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Therapeutic vulnerabilities and pan-cancer landscape of BRAF class III mutations in epithelial solid tumors

Kinase-impaired class III BRAF mutations have recently received attention as a possible prognostic factor and therapeutic target. Class III BRAF variants differ from class I and class II mutations in terms of mechanism of pathway activation and therapeutic vulnerabilities. Genomic landscape analyses of tumors in large real-world cohorts represent a great opportunity to further characterize tumor-related molecular events and treatment vulnerabilities, however, such data is not yet available for tumors with BRAF class III mutations.

Two-tiered mutualism improves survival and competitiveness of cross-feeding soil bacteria

Metabolic cross-feeding is a pervasive microbial interaction type that affects community stability and functioning and directs carbon and energy flows. The mechanisms that underlie these interactions and their association with metal/metalloid biogeochemistry, however, remain poorly understood. Here, we identified two soil bacteria, Bacillus sp. BP-3 and Delftia sp. DT-2, that engage in a two-tiered mutualism. Strain BP-3 has low utilization ability of pyruvic acid while strain DT-2 lacks hexokinase, lacks a phosphotransferase system, and is defective in glucose utilization. When strain BP-3 is grown in isolation with glucose, it releases pyruvic acid to the environment resulting in acidification and eventual self-killing. However, when strain BP-3 is grown together with strain DT-2, strain DT-2 utilizes the released pyruvic acid to meet its energy requirements, consequently rescuing strain BP-3 from pyruvic acid-induced growth inhibition. The two bacteria further enhance their collective competitiveness against other microbes by using arsenic as a weapon. Strain DT-2 reduces relatively non-toxic methylarsenate [MAs(V)] to highly toxic methylarsenite [MAs(III)], which kills or suppresses competitors, while strain BP-3 detoxifies MAs(III) by methylation to non-toxic dimethylarsenate [DMAs(V)]. These two arsenic transformations are enhanced when strains DT-2 and BP-3 are grown together. The two strains, along with their close relatives, widely co-occur in soils and their abundances increase with the soil arsenic concentration. Our results reveal that these bacterial types employ a two-tiered mutualism to ensure their collective metabolic activity and maintain their ecological competitive against other soil microbes. These findings shed light on the intricateness of bacterial interactions and their roles in ecosystem functioning.

Genomic evidence that microbial carbon degradation is dominated by iron redox metabolism in thawing permafrost

Microorganisms drive many aspects of organic carbon cycling in thawing permafrost soils, but the compositional trajectory of the post-thaw microbiome and its metabolic activity remain uncertain, which limits our ability to predict permafrost–climate feedbacks in a warming world. Using quantitative metabarcoding and metagenomic sequencing, we determined relative and absolute changes in microbiome composition and functional gene abundance during thaw incubations of wet sedge tundra collected from northern Alaska, USA. Organic soils from the tundra active-layer (0–50 cm), transition-zone (50–70 cm), and permafrost (70+ cm) depths were incubated under reducing conditions at 4 °C for 30 days to mimic an extended thaw duration. Following extended thaw, we found that iron (Fe)-cycling Gammaproteobacteria, specifically the heterotrophic Fe(III)-reducing Rhodoferax sp. and chemoautotrophic Fe(II)-oxidizing Gallionella sp., increased by 3–5 orders of magnitude in absolute abundance within the transition-zone and permafrost microbiomes, accounting for 65% of community abundance. We also found that the abundance of genes for Fe(III) reduction (e.g., MtrE) and Fe(II) oxidation (e.g., Cyc1) increased concurrently with genes for benzoate degradation and pyruvate metabolism, in which pyruvate is used to generate acetate that can be oxidized, along with benzoate, to CO2 when coupled with Fe(III) reduction. Gene abundance for CH4 metabolism decreased following extended thaw, suggesting dissimilatory Fe(III) reduction suppresses acetoclastic methanogenesis under reducing conditions. Our genomic evidence indicates that microbial carbon degradation is dominated by iron redox metabolism via an increase in gene abundance associated with Fe(III) reduction and Fe(II) oxidation during initial permafrost thaw, likely increasing microbial respiration while suppressing methanogenesis in wet sedge tundra.

Synthesis and reactivity of an antimony(III) dication

The proximity effect, frequently encountered in enzyme catalysis, entails bringing two or more molecules close together, forcing a reaction to occur. The presence of multiple binding sites at the active centre is required to facilitate the preorganization of reactants prior to reaction. We investigate this concept in a main-group compound by accessing a tricoordinate antimony dication, [TpMe2Sb]2+, where TpMe2 = tris(3,5-dimethylpyrazolyl)borate, that is charge balanced by two [B(C6F5)4] anions. [TpMe2Sb]2+ readily reacts with anionic (X) and neutral (L) donor ligands, resulting in stable disphenoidal geometry complexes of the types [TpMe2SbX]+ and [TpMe2SbL]2+, respectively. Consequently, [TpMe2Sb(HNPh2)]2+ was obtained upon the addition of HNPh2 to the dication. As evidenced by density functional theory calculations, further treatment of [TpMe2Sb(HNPh2)]2+ with styrene resulted in a weak van der Waals interaction between the arene ring and the 5s lone pair on the antimony centre, eventually facilitating a hydroamination reaction. Our investigations open avenues for exploring intermolecular processes promoted by low-oxidation-state heavier main-group compounds.

Enantioselective C–H annulations enabled by either nickel- or cobalt-electrocatalysed C–H activation for catalyst-controlled chemodivergence

Enantioselective electrocatalysis shows unique potential for the sustainable assembly of enantiomerically enriched molecules. This approach allows electro-oxidative C–H activation to be performed paired to the hydrogen evolution reaction. Recent progress has featured scarce transition metals with limited availability. Here we reveal that the earth-abundant 3d transition metals nickel and cobalt exhibit distinctive performance for enantioselective electrocatalysis with chemodivergent reactivity patterns. Enantioselective desymmetrizations of strained bicyclic alkenes were achieved through C–H annulations. A data-driven optimization of chiral N,O-bidentate salicyloxazoline-type ligands was crucial for enhancing enantioselectivity in nickel electrocatalysis. Notably, in the transition state of the enantio-determining step, secondary weak attractive ππ and CH–π interactions were identified, reflecting the informed adaptations in the ligand design. Detailed mechanistic investigations by experimental and computational studies revealed for the nickel electrocatalysis a C–N bond-forming reductive elimination from nickel(III) and for the cobalt electrocatalysis a C–C bond-forming nucleophilic addition from cobalt(III) as the product-determining steps.

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