Phylogenetic analysis of HpnP reveals the origin of 2-methylhopanoid production in Alphaproteobacteria.

Hopanoids are bacterial steroid-like lipids that can be preserved in the rock record on billion-year timescales. 2-Methylhopanoids are of particular interest to geobiologists because methylation is one of the few chemical modifications that remain after diagenesis and catagenesis. 2-Methylhopanes, the molecular fossils of 2-methylhopanoids, are episodically enriched in the rock record, but we do not have a robust interpretation for their abundance patterns. Here, we exploit the evolutionary record found in molecular sequences from extant organisms to reconstruct the biosynthetic history of 2-methylhopanoids using the C-2 hopanoid methylase, HpnP. Based on HpnP phylogenetic analysis, we find that 2-methylhopanoids originated in a subset of the Alphaproteobacteria. This conclusion is statistically robust and reproducible in multiple trials varying the outgroup, trimming stringency, and ingroup dataset used to infer the evolution of this protein family. The capacity for 2-methylhopanoid production was likely horizontally transferred from the Alphaproteobacteria into the Cyanobacteria after the Cyanobacteria's major divergences. Together, these results suggest that the ancestral function of 2-methylhopanoids was not related to oxygenic photosynthesis but instead to a trait already present in the Alphaproteobacteria. Moreover, given that early 2-methylhopane deposits could have been made solely by Alphaproteobacteria before the acquisition of hpnP by Cyanobacteria, and that the Alphaproteobacteria are thought to be ancestrally aerobic, we infer that 2-methylhopanoids likely arose after the oxygenation of the atmosphere. This finding is consistent with the geologic record-the oldest syngenetic 2-methylhopanes occur after the rise of oxygen, in middle Proterozoic strata of the Barney Creek Formation.

Design and synthesis of bicyclic heterocycles as potent γ-secretase modulators.

The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.

Tricyclic 3,4-dihydropyrimidine-2-thione derivatives as potent TRPA1 antagonists.

The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.

On total turbulent energy and the passive and active role of buoyancy in turbulent momentum and mass transfer.

Measurements of turbulent fluctuations of horizontal and vertical components of velocity, salinity and suspended particulate matter are presented. Turbulent Prandtl numbers are found to increase with stratification and to become larger than 1. Consequently, the vertical turbulent mass transport is suppressed by buoyancy forces, before the turbulent kinetic energy (TKE) and vertical turbulent momentum exchange are inhibited. With increasing stratification, the buoyancy fluxes do not cease, instead they become countergradient. We find that buoyantly driven motions play an active role in the transfer of mass. This is in agreement with trends derived from Monin-Obukhov scaling. For positive Richardson flux numbers (Ri f ), the log velocity profile in the near-bed layer requires correction with a drag reduction. For negative Ri f , the log velocity profile should be corrected with a drag increase, with increasing |Ri f |. This highlights the active role played by buoyancy in momentum transfer and the production of TKE. However, the data do not appear to entirely follow Monin-Obukhov scaling. This is consistent with the notion that the turbulence field is not in equilibrium. The large stratification results in the decay of turbulence and countergradient buoyancy fluxes act to restore equilibrium in the energy budget. This implies that there is a finite adjustment timescale of the turbulence field to changes in velocity shear and density stratification. The energy transfers associated with the source and sink function of the buoyancy flux can be modeled with the concept of total turbulent energy.

5-sulfonyl-benzimidazoles as selective CB2 agonists-part 2.

In a previous communication, the SAR of a series of potent and selective 5-sulfonyl-benzimidazole CB2-receptor agonists was described. The lack of in vivo activity of compounds from this series was attributed to their poor solubility and metabolic stability. In this Letter, we report on the further optimization of this series, leading to the relatively polar and peripherically acting CB2 agonists 41 and 49. Although both compounds were not active in acute pain models, the less selective compound 41 displayed good, sustained activity in a chronic model of neuropathic pain without the tolerance observed with morphine. In addition, both 41 and 49 delayed the onset of clinical symptoms in an experimental model for Multiple sclerosis.

5-Sulfonyl-benzimidazoles as selective CB2 agonists.

A novel series of benzimidazole CB2-receptor agonists was synthesized and the structure-activity relationship explored. The results showed agonistic activities with an EC(50) up to 0.5 nM and excellent selectivity (>4000-fold) over the CB1 receptor. The size of the substituent on the 2-position determined the level of agonism, ranging from inverse agonism to partial agonism to full agonism, which was more pronounced for the rat CB2 receptor. A wide variation of sulfonyl substituents at the benzimidazole 5-position was tolerated, which was used to optimize the drug-like properties. This resulted into lead compound 14j that can be used to investigate the potential of a selective, peripherically acting CB2 agonist. The in vitro profile of key compounds is displayed using pie bar charts (VlaaiVis).

[Pregnancy and severe pancreatitis (author's transl)]. / Grossesse et pancréatite grave.

We studied the relationship between pregnancy and pancreatitis together with reviewing the bibliography after having had 4 cases. As far as the aetiology is concerned there does not seem to be a mechanical factor associated with the pregnant uterus but a vesicular factor (gall bladder) of stasis and hypersecretion, with hyperlipidaemia of pregnancy and pancreatic oversecretion in pregnancy, all of which are finally associated with a neuro-vegetative lack of tone and with the part played by certain drugs that are often prescribed in pregnancy. The fetal prognosis is relatively good except for the risks of premature delivery. Management of a case of acute severe pancreatitis is difficult to work out. All the same, the treatment should be above all conservative, which means medical. Surgery should be reserved for those cases with definite indications such as progressive deterioration in spite of medical treatment with the knowledge beforehand that it will not make much difference to the final prognosis.

[Pharmacologic complications of the unequal reactivity of constituent elements of the myocardium to the parasympathetic system]. / Incidences pharmacologiques de l'inégale réactivité des éléments constitutifs fu myocarde au système parasympathique.

Pharmacological consequences of the unequal reactivity of the myocardial different parts to parasympathic system. The effects of acetylcholine on the various levels of cardiac automatism are studied on open chest dogs with extracorporeal circulation. This drug depresses the sinus node, and more specially the atrio-ventricular node (AV node), but does not alter the His bundle and the Purkinje fibers activity. The sensitivity of the intra-cardiac conduction to acetylcholine also depends upon the considered level of conduction: measured with a bipolar electrode situated upon the His bundle, this one is lowered electively in the atrio-ventricular part. So, the A, V. node can be considered as the elective place of action of acetylcholine on the double point of view of automatism and conduction. Drugs modifying the vagal tonus see their action altered, either in a plus way (antiarrhythmic agents), either in a minus way (cardiac glycosides, halogenated hydrocarbons).

Treatment of cerebral embolism in heart surgery.

The results in the treatment of air embolism in open heart surgery are presented. Two cases of gaseous cerebral embolism are described. One of the patients had a period of unconsciousness of 54 hours, the other of 17 days. Therapy included administration of vasoactive drugs (xanthinol nicotinate 1500 mg 2 times daily as an intravenous drip) combined with superficial hypothermia (32 degrees C). In both cases complete recovery was achieved.