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Summary Parkinson’s disease (PD) has been attributed to a combination of genetic and nongenetic factors. We studied a set of monozygotic twins harboring the heterozygous glucocerebrosidase mutation ( GBA N370S) but clinically discordant for PD. We applied induced pluripotent stem cell (iPSC) technology for PD disease modeling using the twins’ fibroblasts to evaluate and dissect the genetic and nongenetic contributions. Utilizing fluorescence-activated cell sorting, we obtained a homogenous population of “footprint-free” iPSC-derived midbrain dopaminergic (mDA) neurons. The mDA neurons from both twins had ∼50% GBA enzymatic activity, ∼3-fold elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. Interestingly, the affected twin’s neurons showed an even lower dopamine level, increased monoamine oxidase B (MAO-B) expression, and impaired intrinsic network activity. Overexpression of wild-type GBA and treatment with MAO-B inhibitors normalized α-synuclein and dopamine levels, suggesting a combination therapy for the affected twin. [ABSTRACT FROM AUTHOR]

Abstract: Three-dimensional aggregation cultures allow for complex development of differentiated human induced pluripotent stem cells. However, this approach is not easily amenable to live-cell imaging and electrophysiological applications due to the thickness and the geometry of the tissue. Here, we present an improvement on the traditional aggregation method by combining the use of cell culture inserts with serum-free embryoid bodies (SFEBs). The use of this technique allows the structures to maintain their three-dimensional structure while thinning substantially. We demonstrate that this technique can be used for electrophysiological recodings as well as live-cell calcium imaging combined with electrical stimulation, akin to organotypic slice preparations. This provides an important experimental tool that can be used to bridge 3-D structures with traditional monolayer approaches used in stem cell applications. [Copyright &y& Elsevier]

Background: Cognitive dysfunction and cerebral vascular accidents remain some of the most devastating problems related to cardiac surgery. Despite the major advances in perioperative care and operative technique in coronary artery bypass, this cohort of patients appears to have poor cerebral physiologic reserve. The aim of this study was to describe regional cerebral perfusion of patients with coronary artery disease referred for coronary artery bypass grafting. Methods: Eighty-two consecutive patients with coronary artery disease referred for coronary artery bypass grafting were enrolled after providing informed consent in an institutional review board–approved study. Patients with prior cerebral vascular accident, transient ischemic attacks, head trauma, or other neurologic afflictions were excluded from the study. We prospectively measured preoperative regional cerebral perfusion using single photon emission computed tomography (SPECT) imaging of 12 regions. Patients were determined to have an abnormal SPECT if regional cerebral perfusion was less than 2 standard deviations below the mean of age-matched controls. Results: The mean age was 67.5 (range, 34-89) years. The study group comprised 22% women and 78% men with known risk factors for atherosclerosis: current tobacco use (30%), hypertension (69%), and diabetes (27%). Seventy-five percent of the SPECT scans demonstrated abnormal regional cerebral perfusions, which were associated with older age (P < .008), current tobacco use (P < .005), and diabetes mellitus (P < .005). The incidence of postoperative cerebral vascular accident was 5% and only occurred in patients with abnormal regional cerebral perfusion. Conclusion: Seventy-five percent of patients undergoing coronary bypass grafting have a significant impairment in regional cerebral perfusion compared with published age-matched controls, which may contribute to their proclivity for cerebral complications. [Copyright &y& Elsevier]

Abstract: A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-d-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama–Itô cyclization, and a useful modification of the Barton decarboxylation protocol. [Copyright &y& Elsevier]