Inhibition of diacylglycerol–sensitive TRPC channels by synthetic and natural steroids

TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca2+ signaling in numerous cell types. Important physiological functions such as vasoregulation, neuronal growth, and pheromone recognition have been assigned to this class of ion channels. Despite their physiological relevance, few selective pharmacological tools are available to study TRPC channel function. We, therefore, screened a selection of pharmacologically active compounds for TRPC modulating activity. We found that the synthetic gestagen norgestimate inhibited diacylglycerol-sensitive TRPC3 and TRPC6 with IC50s of 3–5 µM, while half-maximal inhibition of TRPC5 required significantly higher compound concentrations (>10 µM). Norgestimate blocked TRPC-mediated vasopressin-induced cation currents in A7r5 smooth muscle cells and caused vasorelaxation of isolated rat aorta, indicating that norgestimate could be an interesting tool for the investigation of TRP channel function in native cells and tissues. The steroid hormone progesterone, which is structurally related to norgestimate, also inhibited TRPC channel activity with IC50s ranging from 6 to 18 µM but showed little subtype selectivity. Thus, TRPC channel inhibition by high gestational levels of progesterone may contribute to the physiological decrease of uterine contractility and immunosuppression during pregnancy

A Theoretical Investigation of the Drag of Generalized Aircraft Configurations in Supersonic Flow

It seems possible that, in supersonic flight, unconventional arrangements of wings and bodies may offer advantages in the form of drag reduction. It is the purpose of this report to consider the methods for determining the pressure drag for such unconventional configurations, and to consider a few of the possibilities for drag reduction in highly idealized aircraft. The idealized aircraft are defined by distributions of lift and volume in three-dimensional space, and Hayes' method of drag evaluation, which is well adapted to such problems, is the fundamental tool employed. Other methods of drag evaluation are considered also wherever they appear to offer amplifications. The basic singularities such as sources, dipoles, lifting elements and volume elements are discussed, and some of the useful inter-relations between these elements are presented. Hayes' method of drag evaluation is derived in detail starting with the general momentum theorem. In going from planar systems to spatial systems certain new problems arise. For example, interference between lift and thickness distributions generally appears, and such effects are used to explain the difference between the non-zero wave drag of Sears-Haack bodies and the zero wave drag of Ferrari's ring wing plus central body. Another new feature of the spatial systems is that optimum configurations generally are not unique, there being an infinite family of lift or thickness distributions producing the same minimum drag. However it is shown that all members of an optimum family produce the same flow field in a certain region external to the singularity distribution. Other results of the study indicate that certain spatial distributions may produce materially less wave drag and vortex drag than comparable planar systems. It is not at all certain that such advantages can be realized in practical aircraft designs, but further investigation seems to be warranted

History of Sedimentation and Contamination in Valley Mill Reservoir, Springfield, Missouri

The Valley Mill Reservoir (VMR) was constructed between 1851 and 1871 and drains an important recharge area of the drinking water watershed for Springfield, Missouri. Presently, management efforts to protect downstream water quality are aimed at using VMR as a non-point pollution and sedimentation basin since its watershed is planned for continued urban development. The morphometry of VMR is typical of most reservoirs with an elongated basin and the deepest point being near the dam. Sedimentation within the reservoir has created a delta formation with upstream wetlands and floodplains acting as part of the delta especially during the past. Little evidence is found to indicate that resuspension and sediment focusing is occurring after initial deposition. Sedimentation rates ranged from 0.4 to 1.6 cm/yr from 1871 to 1954, while from 1954 to 1964 sedimentation rates increased dramatically ranging from 2.0 to 5.5 cm/yr. Then from 1964/69 to 1978, rates decreased to 0.7 to 1.9 cm/yr. From 1978 to 2000, sedimentation rates ranged from 0.3 to 2.1 cm/yr. During 2000, a large storm event left a 2 to 5 cm thick sediment deposit. Post-2000 sedimentation rates stayed high with a range of 2 to 4.5 cm/yr. Core sediments within VMR indicate that land use changes within the watershed have increased P and Zn concentrations in the upper 5 to 65 cm. Lead also increased over background levels but since the late 1970’s began decreasing due to the banning of Pb in the environment. Around 1970, after the construction of major highways and increased urban land uses, P, Pb and Zn became enriched over background levels. Initial enrichment of Cu and Hg began much earlier than 1970

Tendon Locking for Antagonistic Configuration- and Stiffness-Control in Soft Robots

Some applications, such as surgical interventions, require that potential soft robots have the capability to alter their shape and enhance their force output on demand. This paper presents an antagonistic stiffening mechanism combining pneumatic actuation with tendon locking to achieve configuration- and stiffness control. Elongation of a soft pneumatic section, resulting from air actuation, is opposed by constraining the length of integrated tendons. These tendons can be locked in length by pneumatically activated levers at the base of each segment. Hence, tendon locking will not affect the configuration of other segments of a multi-segment manipulator. Our concept achieves a stiffness increase of up to 201.7% and a larger, more uniform radial workspace compared to the widely used pneumatic actuation concept while maintaining the low technical effort required for actuation. We also demonstrate how our actuation concept enables independent control of stiffness levels for individual segments of a multi-segment manipulator and their MR compatibility

Experimental investigation of the tire wear process using camera-assisted observation assessed by numerical modeling

This paper presents a novel experimental method to study the abrasion mechanism of car tires. It is based on the detection of microscopic movements associated with material damage (cracking) on the rubber tread. This is referred to as degrading layer relaxation. It correlates with the wear rate and, interestingly, the direction of the pattern's movement is opposite to the lateral forces during cornering. To measure and analyze the microscopic movements, a new camera-based method with feature point matching using video stabilization was developed. Besides extensive experimental investigation, the formation and propagation of microcracks are investigated using a simplified numerical model in which a phase field approach coupled with a viscoelastic constitutive behavior is implemented in a finite element framework

Einsatz von Sedativa in den letzten sieben Lebenstagen bei Patient*innen mit malignen Erkrankungen auf Krankenhausstationen der Hämatologie/Onkologie

Hintergrund: Trotz des kontinuierlichen Fortschrittes in der Medizin gibt es weiterhin Erkrankungen, die kurativ nicht behandelbar sind. In solchen Situationen kann die Palliativversorgung helfen, das Leiden zu lindern und die Lebensqualität zu steigern. Wenn alle Therapiekonzepte zur Leidenslinderung versagt haben, kann eine Sedierung in der Palliativversorgung eine letztmögliche Behandlungsoption sein. Bislang mangelt es an einer einheitlichen Definition und Kriterien für Sedierung in der Palliativversorgung, weshalb die in der Literatur angegebenen Prävalenzen einer solchen Sedierung stark divergieren. Zudem wurden der Einsatz von Sedativa und Sedierung außerhalb der spezialisierten Palliativversorgung bisher kaum untersucht. Zielsetzung: Ziel der vorliegenden Doktorarbeit war es, den Einsatz von Sedativa in den letzten sieben Lebenstagen bei Patient*innen mit malignen Erkrankungen auf Krankenhausstationen der Hämatologie/Onkologie zu beschreiben. Die Charakteristika der Anwendung von Sedativa sollten erfasst und die soziodemographischen und klinischen Charakteristika zwischen Patient*innen, die Sedativa (mit kontinuierlichen Effekt) erhielten, und Patient*innen, die keine Sedativa (mit kontinuierlichem Effekt) erhielten, verglichen werden. Methoden: Es wurde eine retrospektive Kohorten-Studie in Form einer Aktenanalyse der Daten der letzten sieben Lebenstage von Patient*innen mit malignen Erkrankungen, die in zwei Münchener Kliniken für Hämatologie/Onkologie im Zeitraum zwischen dem 1. Januar 2015 und dem 31. Dezember 2017 verstarben, durchgeführt. Im Rahmen dieser Studie wurden nur solche Medikamente als „Sedativa“ untersucht, die in Leitlinien für Sedierung in der Palliativversorgung empfohlen werden (Haloperidol, Levomepromazin, Clonazepam, Diazepam, Flunitrazepam, Lorazepam, Lormetazepam, Midazolam, Oxazepam, Propofol). „Sedativa mit kontinuierlichem Effekt” wurden definiert als kontinuierliche parenterale Infusion für ≥ 0,5 Stunden oder wiederholte Applikationen, die erwartungsgemäß zu einer Sedierung für ≥ 24 Stunden führen. Die als „wahrscheinlich mindestens mäßiggradig sedierend“ beurteilte Dosis wurde als 24 mg für parenterales Midazolam und 4 mg für orales Lorazepam definiert. Die Reinigung und Analyse der Daten erfolgte mit dem Statistikprogramm R, Version 3.6.1. Es wurden deskriptive und bivariate statistische Analysen durchgeführt. Je nach Zielgröße und Verteilungsannahme wurden der Mann-Whitney-U-Test, der Chi-Quadrat-Test oder der exakte Test nach Fischer verwendet. Es wurde ein Signifikanzniveau von fünf Prozent verwendet. Ergebnisse: 231 Patient*innen wurden in die Studie eingeschlossen. 104 Patient*innen waren weiblich. Mittleres Alter aller Patient*innen war 69 Jahre (60-77;22-93). In ihrer letzten Lebenswoche erhielten 169/231 Patient*innen (73 %) mindestens einmal ein Sedativum. 120/169 Patient*innen (71 %) wurde ein Sedativum mit kontinuierlichem Effekt verabreicht. 40/231 aller Patient*innen (17 %) erhielten Sedativa in einer „wahrscheinlich mindestens mäßiggradig sedierenden“ Dosis. Insgesamt wurden bei 18/231 aller Patient*innen (8 %) die Begriffe „Sedierung“ oder „sedierend“ in der Patient*innenakte dokumentiert. Je näher das Versterben der Patient*innen rückte, desto häufiger wurden Sedativa eingesetzt. Die Benzodiazepine Midazolam (bei 116/231 aller Patient*innen (50 %)) und Lorazepam (bei 102/231 aller Patient*innen (44 %)) wurden am häufigsten eingesetzt. Die Tagesgesamtdosis von Midazolam lag im Median bei 10 mg/d, die von Lorazepam bei 1 mg/d. Patient*innen, die Sedativa erhielten, waren im Vergleich zu Patient*innen, die keine Sedativa erhielten, jünger (p=0,024), wurden länger stationär behandelt (p=0,011) und häufiger von einem Palliativdienst im Krankenhaus betreut (p<0,001). Sie wurden außerdem häufiger enteral oder parenteral ernährt (p=0,029) und mit Opioiden behandelt (p<0,001). Patient*innen, die Sedativa mit kontinuierlichem Effekt erhielten, waren jünger (p<0,001), öfter weiblich (p=0,025), hatten einen längeren stationären Aufenthalt (p=0,036) und häufiger solide Tumore (p=0,026). Sie wurden häufiger von einem Palliativdienst mitbetreut (p<0,001), vermehrt begleitend enteral oder parenteral ernährt (p=0,022) und häufiger zusätzlich mit Opioiden behandelt (p<0,001), als Patient*innen, die keine Sedativa mit kontinuierlichem Effekt erhielten. Diskussion: Die vorliegende Arbeit zeigt, dass Sedativa auch auf Krankenhausstationen außerhalb der spezialisierten Palliativversorgung am Lebensende häufig eingesetzt werden. Auch bei Einsatz von Sedativa mit kontinuierlichem Effekt in einer „wahrscheinlich mindestens mäßiggradig sedierenden“ Dosis wurde dies nur bei einer Minderheit auch als „Sedierung“ in der Patient*innenakte vermerkt. Dies könnte auf eine Unsicherheit hinweisen, ab wann der Einsatz von Sedativa auch wirklich eine Sedierung darstellt. Perspektivisch sind deswegen einheitliche, objektive und messbare Kriterien wichtig, um – trotz aller interindividuellen Variabilität – bei dieser Einordnung zu unterstützen. Zusätzlich kann die Erstellung von Standard Operating Procedures (SOP), also standardisierten Vorgehensweisen für einzelne Kliniken, für den Einsatz von Sedativa und Sedierung am Lebensende dazu beitragen, die Indikationsstellung sowie die Dokumentation und Überwachung des Einsatzes von Sedativa, insbesondere in sedierenden Dosen, gemäß best-practice- Standards zu gewährleisten

Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population : a population-based cohort study

Background : Non-communicable diseases (NCDs) are leading causes of premature disability and death worldwide. However, the lifetime risk of developing any NCD is unknown, as are the effects of shared common risk factors on this risk. Methods and findings : Between July 6, 1989, and January 1, 2012, we followed participants from the prospective Rotterdam Study aged 45 years and older who were free from NCDs at baseline for incident stroke, heart disease, diabetes, chronic respiratory disease, cancer, and neurodegenerative disease. We quantified occurrence/co-occurrence and remaining lifetime risk of any NCD in a competing risk framework. We additionally studied the lifetime risk of any NCD, age at onset, and overall life expectancy for strata of 3 shared risk factors at baseline: smoking, hypertension, and overweight. During 75,354 person-years of follow-up from a total of 9,061 participants (mean age 63.9 years, 60.1% women), 814 participants were diagnosed with stroke, 1,571 with heart disease, 625 with diabetes, 1,004 with chronic respiratory disease, 1,538 with cancer, and 1,065 with neurodegenerative disease. NCDs tended to co-occur substantially, with 1,563 participants (33.7% of those who developed any NCD) diagnosed with multiple diseases during follow-up. The lifetime risk of any NCD from the age of 45 years onwards was 94.0% (95% CI 92.9%-95.1%) for men and 92.8% (95% CI 91.8%-93.8%) for women. These risks remained high (> 90.0%) even for those without the 3 risk factors of smoking, hypertension, and overweight. Absence of smoking, hypertension, and overweight was associated with a 9.0-year delay (95% CI 6.3-11.6) in the age at onset of any NCD. Furthermore, the overall life expectancy for participants without these risk factors was 6.0 years (95% CI 5.2-6.8) longer than for those with all 3 risk factors. Participants aged 45 years and older without the 3 risk factors of smoking, hypertension, and overweight at baseline spent 21.6% of their remaining lifetime with 1 or more NCDs, compared to 31.8% of their remaining life for participants with all of these risk factors at baseline. This difference corresponds to a 2-year compression of morbidity of NCDs. Limitations of this study include potential residual confounding, unmeasured changes in risk factor profiles during follow-up, and potentially limited generalisability to different healthcare settings and populations not of European descent. Conclusions : Our study suggests that in this western European community, 9 out of 10 individuals aged 45 years and older develop an NCD during their remaining lifetime. Among those individuals who develop an NCD, at least a third are subsequently diagnosed with multiple NCDs. Absence of 3 common shared risk factors is associated with compression of morbidity of NCDs. These findings underscore the importance of avoidance of these common shared risk factors to reduce the premature morbidity and mortality attributable to NCDs

Automating the search of molecular motor templates by evolutionary methods

The first author is supported by a FPU grant (AP2007-03704) from the Ministerio de Educación of the Spanish Government, and has been supported by the BioEmergences project (code 28892) of the Sixth Framework Programme of the European Union. Our research group has been partially supported by the local government (Junta de Andalucía) through a grant for the GENEX project (P09-TIC-5123).Biological molecular motors are nanoscale devices capable of transforming chemical energy into mechanical work, which are being researched in many scientific disciplines. From a computational point of view, the characteristics and dynamics of these motors are studied at multiple time scales, ranging from very detailed and complex molecular dynamics simulations spanning a few microseconds, to extremely simple and coarse-grained theoretical models of their working cycles. However, this research is performed only in the (relatively few) instances known from molecular biology. In this work, results from elastic network analysis and behaviour-finding methods are applied to explore a subset of the configuration space of template molecular structures that are able to transform chemical energy into directed movement, for a fixed instance of working cycle. While using methods based on elastic networks limits the scope of our results, it enables the implementation of computationally lightweight methods, in a way that evolutionary search techniques can be applied to discover novel molecular motor templates. The results show that molecular motion can be attained from a variety of structural configurations, when a functional working cycle is provided. Additionally, these methods enable a new computational way to test hypotheses about molecular motors