Tumor cell α3β1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis

Arrest of circulating tumor cells in distant organs is required for hematogenous metastasis, but the tumor cell surface molecules responsible have not been identified. Here, we show that the tumor cell α3β1 integrin makes an important contribution to arrest in the lung and to early colony formation. These analyses indicated that pulmonary arrest does not occur merely due to size restriction, and raised the question of how the tumor cell α3β1 integrin contacts its best-defined ligand, laminin (LN)-5, a basement membrane (BM) component. Further analyses revealed that LN-5 is available to the tumor cell in preexisting patches of exposed BM in the pulmonary vasculature. The early arrest of tumor cells in the pulmonary vasculature through interaction of α3β1 integrin with LN-5 in exposed BM provides both a molecular and a structural basis for cell arrest during pulmonary metastasis

D-LMBmap: a fully automated deep-learning pipeline for whole-brain profiling of neural circuitry.

Acknowledgements: This work was supported by the Medical Research Council, as part of United Kingdom Research and Innovation (UK Research and Innovation) (MC_UP_1201/22). For the purpose of open access, the Medical Research Council Laboratory of Molecular Biology has applied a CC BY public copyright license to any Author Accepted Manuscript version arising. This work was also partially funded by NARSAD Young Investigator Award (2020, BBRF) to J.R. and Ministry of Science and Technology (2022ZD0206700) and the Beijing Municipal Government of P.R.C. to R.L. We thank D. Friedmann for advice on Adipo-Clear, J. Kebschull and D. Friedmann for data sharing, and L. Luo, M. Hastings, A.M.J. Adams and J. Song for critique on the manuscript.Funder: Medical Research Council, as part of the United Kingdom Research and Innovation, MC_UP_1201/22Recent proliferation and integration of tissue-clearing methods and light-sheet fluorescence microscopy has created new opportunities to achieve mesoscale three-dimensional whole-brain connectivity mapping with exceptionally high throughput. With the rapid generation of large, high-quality imaging datasets, downstream analysis is becoming the major technical bottleneck for mesoscale connectomics. Current computational solutions are labor intensive with limited applications because of the exhaustive manual annotation and heavily customized training. Meanwhile, whole-brain data analysis always requires combining multiple packages and secondary development by users. To address these challenges, we developed D-LMBmap, an end-to-end package providing an integrated workflow containing three modules based on deep-learning algorithms for whole-brain connectivity mapping: axon segmentation, brain region segmentation and whole-brain registration. D-LMBmap does not require manual annotation for axon segmentation and achieves quantitative analysis of whole-brain projectome in a single workflow with superior accuracy for multiple cell types in all of the modalities tested

Renewable fatty acid ester production in Clostridium

Bioproduction of renewable chemicals is considered as an urgent solution for fossil energy crisis. However, despite tremendous efforts, it is still challenging to generate microbial strains that can produce target biochemical to high levels. Here, we report an example of biosynthesis of high-value and easy-recoverable derivatives built upon natural microbial pathways, leading to improvement in bioproduction efficiency. By leveraging pathways in solventogenic clostridia for co-producing acyl-CoAs, acids and alcohols as precursors, through rational screening for host strains and enzymes, systematic metabolic engineering-including elimination of putative prophages, we develop strains that can produce 20.3 g/L butyl acetate and 1.6 g/L butyl butyrate. Techno-economic analysis results suggest the economic competitiveness of our developed bioprocess. Our principles of selecting the most appropriate host for specific bioproduction and engineering microbial chassis to produce high-value and easy-separable end products may be applicable to other bioprocesses.This article is published as Feng, Jun, Jie Zhang, Yuechao Ma, Yiming Feng, Shangjun Wang, Na Guo, Haijiao Wang et al. "Renewable fatty acid ester production in Clostridium." Nature Communications 12, no. 1 (2021): 4368. DOI: 10.1038/s41467-021-24038-3. Copyright 2021 The Author(s). Attribution 4.0 International (CC BY 4.0). Posted with permission

Renewable fatty acid ester production in Clostridium

Bioproduction of renewable chemicals is considered as an urgent solution for fossil energy crisis. However, despite tremendous efforts, it is still challenging to generate microbial strains that can produce target biochemical to high levels. Here, we report an example of biosynthesis of high-value and easy-recoverable derivatives built upon natural microbial pathways, leading to improvement in bioproduction efficiency. By leveraging pathways in solventogenic clostridia for co-producing acyl-CoAs, acids and alcohols as precursors, through rational screening for host strains and enzymes, systematic metabolic engineering-including elimination of putative prophages, we develop strains that can produce 20.3 g/L butyl acetate and 1.6 g/L butylbutyrate. Techno-economic analysis results suggest the economic competitiveness of our developed bioprocess. Our principles of selecting the most appropriate host for specific bioproduction and engineering microbial chassis to produce high-value and easy-separable end products may be applicable to other bioprocesses.La bioproducción de productos químicos renovables se considera una solución urgente para la crisis de la energía fósil. Sin embargo, a pesar de los tremendos esfuerzos, sigue siendo un desafío generar cepas microbianas que puedan producir bioquímicos objetivo a niveles altos. Aquí, presentamos un ejemplo de biosíntesis de derivados de alto valor y fáciles de recuperar construidos sobre rutas microbianas naturales, lo que lleva a una mejora en la eficiencia de la bioproducción. Aprovechando las vías de los clostridios solventogénicos para la coproducción de acil-CoAs, ácidos y alcoholes como precursores, mediante la detección racional de cepas y enzimas del hospedador, ingeniería metabólica sistemática, incluida la eliminación de profagos putativos, desarrollamos cepas que pueden producir 20,3 g / L de butilo. acetato y 1,6 g / l de butirato de butilo. Los resultados del análisis tecnoeconómico sugieren la competitividad económica de nuestro bioproceso desarrollado. Nuestros principios de seleccionar el anfitrión más apropiado para la bioproducción específica y la ingeniería de chasis microbianos para producir productos finales de alto valor y fáciles de separar pueden ser aplicables a otros bioprocesos.Universidad Nacional, Costa RicaEscuela de Quimic

Infrared nano-imaging of Dirac magnetoexcitons in graphene

Magnetic fields can have profound effects on the motion of electrons in quantum materials. Two-dimensional electron systems subject to strong magnetic fields are expected to exhibit quantized Hall conductivity, chiral edge currents and distinctive collective modes referred to as magnetoplasmons and magnetoexcitons. Generating these propagating collective modes in charge-neutral samples and imaging them at their native nanometre length scales have thus far been experimentally elusive. Here we visualize propagating magnetoexciton polaritons at their native length scales and report their magnetic-field-tunable dispersion in near-charge-neutral graphene. Imaging these collective modes and their associated nano-electro-optical responses allows us to identify polariton-modulated optical and photo-thermal electric effects at the sample edges, which are the most pronounced near charge neutrality. Our work is enabled by innovations in cryogenic near-field optical microscopy techniques that allow for the nano-imaging of the near-field responses of two-dimensional materials under magnetic fields up to 7 T. This nano-magneto-optics approach allows us to explore and manipulate magnetopolaritons in specimens with low carrier doping via harnessing high magnetic fields

Identification of recurrent USP48 and BRAF mutations in Cushing’s disease

Abstract Cushing’s disease results from corticotroph adenomas of the pituitary that hypersecrete adrenocorticotropin (ACTH), leading to excess glucocorticoid and hypercortisolism. Mutations of the deubiquitinase gene USP8 occur in 35–62% of corticotroph adenomas. However, the major driver mutations in USP8 wild-type tumors remain elusive. Here, we report recurrent mutations in the deubiquitinase gene USP48 (predominantly encoding p.M415I or p.M415V; 21/91 subjects) and BRAF (encoding p.V600E; 15/91 subjects) in corticotroph adenomas with wild-type USP8. Similar to USP8 mutants, both USP48 and BRAF mutants enhance the promoter activity and transcription of the gene encoding proopiomelanocortin (POMC), which is the precursor of ACTH, providing a potential mechanism for ACTH overproduction in corticotroph adenomas. Moreover, primary corticotroph tumor cells harboring BRAF V600E are sensitive to the BRAF inhibitor vemurafenib. Our study thus contributes to the understanding of the molecular mechanism of the pathogenesis of corticotroph adenoma and informs therapeutic targets for this disease