Nanomolar-potency 'co-potentiator' therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants.

Available CFTR modulators provide no therapeutic benefit for cystic fibrosis (CF) caused by many loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, including N1303K. We previously introduced the concept of 'co-potentiators' (combination-potentiators) to rescue CFTR function in some minimal function CFTR mutants. Herein, a screen of ~120,000 drug-like synthetic small molecules identified active co-potentiators of pyrazoloquinoline, piperidine-pyridoindole, tetrahydroquinoline and phenylazepine classes, with EC50 down to ~300 nM following initial structure-activity studies. Increased CFTR chloride conductance by up to 8-fold was observed when a co-potentiator (termed 'Class II potentiator') was used with a classical potentiator ('Class I potentiator') such as VX-770 or GLPG1837. To investigate the range of CFTR mutations benefitted by co-potentiators, 14 CF-associated CFTR mutations were studied in transfected cell models. Co-potentiator efficacy was found for CFTR missense, deletion and nonsense mutations in nucleotide binding domain-2 (NBD2), including W1282X, N1303K, c.3700A > G and Q1313X (with corrector for some mutations). In contrast, CFTR mutations G85E, R334W, R347P, V520F, R560T, A561E, M1101K and R1162X showed no co-potentiator activity, even with corrector. Co-potentiator efficacy was confirmed in primary human bronchial epithelial cell cultures generated from a N1303K homozygous CF subject. The Class II potentiators identified here may have clinical benefit for CF caused by mutations in the NBD2 domain of CFTR

Geothermal Play Fairway Analysis, Part 1: Example from the Snake River Plain, Idaho

The Snake River Plain (SRP) volcanic province overlies the track of the Yellowstone hotspot, a thermal anomaly that extends deep into the mantle. Most of the area is underlain by a basaltic volcanic province that overlies a mid-crustal intrusive complex, which in turn provides the long-term heat flux needed to sustain geothermal systems. Previous studies have identified several known geothermal resource areas within the SRP. For the geothermal study presented herein, our goals were to: (1) adapt the methodology of Play Fairway Analysis (PFA) for geothermal exploration to create a formal basis for its application to geothermal systems, (2) assemble relevant data for the SRP from publicly available and private sources, and (3) build a geothermal PFA model for the SRP and identify the most promising plays, using GIS-based software tools that are standard in the petroleum industry. The study focused on identifying three critical resource parameters for exploitable hydrothermal systems in the SRP: heat source, reservoir and recharge permeability, and cap or seal. Data included in the compilation for heat source were heat flow, distribution and ages of volcanic vents, groundwater temperatures, thermal springs and wells, helium isotope anomalies, and reservoir temperatures estimated using geothermometry. Reservoir and recharge permeability was inferred from the analysis of stress orientations and magnitudes, post-Miocene faults, and subsurface structural lineaments based on magnetics and gravity data. Data for cap or seal included the distribution of impermeable lake sediments and clay-seal associated with hydrothermal alteration below the regional aquifer. These data were used to compile Common Risk Segment maps for heat, permeability, and seal, which were combined to create a Composite Common Risk Segment map for all southern Idaho that reflects the risk associated with geothermal resource exploration and identifies favorable resource tracks. Our regional assessment indicated that undiscovered geothermal resources may be located in several areas of the SRP. Two of these areas, the western SRP and Camas Prairie, were selected for more detailed assessment, during which heat, permeability, and seal were evaluated using newly collected field data and smaller grid parameters to refine the location of potential resources. These higher resolution assessments illustrate the flexibility of our approach over a range of scales

The Effect of CardioWaves Interval Training on Resting Blood Pressure, Resting Heart Rate, and Mind-Body Wellness

International Journal of Exercise Science 9(1): 89-100, 2016. An experimental study to examine the effects of CardioWaves interval training (CWIT) and continuous training (CT) on resting blood pressure, resting heart rate, and mind-body wellness. Fifty-two normotensive (blood pressure \u3c120/80 mmHg), pre-hypertensive (120–139/80–89 mmHg), and hypertensive (\u3e140/90 mmHg) participants were randomly assigned and equally divided between the CWIT and CT groups. Both groups participated in the assigned exercise protocol 30 minutes per day, four days per week for eight weeks. Resting blood pressure, resting heart rate, and mind-body wellness were measured pre- and post-intervention. A total of 47 participants (15 females and 32 males) were included in the analysis. The CWIT group had a non-significant trend of reduced systolic blood pressure (SBP) and increased diastolic blood pressure (DBP) while the CT group had a statistically significant decrease in awake SBP (p = 0.01) and total SBP (p = 0.01) and a non-significant decrease in DBP. With both groups combined, the female participants had a statistically significant decrease in awake SBP (p = 0.002), asleep SBP (p = 0.01), total SBP (p = 0.003), awake DBP (p = 0.02), and total DBP (p = 0.05). The male participants had an increase in SBP and DBP with total DBP showing a statistically significant increase (p = 0.05). Neither group had a consistent change in resting heart rate. Both groups showed improved mind-body wellness. CWIT and CT reduced resting blood pressure, with CT having a greater effect. Resting heart rate did not change in either group. Additionally, both CWIT and CT improved mind-body wellness

Mountain Home Air Force Base, Idaho Geothermal Resource Assessment and Future Recommendations

The U.S. Air Force is facing a number of challenges as it moves into the future, one of the biggest being how to provide safe and secure energy to support base operations. A team of scientists and engineers met at Mountain Home Air Force Base in early 2011 near Boise, Idaho, to discuss the possibility of exploring for geothermal resources under the base. The team identified that there was a reasonable potential for geothermal resources based on data from an existing well. In addition, a regional gravity map helped identify several possible locations for drilling a new well. The team identified several possible sources of funding for this well—the most logical being to use U.S. Department of Energy funds to drill the upper half of the well and U.S. Air Force funds to drill the bottom half of the well. The well was designed as a slimhole well in accordance with State of Idaho Department of Water Resources rules and regulations. Drilling operations commenced at the Mountain Home site in July of 2011 and were completed in January of 2012. Temperatures increased gradually, especially below a depth of 2000 ft. Temperatures increased more rapidly below a depth of 5500 ft. The bottom of the well is at 5976 ft, where a temperature of about 140°C was recorded. The well flowed artesian from a depth below 5600 ft, until it was plugged off with drilling mud. Core samples were collected from the well and are being analyzed to help understand permeability at depth. Additional tests using a televiewer system will be run to evaluate orientation and directions at fractures, especially in the production zone. A final report on the well exploitation will be forthcoming later this year. The Air Force will use it to evaluate the geothermal resource potential for future private development options at Mountain Home Air Force Base. In conclusion, Recommendation for follow-up efforts include the following

Exploration and Resource Assessment at Mountain Home Air Force Base, Idaho Using an Integrated Team Approach

The U.S. Air Force is facing a number of challenges as it moves into the future, one of the biggest being how to provide safe and secure energy to support base operations. A team of scientists and engineers met at Mountain Home Air Force Base near Boise, Idaho, to discuss the possibility of exploring for geothermal resources under the base. The team identified that there was a reasonable potential for geothermal resources based on data from an existing well. In addition, a regional gravity map helped identify several possible locations for drilling a new well. The team identified several possible sources of funding for this well—the most logical being to use U.S. Department of Energy funds to drill the upper half of the well and U.S. Air Force funds to drill the bottom half of the well. The well was designed as a slimhole well in accordance with State of Idaho Department of Water Resources rules and regulations. Drilling operations commenced at the Mountain Home site in July of 2011 and were completed in January of 2012. Temperatures increased gradually, especially below a depth of 2000 ft. Temperatures increased more rapidly below a depth of 5500 ft. The bottom of the well is at 5976 ft, where a temperature of about 140°C was recorded. The well flowed artesian from a depth below 5600 ft, until it was plugged off with drilling mud. Core samples were collected from the well and are being analyzed to help understand permeability at depth. Additional tests using a televiewer system will be run to evaluate orientation and directions at fractures, especially in the production zone. A final report on the well exploitation will be forthcoming later this year. The Air Force will use it to evaluate the geothermal resource potential for future private development options at Mountain Home AFB

Effect of an 860-m thick, cold, freshwater aquifer on geothermal potential along the axis of the eastern Snake River Plain, Idaho

A 1912-m exploration corehole was drilled along the axis of the eastern Snake River Plain, Idaho. Two temperature logs run on the corehole display an obvious inflection point at about 960 m. Such behavior is indicative of downward fluid flow in the wellbore. The geothermal gradient above 935 m is 4.5 °C/km, while the gradient is 72–75 °C/km from 980 to 1440 m. Projecting the higher gradients upward to where they intersect the lower gradient on the temperature logs places the bottom of the cold, freshwater Snake River Plain aquifer, which suppresses the geothermal gradient at this location, at least 860 m below the surface. The average heat flow for the corehole between 983 and 1550 m is 132 mW/m2. Although the maximum bottom-hole temperature extrapolated from a measured time–temperature curve was only 59.3 °C, geothermometers suggest an equilibrium temperature on the order of 125–140 °C based on a single fluid sample from 1070 m. Furthermore, below 960 m the basalt core shows obvious signs of alteration, including a distinct color change, the formation of smectite clay, and the presence of secondary minerals filling vesicles and fracture zones. This alteration boundary could act as an effective cap or seal for a hot-water geothermal system

Geothermal Play Fairway Analysis, Part 2: GIS Methodology

Play Fairway Analysis (PFA) in geothermal exploration originates from a systematic methodology developed within the petroleum industry and is based on a geologic, geophysical, and hydrologic framework of identified geothermal systems. We tailored this methodology to study the geothermal resource potential of the Snake River Plain and surrounding region, but it can be adapted to other geothermal resource settings. We adapted the PFA approach to geothermal resource exploration by cataloging the critical elements controlling exploitable hydrothermal systems, establishing risk matrices that evaluate these elements in terms of both probability of success and level of knowledge, and building a code-based ‘processing model’ to process results. A geographic information system was used to compile a range of different data types, which we refer to as elements (e.g., faults, vents, heat flow, etc.), with distinct characteristics and measures of confidence. Discontinuous discrete data (points, lines, or polygons) for each element were transformed into continuous interpretive 2D grid surfaces called evidence layers. Because different data types have varying uncertainties, most evidence layers have an accompanying confidence layer which reflects spatial variations in these uncertainties. Risk layers, as defined here, are the product of evidence and confidence layers, and are the building blocks used to construct Common Risk Segment (CRS) maps for heat, permeability, and seal, using a weighted sum for permeability and heat, but a different approach with seal. CRS maps quantify the variable risk associated with each of these critical components. In a final step, the three CRS maps were combined into a Composite Common Risk Segment (CCRS) map, using a modified weighted sum, for results that reveal favorable areas for geothermal exploration. Additional maps are also presented that do not mix contributions from evidence and confidence (to allow an isolated view of evidence and confidence), as well as maps that calculate favorability using the product of components instead of a weighted sum (to highlight where all components are present). Our approach helped to identify areas of high geothermal favorability in the western and central Snake River Plain during the first phase of study and helped identify more precise local drilling targets during the second phase of work. By identifying favorable areas, this methodology can help to reduce uncertainty in geothermal energy exploration and development

Evaluation of the Geothermal Potential of the Western Snake River Plain Based on a Deep Corehole on the Mountain Home AFB Near Mountain Home, Idaho

A geothermal exploration corehole was drilled to a total depth of 1821.5 m on the Mountain Home Air Force Base near Mountain Home, Idaho. The corehole was used to collect an unusually large amount of data, including uniaxial compressive stress (UCS) experiments on core samples, to evaluate the geothermal potential of the western Snake River Plain. In addition, unlike many exploration holes in this region, a fluid entry was encountered at 1745.3 m and flowed artesian to the surface. A maximum temperature of 149.4 °C was calculated for the entry. A temperature log run on the corehole from 3 to 1675 m is nearly linear with little variation. The average geothermal gradient is 73 °C/km, and the average heat flow between 200 and 1500 m is 102 ± 15 mW/m2. Chemical analyses of a sample from the fluid entry suggest that a significant proportion of the water is not meteoric. Five geothermometers show equilibrium temperature in the range of 133–157 °C. Furthermore, based on the unconfined UCS experiments on basalt core samples, a brittle unit was found to comprise the fractured reservoir that the geothermal water flows from, while an overlying ductile unit acts as a hydrothermal caprock. This implies that the reservoir/caprock pair may be a target for future exploration wells drilled to delineate the extent of the potential resource and the boundaries of the connected fracture network

Airway Microbiota and Pathogen Abundance in Age-Stratified Cystic Fibrosis Patients

Bacterial communities in the airways of cystic fibrosis (CF) patients are, as in other ecological niches, influenced by autogenic and allogenic factors. However, our understanding of microbial colonization in younger versus older CF airways and the association with pulmonary function is rudimentary at best. Using a phylogenetic microarray, we examine the airway microbiota in age stratified CF patients ranging from neonates (9 months) to adults (72 years). From a cohort of clinically stable patients, we demonstrate that older CF patients who exhibit poorer pulmonary function possess more uneven, phylogenetically-clustered airway communities, compared to younger patients. Using longitudinal samples collected form a subset of these patients a pattern of initial bacterial community diversification was observed in younger patients compared with a progressive loss of diversity over time in older patients. We describe in detail the distinct bacterial community profiles associated with young and old CF patients with a particular focus on the differences between respective “early” and “late” colonizing organisms. Finally we assess the influence of Cystic Fibrosis Transmembrane Regulator (CFTR) mutation on bacterial abundance and identify genotype-specific communities involving members of the Pseudomonadaceae, Xanthomonadaceae, Moraxellaceae and Enterobacteriaceae amongst others. Data presented here provides insights into the CF airway microbiota, including initial diversification events in younger patients and establishment of specialized communities of pathogens associated with poor pulmonary function in older patient populations

Functional MRI evidence for the decline of word retrieval and generation during normal aging

International audienceThis fMRI study aimed to explore the effect of normal aging on word retrieval and generation. The question addressed is whether lexical production decline is determined by a direct mechanism, which concerns the language operations or is rather indirectly induced by a decline of executive functions. Indeed, the main hypothesis was that normal aging does not induce loss of lexical knowledge, but there is only a general slowdown in retrieval mechanisms involved in lexical processing , due to possible decline of the executive functions. We used three tasks (verbal fluency, object naming , and semantic categorization). Two groups of participants were tested (Young, Y and Aged, A), without cognitive and psychiatric impairment and showing similar levels of vocabulary. Neuropsychological testing revealed that older participants had lower executive function scores, longer processing speeds, and tended to have lower verbal fluency scores. Additionally, older participants showed higher scores for verbal automa-tisms and overlearned information. In terms of behav-ioral data, older participants performed as accurate as younger adults, but they were significantly slower for the semantic categorization and were less fluent for verbal fluency task. Functional MRI analyses suggested that older adults did not simply activate fewer brain regions involved in word production, but they actually showed an atypical pattern of activation. Significant correlations between the BOLD (Blood Oxygen Level Dependent) signal of aging-related (A > Y) regions and cognitive scores suggested that this atypical pattern of the activation may reveal several compensatory mechanisms (a) to overcome the slowdown in retrieval, due to the decline of executive functions and processing speed and (b) to inhibit verbal automatic processes. The BOLD signal measured in some other aging-dependent regions did not correlate with the behavioral and neuro-psychological scores, and the overactivation of these uncorrelated regions would simply reveal dedifferentia-tion that occurs with aging. Altogether, our results suggest that normal aging is associated with a more difficult access to lexico-semantic operations and representations by a slowdown in executive functions, without any conceptual loss