Enantioselective Total Synthesis of Hyperforin

A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.Chemistry and Chemical Biolog

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination

Cholesterol Metabolism Is Required for Intracellular Hedgehog Signal Transduction In Vivo

We describe the rudolph mouse, a mutant with striking defects in both central nervous system and skeletal development. Rudolph is an allele of the cholesterol biosynthetic enzyme, hydroxysteroid (17-beta) dehydrogenase 7, which is an intriguing finding given the recent implication of oxysterols in mediating intracellular Hedgehog (Hh) signaling. We see an abnormal sterol profile and decreased Hh target gene induction in the rudolph mutant, both in vivo and in vitro. Reduced Hh signaling has been proposed to contribute to the phenotypes of congenital diseases of cholesterol metabolism. Recent in vitro and pharmacological data also indicate a requirement for intracellular cholesterol synthesis for proper regulation of Hh activity via Smoothened. The data presented here are the first in vivo genetic evidence supporting both of these hypotheses, revealing a role for embryonic cholesterol metabolism in both CNS development and normal Hh signaling

Enantioselective Total Synthesis of Hyperforin

A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]­nonane core and set two key quaternary stereocenters

Total Synthesis of (−)-Nemorosone and (+)-Secohyperforin

A general strategy for the synthesis of polycyclic polyprenylated acylphloroglucinols is described in which a scalable, Lewis acid catalyzed epoxide-opening cascade cyclization is used to furnish common intermediate <b>4</b>. The utility of this approach is exemplified by the total syntheses of both <i>ent</i>-nemorosone and (+)-secohyperforin, which were each accomplished in four steps from this intermediate

Is it time to revise the diagnostic criteria for apathy in brain disorders? the 2018 international consensus group

International audienceBackground. Apathy is a very common behavioural and psychological symptom across brain disorders. In the last decade, there have been considerable advances in research on apathy and motivation. It is thus important to revise the apathy diagnostic criteria published in 2009. The main objectives were to: a) revise the definition of apathy; b) update the list of apathy dimensions; c) operationalise the diagnostic criteria; and d) suggest appropriate assessment tools including new technologies.Methods. The expert panel (N=17) included researchers and health care professionals working on brain disorders and apathy, a representative of a regulatory body, and a representative of the pharmaceutical industry. The revised diagnostic criteria for apathy were developed in a two-step process. First, following the standard Delphi methodology, the experts were asked to answer questions via web-survey in two rounds. Second, all the collected information was discussed onthe occasion of the 26th European Congress of Psychiatry held in Nice (France).Results. Apathy was defined as a quantitative reduction of goal-directed activity in comparison to the patient’s previous level of functioning (criterion A). Symptoms must persist for at least four weeks, and affect at least two of the three apathy dimensions (behaviour/cognition; emotion; social interaction; criterion B). Apathy should cause identifiable functional impairments (criterion C), and should not be fully explained by other factors, such as effects of a substance or major changes in the patient’s environment.Conclusions. The new diagnostic criteria for apathy provide a clinical and scientific framework to increase the validity of apathy as a clinical construct. This should also help to pave the path for apathy in brain disorders to be an interventional target

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition <i>in vivo</i>. Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor <b>KZR-504</b> (<b>12</b>)

The impact of drainage displacement patterns and Haines jumps on CO2 storage efficiency

Injection of CO2 deep underground into porous rocks, such as saline aquifers, appears to be a promising tool for reducing CO2 emissions and the consequent climate change. During this process CO2 displaces brine from individual pores and the sequence in which this happens determines the efficiency with which the rock is filled with CO2 at the large scale. At the pore scale, displacements are controlled by the balance of capillary, viscous and inertial forces. We simulate this process by a numerical technique, multi-GPU Lattice Boltzmann, using X-ray images of the rock pores. The simulations show the three types of fluid displacement patterns, at the larger scale, that have been previously observed in both experiments and simulations: viscous fingering, capillary fingering and stable displacement. Here we examine the impact of the patterns on storage efficiency and then focus on slow flows, where displacements at the pore scale typically happen by sudden jumps in the position of the interface between brine and CO2, Haines jumps. During these jumps, the fluid in surrounding pores can rearrange in a way that prevent later displacements in nearby pores, potentially reducing the efficiency with which the CO2 fills the total available volume in the rock