Preparation of anti-vicinal amino alcohols: asymmetric synthesis of D-erythro-Sphinganine, (+)-spisulosine and D-ribo-phytosphingosine

Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM-ether directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor D-erythro-sphinganine and the antitumor agent (+)-spisulosine, while the Overman rearrangement of chiral allylic trichloroacetimidates generated by asymmetric reduction of an alpha,beta-unsaturated methyl ketone allowed rapid access to both D-ribo-phytosphingosine and L-arabino-phytosphingosine

A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies

Biochemical metabolism of young plants of Ucuúba (Virola surinamensis) in the presence of cadmium.

Virola surinamensis is a forest species widely distributed in the estuaries of the Amazon. These ecosystems are susceptible to contamination by Cadmium (Cd), indicating that the plant has strategies for tolerating this metal. The aim of this study was to assess the nitrogen and carbon metabolism of young plants of Ucuúba (Virola surinamensis) in the presence of cadmium with the perspective of the phytoremediation of contaminated environments. The used experimental design was a completely randomized design with five Cd concentrations (0,15, 30, 45, and 60 mg L? 1), for 60 days. In general, Cd did not affect nitrate concentration in the root but had a positive effect on leaves. The reduction of nitrate reductase (NR) in plants exposed to Cd was followed by a decrease in ammonia, total soluble amino acids (TSA), and total soluble proteins (TSP). Cd promoted an increase in the concentration of total soluble carbohydrates (TSC), proline, sucrose, and reducing sugars in the plants. The increas

Refined physical parameters for Chariklo's body and rings from stellar occultations observed between 2013 and 2020

Context. The Centaur (10199) Chariklo has the first ring system discovered around a small object. It was first observed using stellar occultation in 2013. Stellar occultations allow sizes and shapes to be determined with kilometre accuracy, and provide the characteristics of the occulting object and its vicinity. Aims. Using stellar occultations observed between 2017 and 2020, our aim is to constrain the physical parameters of Chariklo and its rings. We also determine the structure of the rings, and obtain precise astrometrical positions of Chariklo. Methods. We predicted and organised several observational campaigns of stellar occultations by Chariklo. Occultation light curves were measured from the datasets, from which ingress and egress times, and the ring widths and opacity values were obtained. These measurements, combined with results from previous works, allow us to obtain significant constraints on Chariklo's shape and ring structure. Results. We characterise Chariklo's ring system (C1R and C2R), and obtain radii and pole orientations that are consistent with, but more accurate than, results from previous occultations. We confirm the detection of W-shaped structures within C1R and an evident variation in radial width. The observed width ranges between 4.8 and 9.1 km with a mean value of 6.5 km. One dual observation (visible and red) does not reveal any differences in the C1R opacity profiles, indicating a ring particle size larger than a few microns. The C1R ring eccentricity is found to be smaller than 0.022 (3σ), and its width variations may indicate an eccentricity higher than ~0.005. We fit a tri-axial shape to Chariklo's detections over 11 occultations, and determine that Chariklo is consistent with an ellipsoid with semi-axes of 143.8-1.5+1.4, 135.2-2.8+1.4, and 99.1-2.7+5.4 km. Ultimately, we provided seven astrometric positions at a milliarcsecond accuracy level, based on Gaia EDR3, and use it to improve Chariklo's ephemeris.Fil: Morgado, B.E.. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Sicardy, Bruno. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Braga Ribas, Felipe. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; Brasil. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Universidade Tecnologia Federal do Parana; BrasilFil: Desmars, Josselin. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Gomes Júnior, Altair Ramos. Universidade de Sao Paulo; BrasilFil: Bérard, D.. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Leiva, Rodrigo. Universidad de Chile; Chile. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Vieira Martins, Roberto. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Benedetti Rossi, G.. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Universidade Federal de Sao Paulo; BrasilFil: Santos Sanz, Pablo. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Camargo, Julio Ignacio Bueno. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Duffard, R.. Universidade Federal do Rio de Janeiro; BrasilFil: Rommel, F.L.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Assafin, M.. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Boufleur, R.C.. Universidad Nacional de Córdoba; ArgentinaFil: Colas, F.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Kretlow, Mike. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Beisker, W.. University of North Carolina; Estados UnidosFil: Sfair, Rafael. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Snodgrass, Colin. University of Edinburgh; Reino UnidoFil: Morales, N.. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Fernández Valenzuela, E.. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Amaral, L.S.. Massachusetts Institute of Technology; Estados UnidosFil: Amarante, A.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Artola, R.A.. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Backes, M.. Universidad Nacional de Córdoba; ArgentinaFil: Bath, K. L.. University of North Carolina; Estados UnidosFil: Bouley, S.. University of St. Andrews; Reino UnidoFil: Garcia Lambas, Diego Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; ArgentinaFil: Schneiter, Ernesto Matías. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Ingeniería Económica y Legal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; Argentin

The Genomic and Immune Landscapes of Lethal Metastatic Breast Cancer.

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.CRUK