RESUMEN
Tandem catalysis enables the rapid construction of complex architectures from simple building blocks. This Perspective shares our interest in combining stereoselective hydrogenation with transformations such as isomerization, oxidation, and epimerization to solve diverse challenges. We highlight the use of tandem hydrogenation for preparing complex natural products from simple prochiral building blocks and present tandem catalysis involving transfer hydrogenation and dynamic kinetic resolution. Finally, we underline recent breakthroughs and opportunities for asymmetric hydrogenation.
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Compuestos Orgánicos/síntesis química , Catálisis , Hidrogenación , Estructura Molecular , Compuestos Orgánicos/química , Oxidación-Reducción , EstereoisomerismoRESUMEN
By using Rh-H catalysis, we couple α-nitroesters and alkynes to prepare α-amino-acid precursors. This atom-economical strategy generates two contiguous stereocenters, with high enantio- and diastereocontrol. In this transformation, the alkyne undergoes isomerization to generate a RhIII -π-allyl electrophile, which is trapped by an α-nitroester nucleophile. A subsequent reduction with In powder transforms the allylic α-nitroesters to the corresponding α,α-disubstituted α-amino esters.
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Alquinos/química , Ésteres/química , Aminoácidos/química , Catálisis , Complejos de Coordinación/química , Hidrógeno/química , Rodio/química , EstereoisomerismoRESUMEN
The anatomical and functional architecture of the human brain is mainly determined by prenatal transcriptional processes. We describe an anatomically comprehensive atlas of the mid-gestational human brain, including de novo reference atlases, in situ hybridization, ultra-high-resolution magnetic resonance imaging (MRI) and microarray analysis on highly discrete laser-microdissected brain regions. In developing cerebral cortex, transcriptional differences are found between different proliferative and post-mitotic layers, wherein laminar signatures reflect cellular composition and developmental processes. Cytoarchitectural differences between human and mouse have molecular correlates, including species differences in gene expression in subplate, although surprisingly we find minimal differences between the inner and outer subventricular zones even though the outer zone is expanded in humans. Both germinal and post-mitotic cortical layers exhibit fronto-temporal gradients, with particular enrichment in the frontal lobe. Finally, many neurodevelopmental disorder and human-evolution-related genes show patterned expression, potentially underlying unique features of human cortical formation. These data provide a rich, freely-accessible resource for understanding human brain development.
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Encéfalo/metabolismo , Feto/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Transcriptoma , Anatomía Artística , Animales , Atlas como Asunto , Encéfalo/embriología , Secuencia Conservada/genética , Feto/citología , Feto/embriología , Redes Reguladoras de Genes/genética , Humanos , Ratones , Neocórtex/embriología , Neocórtex/metabolismo , Especificidad de la EspecieRESUMEN
An efficient synthesis of S-allyl thioimidate hydrobromide salts via coupling of thioamides with allyl bromide derivatives is described. A range of mono-, di-, and trisubstituted olefins as well as alkyl- and arylthioamides with variations in electronics are tolerated. A rapid anti-diastereoselective halocyclization of these salts provides a variety of substituted alkyl- and arylthiazolines. Initial development of an efficient enantioselective synthesis of quaternary-substituted thiazolines through the organo-catalyzed halocyclization of sulfonate thioimidate salts is also described.
RESUMEN
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of â¼900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography-the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
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Anatomía Artística , Atlas como Asunto , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Perfilación de la Expresión Génica , Transcriptoma/genética , Adulto , Animales , Encéfalo/citología , Calbindinas , Bases de Datos Genéticas , Dopamina/metabolismo , Salud , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Hibridación in Situ , Internet , Macaca mulatta/anatomía & histología , Macaca mulatta/genética , Masculino , Ratones , Neocórtex/anatomía & histología , Neocórtex/citología , Neocórtex/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Densidad Postsináptica/genética , ARN Mensajero/análisis , ARN Mensajero/genética , Proteína G de Unión al Calcio S100/genética , Especificidad de la EspecieRESUMEN
UNLABELLED: Spreading depolarizations (SDs) are recognized as actors in neurological disorders as diverse as migraine and traumatic brain injury (TBI). Migraine aura involves sensory percepts, suggesting that sensory cortices might be intrinsically susceptible to SDs. We used optical imaging, MRI, and field potential and potassium electrode recordings in mice and electrocorticographic recordings in humans to determine the susceptibility of different brain regions to SDs. Optical imaging experiments in mice under isoflurane anesthesia showed that both cortical spreading depression and terminal anoxic depolarization arose preferentially in the whisker barrel region of parietal sensory cortex. MRI recordings under isoflurane, ketamine/xylazine, ketamine/isoflurane, and urethane anesthesia demonstrated that the depolarizations did not propagate from a subcortical source. Potassium concentrations showed larger increases in sensory cortex, suggesting a mechanism of susceptibility. Sensory stimulation biased the timing but not the location of depolarization onset. In humans with TBI, there was a trend toward increased incidence of SDs in parietal/temporal sensory cortex compared with other regions. In conclusion, SDs are inducible preferentially in primary sensory cortex in mice and most likely in humans. This tropism can explain the predominant sensory phenomenology of migraine aura. It also demonstrates that sensory cortices are vulnerable in brain injury. SIGNIFICANCE STATEMENT: Spreading depolarizations (SDs) are involved in neurologic disorders as diverse as migraine and traumatic brain injury. In migraine, the nature of aura symptoms suggests that sensory cortex may be preferentially susceptible. In brain injury, SDs occur at a vulnerable time, during which the issue of sensory stimulation is much debated. We show, in mouse and human, that sensory cortex is more susceptible to SDs. We find that sensory stimulation biases the timing but not the location of the depolarizations. Finally, we show a relative impairment of potassium clearance in sensory cortex, providing a potential mechanism for the susceptibility. Our data help to explain the sensory nature of the migraine aura and reveal that sensory cortices are vulnerable in brain injury.
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Depresión de Propagación Cortical/efectos de los fármacos , Depresión de Propagación Cortical/fisiología , Corteza Somatosensorial/efectos de los fármacos , Animales , Lesiones Encefálicas/fisiopatología , Humanos , Ketamina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Migrañosos/fisiopatología , Cloruro de Potasio/administración & dosificaciónRESUMEN
Migraine with aura is a common but poorly understood sensory circuit disorder. Monogenic models allow an opportunity to investigate its mechanisms, including spreading depolarization (SD), the phenomenon underlying migraine aura. Using fluorescent glutamate imaging, we show that awake mice carrying a familial hemiplegic migraine type 2 (FHM2) mutation have slower clearance during sensory processing, as well as previously undescribed spontaneous "plumes" of glutamate. Glutamatergic plumes overlapped anatomically with a reduced density of GLT-1a-positive astrocyte processes and were mimicked in wild-type animals by inhibiting glutamate clearance. Plume pharmacology and plume-like neural Ca2+ events were consistent with action-potential-independent spontaneous glutamate release, suggesting plumes are a consequence of inefficient clearance following synaptic release. Importantly, a rise in basal glutamate and plume frequency predicted the onset of SD in both FHM2 and wild-type mice, providing a novel mechanism in migraine with aura and, by extension, the other neurological disorders where SD occurs.
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Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Migraña con Aura/genética , Migraña con Aura/metabolismo , Modelos Genéticos , Transducción de Señal/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Técnicas de Cultivo de ÓrganosRESUMEN
Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application. In the current study, we synthesized two bilirubin analogs that can be produced without the use of animal-derived products. Antioxidant activity for the analogs was measured using the ferric-reducing-ability-of-plasma (FRAP) and 2,2V-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. Dose-dependent cytotoxicity and cytoprotective effects were then demonstrated in isolated rat islets. Compound 1 showed similar antioxidant activity to natural bilirubin. Dose-dependent cytotoxicity was seen following treatment with Compound 1 and natural bilirubin at doses >40 µM, resulting in significantly increased cell death when compared to control islets (P < 0.05) or islets treated with doses ≤20 µM (P < 0.05). Following hypoxic challenge, islet cell death was reduced in islets treated with Compound 1 at 10 µM (17.27% ± 0.26%) compared to natural bilirubin at 10 µM (51.36% ± 0.71%; P < 0.0001) or 20 µM (59.02% ± 0.83%; P < 0.0001) and control islets (36.51% ± 0.44%; P < 0.0001). Compound 1 was found to have promising antioxidant and cytoprotective effects, limiting islet cell death in a model of islet transplantation hypoxic stress. Compound 1 may serve as a synthetic drug lead for clinical islet transplantation and further evaluation of this molecule and its analogs is warranted.
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Antioxidantes/síntesis química , Bilirrubina/análogos & derivados , Bilirrubina/síntesis química , Trasplante de Islotes Pancreáticos/métodos , Animales , Antioxidantes/química , Bilirrubina/química , Supervivencia Celular/fisiología , Recuperación de Fluorescencia tras Fotoblanqueo , Estructura Molecular , PorcinosRESUMEN
Over one-third of adults are at risk of developing sleep disorders. Telemedicine is emerging as an effective tool in sleep medicine by allowing people to undergo sleep studies without overnight hospital stays (e.g. monitoring at home). Telemedicine has the potential to overcome several obstacles in the diagnosis and treatment of sleep disorders by offering increased access to sleep specialists, enhancing health-care support for patients in their homes and providing cost-effective professional education. The initial costs for telemedicine equipment and training are not insignificant; however, the benefits may outweigh the expense over time. However, recapturing the initial costs cannot be assumed.
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Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/terapia , Telemedicina/organización & administración , Atención a la Salud/economía , Humanos , Polisomnografía/tendencias , Trastornos del Sueño-Vigilia/economía , Telemedicina/economíaRESUMEN
An estimated 5 million Americans have congestive heart failure (CHF) and one in five over the age of 40 will develop CHF. There are numerous examples of CHF patients living beyond the years normally expected for people with the disease, usually attributed to taking an active role in disease management. A relatively new alternative for CHF outpatient care is telemedicine and e-health. We investigated the effects of a 6-week in-home telemedicine education and monitoring program for those with systolic dysfunction on the utilization of health care resources. We also measured the effects of the unit 4.5 months after its removal (a total of 6 months post introduction of the unit into the home). Concurrently, we assessed participants' perceptions of the value of having a telemedicine unit. Participants in the telemedicine group reported weighing more times a week with less variability than did the control group. Telemedicine led to a reduction in physician and emergency department visits and those in the experimental group reported the unit facilitating self-care, though this was not significantly different from the control group (possibly due to small sample size). These findings suggest a possibility for improvement in control of CHF when telemedicine is implemented. Our review of the literature also supports the role of telemedicine in facilitating home health care and self-management for CHF patients. There are many challenges still to be addressed before this potential can be reached and further research is needed to identify opportunities in telemedicine.