Small Molecular Inhibitors Block TRPM4 Currents in Prostate Cancer Cells, with Limited Impact on Cancer Hallmark Functions.

Transient receptor potential melastatin 4 (TRPM4) is a broadly expressed Ca2+ activated monovalent cation channel that contributes to the pathophysiology of several diseases. For this study, we generated stable CRISPR/Cas9 TRPM4 knockout (K.O.) cells from the human prostate cancer cell line DU145 and analyzed the cells for changes in cancer hallmark functions. Both TRPM4-K.O. clones demonstrated lower proliferation and viability compared to the parental cells. Migration was also impaired in the TRPM4-K.O. cells. Additionally, analysis of 210 prostate cancer patient tissues demonstrates a positive association between TRPM4 protein expression and local/metastatic progression. Moreover, a decreased adhesion rate was detected in the two K.O. clones compared to DU145 cells. Next, we tested three novel TRPM4 inhibitors with whole-cell patch clamp technique for their potential to block TRPM4 currents. CBA, NBA and LBA partially inhibited TRPM4 currents in DU145 cells. However, none of these inhibitors demonstrated any TRPM4-specific effect in the cellular assays. To evaluate if the observed effect of TRPM4 K.O. on migration, viability, and cell cycle is linked to TRPM4 ion conductivity, we transfected TRPM4-K.O. cells with either TRPM4 wild-type or a dominant-negative mutant, non-permeable to Na+. Our data showed a partial rescue of the viability of cells expressing functional TRPM4, while the pore mutant was not able to rescue this phenotype. For cell cycle distribution, TRPM4 ion conductivity was not essential since TRPM4 wild-type and the pore mutant rescued the phenotype. In conclusion, TRPM4 contributes to viability, migration, cell cycle shift, and adhesion; however, blocking TRPM4 ion conductivity is insufficient to prevent its role in cancer hallmark functions in prostate cancer cells

Direct observation of interface and nanoscale compositional modulation in ternary III-As heterostructure nanowires

Straight, axial InAs nanowire with multiple segments of GaInAs were grown. High resolution X-ray energy-dispersive spectroscopy (EDS) mapping reveal the distribution of group III atoms at the axial interfaces and at the sidewalls. Significant Ga enrichment, accompanied by a structural change is observed at the GaInAs/InAs interfaces and a higher Ga concentration for the early grown GaInAs segments. The elemental map and EDS line profile infer Ga enrichment at the facet junctions between the sidewalls. The relative chemical potentials of ternary alloys and the thermodynamic driving force for liquid to solid transition explains the growth mechanisms behind the enrichment.Comment: 12 Pages, 4 figure

The Idre marginal moraine – an anchorpoint for Middle and Late Weichselian ice sheet chronology

We here report the results of luminescence and cosmogenic exposure dating of the Idre marginal moraine, located in the southern Scandinavian Mountains. This particular moraine is targeted because it is morphologically distinct and marks the margin of a former ice sheet. The till in the moraine contains erratics that provide strong evidence of flow from an ice sheet centred over Norway. The area immediately outside the moraine margin is an older residual soil. Luminescence ages of three samples taken from a sand lense within the moraine indicate that it formed at around 55 ka, during the early warm part of Marine Isotope Stage (MIS) 3. Median exposure ages (10Be) of ten samples from boulders embedded in the surface till indicate that about 30 ka of ice-free time have elapsed since formation of the moraine. The difference between the age of the ridge and the duration of exposure provides a measure of the time of ice-cover in the ice sheet core area. Previous research indicates that final deglaciation of the site occurred at approximately 10 ka ago, which in combination with our results implies that the area around the Idre marginal moraine was ice free for ca. 20 ka, i.e. from around 55 ka to around 35 ka. Thereafter, the area was glaciated and the marginal moraine was covered by the Late Weichselian ice sheet for around 25 ka without experiencing any significant erosion or morphological destruction. While earlier studies have already pointed towards MIS 3 ice free conditions in northern and central Sweden, this study contributes a measurement-based duration estimate for the MIS 3 interstadial

The cost-effectiveness of screening in the community to reduce osteoporotic fractures in older women in the UK: Economic evaluation of the SCOOP Study

The SCOOP study was a two-arm randomized controlled trial conducted in the UK in 12,483 eligible women aged 70 to 85 years. It compared a screening program using the FRAX® risk assessment tool in addition to bone mineral density (BMD) measures versus usual management. The SCOOP study found a reduction in the incidence of hip fractures in the screening arm, but there was no evidence of a reduction in the incidence of all osteoporosis-related fractures. To make decisions about whether to implement any screening program, we should also consider whether the program is likely to be a good use of health care resources, ie, is it cost-effective? The cost per gained quality adjusted life year of screening for fracture risk has not previously been demonstrated in an economic evaluation alongside a clinical trial. We conducted a “within trial” economic analysis alongside the SCOOP study from the perspective of a national health payer, the UK National Health Service (NHS). The main outcome measure in the economic analysis was the cost per quality adjusted life year (QALY) gained over a 5-year time period. We also estimated cost per osteoporosis-related fracture prevented and the cost per hip fracture prevented. The screening arm had an average incremental QALY gain of 0.0237 (95% confidence interval –0.0034 to 0.0508) for the 5-year follow-up. The incremental cost per QALY gained was £2772 compared with the control arm. Cost-effectiveness acceptability curves indicated a 93% probability of the intervention being cost-effective at values of a QALY greater than £20,000. The intervention arm prevented fractures at a cost of £4478 and £7694 per fracture for osteoporosis-related and hip fractures, respectively. The current study demonstrates that a systematic, community-based screening program of fracture risk in older women in the UK represents a highly cost-effective intervention. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc

Deglaciation of Fennoscandia

To provide a new reconstruction of the deglaciation of the Fennoscandian Ice Sheet, in the form of calendar-year time-slices, which are particularly useful for ice sheet modelling, we have compiled and synthesized published geomorphological data for eskers, ice-marginal formations, lineations, marginal meltwater channels, striae, ice-dammed lakes, and geochronological data from radiocarbon, varve, optically-stimulated luminescence, and cosmogenic nuclide dating. This 25 is summarized as a deglaciation map of the Fennoscandian Ice Sheet with isochrons marking every 1000 years between 22 and 13 cal kyr BP and every hundred years between 11.6 and final ice decay after 9.7 cal kyr BP. Deglaciation patterns vary across the Fennoscandian Ice Sheet domain, reflecting differences in climatic and geomorphic settings as well as ice sheet basal thermal conditions and terrestrial versus marine margins. For example, the ice sheet margin in the high-precipitation coastal setting of the western sector responded sensitively to climatic variations leaving a detailed record of prominent moraines and ice-marginal deposits in many fjords and coastal valleys. Retreat rates across the southern sector differed between slow retreat of the terrestrial margin in western and southern Sweden and rapid retreat of the calving ice margin in the Baltic Basin. Our reconstruction is consistent with much of the published research. However, the synthesis of a large amount of existing and new data support refined reconstructions in some areas. For example, we locate the LGM extent of the ice sheet in northwestern Russia further east than previously suggested and conclude that it occurred at a later time than the rest of the ice sheet, at around 17-15 cal kyr BP, and propose a slightly different chronology of moraine formation over southern Sweden based on improved correlations of moraine segments using new LiDAR data and tying the timing of moraine formation to Greenland ice core cold stages. Retreat rates vary by as much as an order of magnitude in different sectors of the ice sheet, with the lowest rates on the high-elevation and maritime Norwegian margin. Retreat rates compared to the climatic information provided by the Greenland ice core record show a general correspondence between retreat rate and climatic forcing, although a close match between retreat rate and climate is unlikely because of other controls, such as topography and marine versus terrestrial margins. Overall, the time slice reconstructions of Fennoscandian Ice Sheet deglaciation from 22 to 9.7 cal kyr BP provide an important dataset for understanding the contexts that underpin spatial and temporal patterns in retreat of the Fennoscandian Ice Sheet, and are an important resource for testing and refining ice sheet models

The importance of the device in asthma therapy

AbstractInhalation is the preferred route for drug delivery in asthma treatment. Successful management of asthma depends on achieving adequate delivery of inhaled drug to the lungs, and to this end the role of the device used for delivery is very important. Aerosolized anti-asthma medications have been available for more than 40 years as pressurized metered dose inhalers (pMDIs), but more recently dry powder inhalers (DPIs) have been developed asan alternative. Laboratory assessment of fine particle dose has been shown to correlate to pulmonary deposition if the assessments are performed with an in vivo-like set up. The DPl Turbuhaler® delivers a high proportion of the dose as fine particles suggesting high pulmonary deposition. This finding has been confirmed by lung deposition studies, which indicate superior pulmonary deposition from Turbuhaler compared with a pMDI. This superior delivery to the lungs with Turbuhaler is reflected in a better clinical effect, as measured by greater improvements in lung function. The DPIs such as Turbuhaler are easy to use, and Turbuhaler has been shown to function well in a constrained situation such as an acute asthmatic exacerbation. Fur thermore, the use of Turbuhaler in acute asthma will provide rapidclinical improvement. The in vivo variability in lung deposition obtained with Turbuhaler is lower than with pMDI, indicating that the performance of Turbuhaler is less dependent on patient competence. Thus, the development of Turbuhaler represents an important step forward in the effective management of asthma

Inhomogeneous Si-doping of gold-seeded InAs nanowires grown by molecular beam epitaxy

We have investigated in-situ Si doping of InAs nanowires grown by molecular beam epitaxy from gold seeds. The effectiveness of n-type doping is confirmed by electrical measurements showing an increase of the electron density with the Si flux. We also observe an increase of the electron density along the nanowires from the tip to the base, attributed to the dopant incorporation on the nanowire facets whereas no detectable incorporation occurs through the seed. Furthermore the Si incorporation strongly influences the lateral growth of the nanowires without giving rise to significant tapering, revealing the complex interplay between axial and lateral growth.This work was supported by the ANR through the Project No. ANR-11-JS04-002-01, and the Ministry of Higher Education and Research, Nord-Pas de Calais Regional Council and FEDER through the “Contrat de Projets Etat Region (CPER) 2007-2013.” P.C. is the recipient of an Australian Research Council Future Fellowship (project number FT120100498)

Mikkeli Osteoporosis Index Identifies Fracture Risk Factors and Osteoporosis and Intervention Thresholds Parallel with FRAX

Osteoporosis Index (MOI) was developed from Fracture Index (FI), a validated fracture risk score, to identify also osteoporosis. MOI risk factors are age, weight, previous fracture, family history of hip fracture or spinal osteoporosis, smoking, shortening of the stature, and use of arms to rise from a chair. The association of these risk factors with BMD was examined in development cohorts of 300 Finnish postmenopausal women with a fracture and in a population control of 434 women aged 65–72. Validation cohorts included 200 fracture patients and a population control of 943 women aged 58–69. MOI identified femoral neck osteoporosis in these cohorts as well as the Osteoporosis Self-Assessment Tool (OST). In the pooled fracture cohort, the association of BMI-based FRAX fracture risk with MOI was good. After BMD measurement, MOI identified well FRAX hip fracture risk-based Intervention Thresholds (ITs) (AUC 0.74–0.90)

Uptake of cerebroside, cholesterol and lecithin by brain myelin and mitochondria

The uptake of emulsified labeled lipids by rat brain myelin and mitochondria was studied. Cerebroside and lecithin uptakes were greatly stimulated by addition of salts, particularly those containing divalent cations. Cholesterol uptake was not influenced by salts. Increasing concentrations of detergent (nonâ ionic) were inhibitory. Delipidated membranes took up much less lipid, but pretreatment with lecithin partially restored the ability to take up cerebroside and cholesterol. The lipid uptake appears to be nonenzymatic and appears to depend on the size of the emulsified particles. The possible role of such a phenomenon in membrane formation and maintenance is discussed.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141986/1/lipd0439.pd

Modelling prevention strategies in Public Health

Various schemes of prevention measures in public health are developed and analyzed on the basis of a general mathematical model. Features related to cost issues, including primary and secondary prevention interventions, differential survival experiences and communicable diseases are in turn used to show the potentialities of the theoretical framework. Statistical estimation procedures are briefly discussed and a numerical application is presented with reference to Italian cancer data