Functionalization of β-caryophyllene generates novel polypharmacology in the endocannabinoid system

The widespread dietary plant sesquiterpene hydrocarbon β-caryophyllene (1) is a CB2 cannabinoid receptor-specific agonist showing anti-inflammatory and analgesic effects in vivo. Structural insights into the pharmacophore of this hydrocarbon, which lacks functional groups other than double bonds, are missing. A structure-activity study provided evidence for the existence of a well-defined sesquiterpene hydrocarbon binding site in CB2 receptors, highlighting its exquisite sensitivity to modifications of the strained endocyclic double bond of 1. While most changes on this element were detrimental for activity, ring-opening cross metathesis of 1 with ethyl acrylate followed by amide functionalization generated a series of new monocyclic amides (11a, 11b, 11c) that not only retained the CB2 receptor functional agonism of 1 but also reversibly inhibited fatty acid amide hydrolase (FAAH), the major endocannabinoid degrading enzyme, without affecting monoacylglycerol lipase (MAGL) and α,β hydrolases 6 and 12. Intriguingly, further modification of this monocyclic scaffold generated the FAAH- and endocannabinoid substrate-specific cyclooxygenase-2 (COX-2) dual inhibitors 11e and 11f, which are probes with a novel pharmacological profile. Our study shows that by removing the conformational constraints induced by the medium-sized ring and by introducing functional groups in the sesquiterpene hydrocarbon 1, a new scaffold with pronounced polypharmacological features within the endocannabinoid system could be generated. The structural and functional repertoire of cannabimimetics and their yet poorly understood intrinsic promiscuity may be exploited to generate novel probes and ultimately more effective drugs.

Functionalization of PAMAM dendrimers with nitronyl nitroxide radicals as models for the outer-sphere relaxation in dentritic potential MRI contrast agents

PAMAM dendrimers functionalized with nitronyl nitroxide radicals were characterized. Quantitative determination of substitution with radicals was performed using EPR and electrochemical methods. The study of the 1H NMR relaxation of the surrounding water showed how the outer-sphere contribution to the relaxivity may be limited by the presence of the dendrimer core.

CstF64: cell cycle regulation and functional role in 3' end processing of replication-dependent histone mRNAs.

The 3' end processing of animal replication-dependent histone mRNAs is activated during G1/S-phase transition. The processing site is recognized by stem-loop binding protein and the U7 snRNP, but cleavage additionally requires a heat-labile factor (HLF), composed of cleavage/polyadenylation specificity factor, symplekin, and cleavage stimulation factor 64 (CstF64). Although HLF has been shown to be cell cycle regulated, the mechanism of this regulation is unknown. Here we show that levels of CstF64 increase toward the S phase and its depletion affects histone RNA processing, S-phase progression, and cell proliferation. Moreover, analyses of the interactions between CstF64, symplekin, and the U7 snRNP-associated proteins FLASH and Lsm11 indicate that CstF64 is important for recruiting HLF to histone precursor mRNA (pre-mRNA)-resident proteins. Thus, CstF64 is central to the function of HLF and appears to be at least partly responsible for its cell cycle regulation. Additionally, we show that misprocessed histone transcripts generated upon CstF64 depletion mainly accumulate in the nucleus, where they are targets of the exosome machinery, while a small cytoplasmic fraction is partly associated with polysomes.

End caps prevent nail migration in elastic stable intramedullary nailing in paediatric femoral fractures: a biomechanical study using synthetic and cadaveric bones.

End caps are intended to prevent nail migration (push-out) in elastic stable intramedullary nailing. The aim of this study was to investigate the force at failure with and without end caps, and whether different insertion angles of nails and end caps would alter that force at failure. Simulated oblique fractures of the diaphysis were created in 15 artificial paediatric femurs. Titanium Elastic Nails with end caps were inserted at angles of 45°, 55° and 65° in five specimens for each angle to create three study groups. Biomechanical testing was performed with axial compression until failure. An identical fracture was created in four small adult cadaveric femurs harvested from two donors (both female, aged 81 and 85 years, height 149 cm and 156 cm, respectively). All femurs were tested without and subsequently with end caps inserted at 45°. In the artificial femurs, maximum force was not significantly different between the three groups (p = 0.613). Push-out force was significantly higher in the cadaveric specimens with the use of end caps by an up to sixfold load increase (830 N, standard deviation (SD) 280 vs 150 N, SD 120, respectively; p = 0.007). These results indicate that the nail and end cap insertion angle can be varied within 20° without altering construct stability and that the risk of elastic stable intramedullary nailing push-out can be effectively reduced by the use of end caps.

Sēfer maḥanē Yiśrā'ēl : enṭhalṭend dînê melîḥā, ḥallā, nēde, hadlāqā

heroizgegeben fon Ber Frenq

Sēfer Maḥanē Yiśrā'ēl : enṭhalṭend dine meliḥe, ḥale, nido, hadloke nebsṭ einem anhange ... tzur kunsṭ der ehe gliklich tzu leben ...

heroizgegeben fon Ber Frenk

Sēfer Maḥanē Yiśrā'ēl : enṭhalṭend dine meliḥe, ḥale, nido, hadloke nebzṭ einem anhang ... tzur kunsṭ in der ehe glikklich tzu leben ...

heroizgegeben fon Ber Frenk

Berākā mešûllešet : enṭhelṭend 3 goṭṭesdiensṭliche fortṭrege gehalṭen in der sinagoge ... im rechṭen Donoi-ufer in Buda-Pesṭ

mimmenî Śimḥā Hallas

Ḥuḳe ḥayim : enṭhalṭend di vikhṭigsṭen ferordnungen iber das yidishe leben im allgemeinen, zo ṿi iber tsitsit, tefilin, tefilah und di ibrigen gottesdienstlikhen gebroykhe

fon Daṿid Ḳassel

Timing of retreat of the Reuss Glacier (Switzerland) at the end of the Last Glacial Maximum

We used cosmogenic 10Be and 36Cl to establish the timing of the onset of deglaciation after the Last Glacial Maximum of the Reuss Glacier, one of the piedmont lobes of the Alpine ice cap that reached the northern Alpine foreland in Switzerland. In this study, we sampled erratic boulders both at the frontal position in the foreland (Lenzburg and Wohlen, canton Aargau) and at the lateral Alpine border position (Seeboden moraine, Rigi, canton Schwyz). The minimum age for the beginning of retreat is 22.2 ± 1.0 ka at the frontal (terminal) position and 20.4 ± 1.0 ka at the lateral position. These ages are directly comparable with exposure ages from the other piedmont lobes in the northern Alpine foreland. Our data from the mountain called Rigi, do not support the hypothesis that boulders located external to the Seeboden moraine were deposited prior to the last glacial cycle. We present a first exposure age from an erratic boulder in a retreat position in the Alpine foreland. The Reuss Glacier was approximately 12 km behind the maximal extent no later than at 18.6 ± 0.9 ka.

Ben yaqqîr : enṭhalṭend Yesôdê had-dat oder gloibenswahrheiṭen und ziṭṭenlehren fir di izraeliṭiše jugend ...

fon Hertz Homberg

Review of Clément Vidal, "The Beginning and the End. The Meaning of Life in a Cosmological Perspective"

No more ground control. Dissertations ideally always have been ambitious, and this one can’t claim to be too humble in these regards. Together the pieces of this work form a world view that the author confesses to finding ‘magnificent’. The story he tells is one in which intelligence and complexity are keys to unlock the universe’s mysteries. Vidal tackles questions like ‘What is philosophy?’, ‘Where does it all come from?’, Where are we going?’, ‘Are we alone in the universe?’ and even ‘What is good and what is evil?’. Questions which philosophers for ages have tried to answer.

Hoiz Jakov : kompendium unzerer riṭualien in der landesšprache ; fasṭ alle im gewehrlichen leben forkommenden religiezen broiche enḥaltṭend ...

heroisgegeben fon Moše ... Rozenṭhal

Weather and War – Economic and social vulnerability in Switzerland at the end of the First World War

Neutral Switzerland – not embedded in the fighting forces – yet was involved in the Great War mainly in economical terms. Since Switzerland is a landlocked country especially agriculture became an important topic of war economy in regard to food security. Until 1916 national food supply was limited but could be maintained through barter trade. In 1916 a crisis on both supply and production level occurred and led to a decline in food availability and to immense price risings causing social turmoil. This paper aims to outline the factors of vulnerability in respect of food in Switzerland during the First World War and further it will show different coping strategies that were undertaken during that time. The paper takes the work of Mario Aeby and Christian Pfister (University of Bern) into consideration that pointed out to weather anomalies during the years 1916 and 1917 aggravating the already tense food situation. Arguing for an overlap of supply and production crisis the paper focuses on agricultural and economic history including environmental impacts. Further the paper addresses the question of what makes a food system resilient to such unforeseen impacts.