Characteristics of Icy Surfaces Prockter, Louise M.; Lopes, Rosaly M. C.; Giese, Bernd ...
Space Science Reviews,
06/2010, Letnik:
153, Številka:
1-4
Journal Article, Book
Recenzirano
The surfaces of the Solar System’s icy satellites show an extraordinary variety of morphological features, which bear witness to exchange processes between the surface and subsurface. In this paper ...we review the characteristics of surface features on the moons of Jupiter, Saturn, Uranus and Neptune. Using data from spacecraft missions, we discuss the detailed morphology, size, and topography of cryovolcanic, tectonic, aeolian, fluvial, and impact features of both large moons and smaller satellites.
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is designed to evaluate the longitudinal outcome of patients with bipolar disorder. The STEP-BD disease-management model is ...built on evidence-based practices and a collaborative care approach designed to maximize specific and nonspecific treatment mechanisms. This prospective study examined the longitudinal relationships between patients' satisfaction with care, levels of hope, and life functioning in the first 1000 patients to enter STEP-BD.
The study used scores from the Care Satisfaction Questionnaire, Beck Hopelessness Scale, Range of Impaired Functioning Tool, Young Mania Rating Scale, and Montgomery-Åsberg Depression Rating Scale at 5 time points during a 1-year interval. Analyses tested mediational pathways between care satisfaction, hope, and life functioning, depression, and mania using mixed-effects (random and fixed) regression models.
Increases in care satisfaction were associated with decreased hopelessness (
P < .01) but not related to symptoms of depression or mania. Similarly, decreased hopelessness was associated with better life functioning (
P < .01) but not related to symptoms of depression or mania. Depression was independently associated with poorer life functioning (
P < .0001).
This study provided support for the hypothesized mediational pathway between care satisfaction, hopelessness, and life functioning. Findings suggest that providing care that maximizes patient hope may be important. By so doing, patients might overcome the learned helplessness/hopelessness that often accompanies a cyclical illness and build a realistic illness-management strategy.
Abstract
Phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling is key to the control of many physiological and pathophysiological processes, and promotes cancer and ...inflammatory disease. Therefore, targeting of PI3K and/or mTOR pathways is currently explored in numerous clinical studies. PQR309 is a novel, brain penetrant, potent and selective pan-PI3K/mTOR inhibitor with PK properties suitable for once a day oral dosing in humans.
Structure activity relationship studies for PI3K and mTOR interactions are presented, including X-Ray analysis of PI3Kgamma co-crystal structures, modeling of PI3Kalpha and mTOR structures, and chemical derivatization. This led to the identification of PQR309 as a potent pan-PI3K and moderate mTOR inhibitor. PQR309 displays excellent selectivity versus PI3K-related lipid kinases (PIKKs) and protein kinases (KINOMEscan), as well as excellent selectivity versus unrelated targets (Cerep expresSProfile).
PQR309 features excellent cell permeability, and was characterized as a BCS class II compound due to its limited water solubility (40 μM). Moreover, PQR309 is not a substrate for P-glycoprotein 1 (P-gp). In A2058 melanoma cells PQR309 demonstrated inhibition of protein kinase B (PKB/Akt; pS473) and ribosomal protein S6 (S6, pSer235/236) phosphorylation with IC50 values of 0.13 μM and 0.58 μM, respectively. In IGF-stimulated MCF7 breast cancer cells, PQR309 at 1 μM inhibited phosphorylation of downstream substrates of PI3K including PKB/Akt, S6, p70S6 kinase, GSK3 and Bad by 60-95%. PQR309 inhibited proliferation of all 58 cell lines of the NCI60 panel (GI50 from 50 to 3300 nM), of the NTRC Oncoline panel (44 cell lines, GI50 from 100-6700 nM) and of a lymphoma cell line panel (40 lymphoma cell lines, GI50 from 25-1740 nM). A concise 4-step synthetic process utilizing a novel protective group strategy provides a robust and scalable supply of PQR309 for clinical trials.
In summary, PQR309 is a novel, potent, dual pan-PI3K/mTOR inhibitor with a balanced PI3K vs. mTOR profile, and displays excellent physico-chemical and pharmacological properties. The safety profile of PQR309 is currently addressed in Phase I clinical studies.
Citation Format: Vladimir Cmiljanovic, Natasa Cmiljanovic, Romina Marone, Florent Beaufils, Xuxiao Zhang, Marketa Zvelebil, Paul Hebeisen, Marc Lang, Juergen Mestan, Anna Melone, Thomas Bohnacker, Eugenio Gaudio, Chiara Tarantelli, Francesco Bertoni, Reto Ritschard, Vincent Pretre, Andreas Wicki, Doriano Fabbro, Petra Hillmann, Roger Williams, Bernd Giese, Matthias P. Wymann. PQR309: Structure-based design, synthesis and biological evaluation of a novel, selective, dual pan-PI3K/mTOR inhibitor. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2664. doi:10.1158/1538-7445.AM2015-2664
Abstract
Background
Antibiotic-resistant bacteria are spread through selective pressure from the use of broad-spectrum empirical therapies, mobile genetic elements that pass resistance genes between ...species, and the inability to rapidly and appropriately respond to their presence. Resistance gene identification is often performed with post culture molecular diagnostic tests. The T2Resistance Panel, which detects methicillin resistance genes mecA/C; vancomycin resistance genes vanA/B; carbapenemases blaKPC, blaOXA-48,blaNDM, blaVIM, and blaIMP; AmpC β-lactamases blaCMY and blaDHA; and extended-spectrum β-lactamases blaCTX-M directly from patient blood samples, is based on T2 magnetic resonance (T2MR), an FDA-cleared technology with demonstrated high sensitivity and specificity for culture-independent bacterial and fungal species identification. Here we report the clinical performance of T2MR detection of resistance genes directly from patient blood samples.
Methods
Patients with a clinical diagnosis of sepsis and an order for blood culture (BC) were enrolled in the study at two sites. BCs were managed using standard procedures and MALDI-TOF for species identification. Resistance testing with the T2MR assay was performed on a direct patient draw and compared with diagnostic test results from concurrent BC specimen and BC specimen taken at other points in time. The potential impact on therapy was evaluated through patient chart review.
Results
T2MR detected the same resistance genes as detected by post culture diagnostics in 100% of samples from concurrent blood draws. Discordant results occurred when T2MR was taken ≥48 hours after BC for patients on antimicrobial therapy. The average time to positive result was 5.9 hours with T2MR vs. 30.6 hours with post-culture molecular testing.
Conclusion
The T2Resistance Panel detected antibiotic resistance genes in clinical samples and displayed agreement with post culture genetic testing. T2MR results were achieved faster than culture-dependent diagnostic testing results and may allow for an earlier change from empiric to directed therapy. The use of culture-independent diagnostics like T2MR could enable a quicker response to antibiotic-resistant organisms for individual patients and developing outbreaks.
Disclosures
All authors: No reported disclosures.
Exome sequencing coupled with homozygosity mapping was used to identify a transition mutation (c.794T>C; p.Leu265Ser) in ELMOD3 at the DFNB88 locus that is associated with nonsyndromic deafness in a ...large Pakistani family, PKDF468. The affected individuals of this family exhibited pre-lingual, severe-to-profound degrees of mixed hearing loss. ELMOD3 belongs to the engulfment and cell motility (ELMO) family, which consists of six paralogs in mammals. Several members of the ELMO family have been shown to regulate a subset of GTPases within the Ras superfamily. However, ELMOD3 is a largely uncharacterized protein that has no previously known biochemical activities. We found that in rodents, within the sensory epithelia of the inner ear, ELMOD3 appears most pronounced in the stereocilia of cochlear hair cells. Fluorescently tagged ELMOD3 co-localized with the actin cytoskeleton in MDCK cells and actin-based microvilli of LLC-PK1-CL4 epithelial cells. The p.Leu265Ser mutation in the ELMO domain impaired each of these activities. Super-resolution imaging revealed instances of close association of ELMOD3 with actin at the plasma membrane of MDCK cells. Furthermore, recombinant human GST-ELMOD3 exhibited GTPase activating protein (GAP) activity against the Arl2 GTPase, which was completely abolished by the p.Leu265Ser mutation. Collectively, our data provide the first insights into the expression and biochemical properties of ELMOD3 and highlight its functional links to sound perception and actin cytoskeleton.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monitoring is a key functionality for automated decision making as it is performed by self-adaptive systems, too. Effective monitoring provides the relevant information on time. This can be achieved ...with exhaustive monitoring causing a high overhead consumption of economical and ecological resources. In contrast, our generic adaptive monitoring approach supports effectiveness with increased efficiency. Also, it adapts to changes regarding the information demand and the monitored system without additional configuration and software implementation effort. The approach observes the executions of runtime model queries and processes change events to determine the currently required monitoring configuration. In this paper we explicate different possibilities to use the approach and evaluate their characteristics regarding the phenomenon detection time and the monitoring effort. Our approach allows balancing between those two characteristics. This makes it an interesting option for the monitoring function of self-adaptive systems because for them usually very short-lived phenomena are not relevant.
The aim of the study was to investigate the role of K+‐channels in agonist induced renal vascular depolarization and vasoconstriction. We measured renal blood flow (RBF) in anesthetized rats using an ...ultrasonic flow probe. Test agents were infused directly into the renal artery. Activation of Kir or KATP using K+ or pinacidil increased RBF significantly (by 7%). Activation of SKCa or BKCa using NS309 or NS1619 had no effect on RBF. Administration of a cocktail of the K+‐channel openers had no additive effect on RBF (8 % increase). The cocktail did reduced the vasoconstriction induced by bolus injections of norepinephrine or angiotensin II (by 24% and 59%, respectively).
A cocktail of K+ channel blockers (TEA, Ba2+, glibenclamide, apamin and 4‐AP) inhibiting BKCa, Kir, KATP, SKCa and Kv, respectively, reduced RBF to 15 % of baseline, while the individual blockers had no or minor effect. Nifedipine and mibefradil respectively abolished and reduced the RBF reduction indicating that the vasoconstriction was mediated via depolarization. These results were confirmed in mice.
We conclude that stimulation of several classes of K+‐channels reduces agonist induced renal vascular depolarization and vasoconstriction. This is in accord with the notion that agonist induced depolarization is mediated by closure of several types of K+ channels.
There is a strong distance dependence on the rate of electron transfer between guanine or 8‐oxoguanine (shaded areas in the diagram) to a radical cation in the DNA sugar backbone. In DNA single ...strands the number of intervening A, T, and C nucleotides has only a weak effect on the electron‐transfer rate.
Because of its widespread accessibly, computed tomographic angiography (CT-A) is a promising technique in the detection of intracranial circulatory arrest in brain death (BD). Several studies ...assessed this tool, but neither have standardized evaluation parameters been developed nor has information about specificity become available.
We conducted a prospective study between January 2008 and April 2012. Thirty patients were admitted to our University Hospital (16 men and 14 women; age, 18-88 years) and underwent CT-A scanning at two occasions: immediately after the first signs of loss of brain stem reflexes and after definitive determination of brain. The results of CT-A were compared with transcranial Doppler ultrasonography and electroencephalogram.
In 3 of 30 patients, we observed a termination of contrast flow at the level of the skull base and foramen magnum in arterial scanning series before the clinical determination of BD. After the clinical determination of BD, the opacification of all vascular territories in arterial phase scanning was found in one case, but venous phase scanning revealed no blood return in internal cerebral veins. In all other cases, contrast filling ceased at level of skull base or below. The specificity of CT-A in the detection of intracranial circulatory arrest was 90%, and sensitivity was 97%.
CT-A is reliable and appropriate technical investigation to detect intracranial circulatory arrest in BD. The evaluation of contrast enhancement in arterial phase scanning seems to be more reliable than that in venous phase. An international consensus about a uniformly applied CT-A protocol for the evaluation of BD should be established.
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