Aging of hematopoietic stem cells (HSCs) is associated with a decline in their regenerative capacity and multi-lineage differentiation potential, contributing to the development of blood disorders. The bone marrow microenvironment has recently been suggested to influence HSC aging, but the underlying mechanisms remain largely unknown. Here, we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as loss of SNS nerves or adrenoreceptor β3 (ADRβ3) signaling in the bone marrow microenvironment of young mice led to premature HSC aging, as evidenced by appearance of HSC phenotypes reminiscent of physiological aging. Strikingly, supplementation of a sympathomimetic acting selectively on ADRβ3 to old mice significantly rejuvenated the in vivo function of aged HSCs, suggesting that the preservation or restitution of bone marrow SNS innervation during aging may hold the potential for new HSC rejuvenation strategies.
Renal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell renal cell carcinomas that have no standard therapy. The oncogenic drivers in these tumours are unknown. Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays. We identify recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%) and MTOR (8%). Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo–YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome. FH deficiency (6%), chromatin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases. Altogether, this study reveals distinct molecular subsets for 76% of our uRCC cohort, which could have diagnostic and therapeutic implications.
tory mechanisms concerning the activation of WT mTORC1 have been proposed, which involves mTOR-interacting proteins RAG, Ras homolog enriched in brain (RHEB), DEP domain containing MTOR-interacting protein (DEPTOR), RAPTOR, PRAS40, and FKBP38 (2,[4][5][6][7][8][9][10]19,[60][61][62][63]. Indeed, a recent study surveyed cancer-derived mTOR activation mutations, which exploited the DEPTOR-centered mechanism (64). However, how activating mutations contribute to the pathogenesis of cancer, especially kidney cancer, and what molecular mechanisms underlie individual activating mutations beyond DEPTOR remain unknown.
The strengthening of polycrystalline metals based on grain refinement has previously been reported to be no longer effective below a critical grain size of approximately 10-15 nm (Refs. 1, 2). That report imposed a limit on grain size tuning for synthesizing stronger materials. Here, we report our study using a diamond-anvil cell coupled with radial X-ray diffraction to track in situ the yield stress and deformation texturing of pure nickel samples with various average grain sizes. Continuous strengthening isobserved from 200 nm to the minimum grain size of 3 nm. Strengthening as a function of grain size is enhanced in the lower grain size regime below 20 nm. We achieved an ultra-high strength of ~ 4.2 gigapascals in nickel, 10 times larger than the values for commercial nickel material. The maximum flow stress of 10.2 gigapascals is reached in 3 nm nickel in the pressure range of this study. Plasticity simulation and transmission electron microscopy (TEM) examination reveal that the high strength observed in 3 nm nickel is caused by the superposition of strengthening mechanisms: partial and full dislocation hardening plus grain boundary plasticity suppression. These results rejuvenate the search for ultra-strong metals via materials engineering.Understanding the strengthening of nanograined metals has been puzzling, as both mixed results of size softening and hardening have been reported [3][4][5][6] . The main challenges in resolving this debate are the difficulty in synthesizing high quality, ultrafine metal samples for traditional tension or hardness tests and making statistically reproducible measurements. Some researchers have pointed out that reported size softening may be related to materials preparation 7 . Porosity, amorphous regions and impurities may be introduced during sample preparation methods like inert gas condensation and electrodeposition, leading to softening in
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