevated when SNA was acutely decreased. Using a novel, randomized experimental design, brachial artery FMD was assessed at SL (344m) and HA (5050m) in 14 participants during mild lower-body negative pressure (LBNP; -10 mmHg) and lower-body positive pressure (LBPP; +10 mmHg). Blood pressure (finger photoplethysmography), heart rate (electrodcardiogram), oxygen saturation (pulse oximetry), and brachial artery blood flow and shear rate (Duplex ultrasound) were recorded during LBNP, control, and LBPP trials. Muscle SNA was recorded (via microneurography) in a subset of participants (n=5). Our findings were: 1) at rest, SNA was elevated (P<0.01), and absolute FMD was reduced (P=0.024), but relative FMD remained unaltered (P=0.061), at HA compared to SL, and 2) despite significantly altering SNA with LBNP (+60.3±25.5%) and LBPP (-37.2±12.7%) (P<0.01), FMD was unaltered at SL (P=0.448), and HA (P=0.537). These data indicate that acute and mild changes in SNA do not directly influence brachial artery FMD at SL or HA

Closing the sea surface mixed layer temperature budget from in situ observations alone: Operation Advection during BoBBLE

Sea surface temperature (SST) is a fundamental driver of tropical weather systems such as monsoon rainfall and tropical cyclones. However, understanding of the factors that control SST variability is lacking, especially during the monsoons when in situ observations are sparse. Here we use a ground-breaking observational approach to determine the controls on the SST variability in the southern Bay of Bengal. We achieve this through the first full closure of the ocean mixed layer energy budget derived entirely from in situ observations during the Bay of Bengal Boundary Layer Experiment (BoBBLE). Locally measured horizontal advection and entrainment contribute more significantly than expected to SST evolution and thus oceanic variability during the observation period. These processes are poorly resolved by state-of-the-art climate models, which may contribute to poor representation of monsoon rainfall variability. The novel techniques presented here provide a blueprint for future observational experiments to quantify the mixed layer heat budget on longer time scales and to evaluate these processes in models

The Nordic Maintenance Care Program – An interview study on the use of maintenance care in a selected group of Danish chiropractors

<p>Abstract</p> <p>Background</p> <p>Although maintenance care appears to be relatively commonly used among chiropractors, the indications for its use are incompletely understood. A questionnaire survey was recently carried out among Swedish chiropractors in order to identify their choice of various management strategies, including maintenance care. That study revealed a common pattern of choice of strategies. However, it would be necessary to verify these findings in another study population and to obtain some additional information best collected through an interview.</p> <p>Objectives</p> <p>The main aim of the present study was to attempt to reproduce the findings in the Swedish study and to obtain more information on the use of maintenance care.</p> <p>Method</p> <p>A group of 11 chiropractors were selected because they used maintenance care. They were interviewed using the questionnaire from the previous Swedish survey. The questionnaire consisted of a simple description of a hypothetical patient with low back pain and nine possible ways in which the case could develop ("scenarios"). They could choose between six different management strategies for each scenario. In addition, the chiropractors were encouraged to provide their own definition of maintenance care in an open-ended question. Interviews were taped, transcribed and analyzed. For the open-ended question, statements were identified relating to six pre hoc defined topics on the inclusion criteria/rationale for maintenance care, the frequency of treatments, and the duration of the maintenance care program.</p> <p>Results</p> <p>The open-ended question revealed that in patients with low back pain, maintenance care appears to be offered to prevent new events. The rationale was to obtain optimal spinal function. There appears to be no common convention on the frequency of treatments and duration of the treatment program was not mentioned by any of the interviewees.</p> <p>Conclusion</p> <p>The results from the questionnaire in the Danish survey showed that the response pattern for the nine scenarios was similar to that obtained in the Swedish survey. There seems to be relative agreement between chiropractors working in different countries and sampled through different methods in relation to their choice of management strategies in patients with low back pain. However, more precise information is needed on the indications for maintenance care and its treatment program, before proceeding to studying its clinical validity.</p

Mortality among Patients with Cleared Hepatitis C Virus Infection Compared to the General Population: A Danish Nationwide Cohort Study

BACKGROUND: The increased mortality in HCV-infected individuals partly stems from viral damage to the liver and partly from risk-taking behaviours. We examined mortality in patients who cleared their HCV-infection, comparing it to that of the general population. We also addressed the question whether prognosis differed according to age, substance abuse (alcohol abuse and injection drug use) and comorbidity. METHODOLOGY/PRINCIPAL FINDINGS: Patients with cleared HCV-infection were categorized into one of 8 groups according to age (20-39 years or 40-69 years) and patient characteristics (no substance abuse/no comorbidity; substance abuse/no comorbidity; no substance abuse/comorbidity; and substance abuse/comorbidity). For each patient, 4 age- and gender-matched individuals without substance abuse or comorbidity were selected from the general population, comprising a total of 8 comparison cohorts. We analyzed 10-year survival and used stratified Cox Regression analysis to compute mortality rate ratios (MRRs), comparing mortality between the 8 patient groups and the comparison cohorts, adjusting for personal income. Among patients without substance abuse or comorbidity, those aged 40-69 years had the same mortality as the comparison cohort (10-year survival: 95% (95% confidence interval [CI]: 93%-97%), MRR: 1.3 (95% CI: 0.8-2.3)), whereas those aged 20-39 years had higher mortality than the comparison cohort (10-year survival: 93% versus 99%, MRR: 5.7 (95% CI: 2.3-14.0). For both age categories, substance abuse and comorbidity decreased survival and increased MRRs. Patients aged 40-69 years with substance abuse and comorbidity suffered from substantial mortality (MRR: 12.5 (95% CI: 5.1-30.6)). CONCLUSIONS: Mortality in patients aged 40-69 years with cleared HCV-infection is comparable to individuals without HCV, provided they have no substance abuse or comorbidity. Any substance abuse and/or comorbidity not captured in the registries used for our study could explain the increased mortality in patients aged 20-39 years without documented substance abuse or comorbidity

'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Land of Addicts? An Empirical Investigation of Habit-Based Asset Pricing Models

A popular explanation of aggregate stock market behavior suggests that assets are priced as if there were a representative investor whose utility is a power function of the difference between aggregate consumption and a “habit” level, where the habit is some function of lagged and (possibly) contemporaneous consumption. But theory does not provide precise guidelines about the parametric functional relationship between the habit and aggregate consumption. This makes for- mal estimation and testing challenging; at the same time, it raises an empirical question about the functional form of the habit that best explains asset pricing data. This paper studies the ability of a general class of habit-based asset pricing models to match the conditional moment restrictions implied by asset pricing theory. Our approach is to treat the functional form of the habit as unknown, and to estimate it along with the rest of the model’s finite dimensional parameters. This semiparametric approach allows us to empirically evaluate a number of interesting hypotheses about the specification of habit-based asset pricing models. Using stationary quarterly data on consumption growth, assets returns and instruments, our empirical results indicate that the estimated habit function is nonlinear, the habit formation is internal, and the estimated time-preference parameter and the power utility parameter are sensible. In addition, our estimated habit function generates a positive stochastic discount factor (SDF) proxy and performs well in explaining cross-sectional stock return data. We find that an internal habit SDF proxy can explain a cross-section of size and book-market sorted portfolio equity returns better than (i) the Fama and French (1993) three-factor model, (ii) the Lettau and Ludvigson (2001b) scaled consumption CAPM model, (iii) an external habit SDF proxy, (iv) the classic CAPM, and (v) the classic consumption CAPM

Multiple rectal carcinoids with diffuse ganglioneuromatosis

BACKGROUND: Rectal carcinoids comprise only about 1% of all anorectal neoplasms. In addition, ganglioneuroma of the gastrointestinal tract is a rare tumor composed ganglion cells, nerve fibers, and supporting cells. Multiple carcinoid tumors with diffuse ganglioneuromatosis limited to the rectum are quite unusual. CASE PRESENTATION: A 69-year-old man was referred to us because of about 100 small submucosal rectal tumors. He underwent abdominoperineal resection. Pathology revealed carcinoid tumors for about 30 submucosal nodules and diffuse ganglioneuromotosis. To date (6 months later) he remains well with no recurrence. CONCLUSION: Although the optimal treatment for the multiple rectal carcinoids remains to be clearly established, it is believed that not all patients with multiple rectal carcinoids (measuring less than 1 cm in diameter) need to have a radical operation. However, the treatment plan for each case should be individualized and a careful follow-up is mandatory