σR/TMEM97 in retinal ganglion cell degeneration.

The sigma 2 receptor (σR) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σR/TMEM97 binding compounds are neuroprotective, suggesting a role of σR/TMEM97 in neurodegenerative processes. To understand the function of σR/TMEM97 in neurodegeneration pathways, we characterized ischemia-induced retinal ganglion cell (RGC) degeneration in TMEM97 mice and found that RGCs in TMEM97 mice are resistant to degeneration.

Characterizing the biomechanical differences between novice and expert point-of-care ultrasound practitioners using a low-cost gyroscope and accelerometer integrated sensor: A pilot study.

Introduction: Point-of-care ultrasound (POCUS) has become an important diagnostic tool in acute care medicine; however, little is known about the biomechanical differences between novice and expert practitioners.

Methods: A low-cost ($50 CAD) gyroscope and accelerometer integrated sensor was assembled and affixed to an ultrasound probe. Seventeen participants, nine novices and eight experts, were recruited to perform three abdominal and four cardiac scans on a standardized patient.

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates.

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either ()-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts. For - or -substituted aryl- or heteroaryldiazoacetates the optimum catalyst was Rh(-Ph-TPCP).

The Rooibos Benefit Sharing Agreement-Breaking New Ground with Respect, Honesty, Fairness, and Care.

The 1992 Convention on Biological Diversity (CBD) and its 2010 Nagoya Protocol brought about a breakthrough in global policy making. They combined a concern for the environment with a commitment to resolving longstanding human injustices regarding access to, and use of biological resources. In particular, the traditional knowledge of indigenous communities was no longer going to be exploited without fair benefit sharing.

Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury.

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 ( K = 5.

Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.

Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation.

Discovery of Aminopiperidine Indoles That Activate the Guanine Nucleotide Exchange Factor SOS1 and Modulate RAS Signaling.

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1).

Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors.

Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol.

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model.

The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons.

Norbenzomorphan Scaffold: Chemical Tool for Modulating Sigma Receptor-Subtype Selectivity.

Some norbenzomorphans exhibit high affinity for sigma 1 and sigma 2 receptors, and varying the position of substituents on the aromatic ring of this scaffold has a significant effect on subtype selectivity. In particular, compounds bearing several different substituents at C7 of the norbenzomorphan ring system exhibit a general preference for the sigma 1 receptor, whereas the corresponding C8-substituted analogues preferentially bind at the sigma 2 receptor. These findings suggest that the norbenzomorphan scaffold may be a unique chemical template that can be easily tuned to prepare small molecules for use as tool compounds to study the specific biological effects arising from preferential binding at either sigma receptor subtype.

Syntheses of Gliocladin C and Related Alkaloids.

A unique approach to gliocladin C and related alkaloids was developed that features an unprecedented nucleophilic addition of a diketopiperazine to an isatin derivative followed by a Friedel-Crafts alkylation of the resultant tertiary alcohol with indole to set the key quaternary center. Chemoselective oxindole reduction and cyclization delivered a pivotal hexahydropyrrolo[2,3-b]indole diketopiperazine intermediate that was readily converted into (±)-gliocladin C, (±)-T988C, and (±)-gliocladine C, culminating in the shortest approach to these alkaloids reported to date.

Norbenzomorphan Framework as a Novel Scaffold for Generating Sigma 2 Receptor/PGRMC1 Subtype-Selective Ligands.

A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure-affinity relationship data are presented showing that 8-substituted 1,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 over the sigma 1 receptor subtype. Indeed, piperazine analogue 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selective for the sigma 2 over the sigma 1 receptor, thereby establishing it as one of the more subtype-selective sigma 2 binding ligands reported to date.

Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma.

High-density lipoproteins (HDLs) mediate cholesterol transport and protection from cardiovascular disease. Although synthetic HDLs have been studied for 30 years, the structures of human plasma-derived HDL and its major protein apolipoprotein apoA-I are unknown. We separated normal human HDL into five density subfractions and then further isolated those containing predominantly apoA-I (LpA-I).

Impact of intracranial pressure monitor prophylaxis on central nervous system infections and bacterial multi-drug resistance.

Background: Routine intracranial pressure monitor (ICP) prophylaxis is not practiced at our institution. Nevertheless, some patients receive de facto prophylaxis as a result of the use of antibiotics for injuries such as open or facial fractures. We tested the hypothesis that prophylactic antibiotics do not reduce the incidence of central nervous system (CNS) infections but instead are associated with the acquisition of multi-drug resistant (MDR) bacterial infections.

Ipsilateral femoral vein compression: a contraindication to thrombin injection of femoral pseudoaneurysms.

Development of a femoral artery pseudoaneurysm occurs in 0.6% to 3.2% of interventional procedures.