资源环境科技发展态势分析平台

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma(1,2). KRAS(G12C) inhibitors(3,4) are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation(4-6), and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.

Characterization of 22-nucleotide short interfering RNAs in plants finds that they accumulate in response to environmental stress, causing translational repression, inhibition of plant growth and enhanced stress responses.

Small interfering RNAs (siRNAs) are essential for proper development and immunity in eukaryotes(1). Plants produce siRNAs with lengths of 21, 22 or 24 nucleotides. The 21- and 24-nucleotide species mediate cleavage of messenger RNAs and DNA methylation(2,3), respectively, but the biological functions of the 22-nucleotide siRNAs remain unknown. Here we report the identification and characterization of a group of endogenous 22-nucleotide siRNAs that are generated by the DICER-LIKE 2 (DCL2) protein in plants. When cytoplasmic RNA decay and DCL4 are deficient, the resulting massive accumulation of 22-nucleotide siRNAs causes pleiotropic growth disorders, including severe dwarfism, meristem defects and pigmentation. Notably, two genes that encode nitrate reductases-NIA1 and NIA2-produce nearly half of the 22-nucleotide siRNAs. Production of 22-nucleotide siRNAs triggers the amplification of gene silencing and induces translational repression both gene specifically and globally. Moreover, these 22-nucleotide siRNAs preferentially accumulate upon environmental stress, especially those siRNAs derived from NIA1/2, which act to restrain translation, inhibit plant growth and enhance stress responses. Thus, our research uncovers the unique properties of 22-nucleotide siRNAs, and reveals their importance in plant adaptation to environmental stresses.

Carbon dioxide enrichment of a mature forest resulted in the emission of the excess carbon back into the atmosphere via enhanced ecosystem respiration, suggesting that mature forests may be limited in their capacity to mitigate climate change.

Atmospheric carbon dioxide enrichment (eCO(2)) can enhance plant carbon uptake and growth(1-5), thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration(6). Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth(3-5), it is unclear whether mature forests respond to eCO(2) in a similar way. In mature trees and forest stands(7-10), photosynthetic uptake has been found to increase under eCO(2) without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO(2) unclear(4,5,7-11). Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO(2) exposure. We show that, although the eCO(2) treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO(2), and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.

River deltas rank among the most economically and ecologically valuable environments on Earth. Even in the absence of sea-level rise, deltas are increasingly vulnerable to coastal hazards as declining sediment supply and climate change alter their sediment budget, affecting delta morphology and possibly leading to erosion(1-3). However, the relationship between deltaic sediment budgets, oceanographic forces of waves and tides, and delta morphology has remained poorly quantified. Here we show how the morphology of about 11,000 coastal deltas worldwide, ranging from small bayhead deltas to mega-deltas, has been affected by river damming and deforestation. We introduce a model that shows that present-day delta morphology varies across a continuum between wave (about 80 per cent), tide (around 10 per cent) and river (about 10 per cent) dominance, but that most large deltas are tide- and river-dominated. Over the past 30 years, despite sea-level rise, deltas globally have experienced a net land gain of 54 +/- 12 square kilometres per year (2 standard deviations), with the largest 1 per cent of deltas being responsible for 30 per cent of all net land area gains. Humans are a considerable driver of these net land gains-25 per cent of delta growth can be attributed to deforestation-induced increases in fluvial sediment supply. Yet for nearly 1,000 deltas, river damming(4) has resulted in a severe (more than 50 per cent) reduction in anthropogenic sediment flux, forcing a collective loss of 12 +/- 3.5 square kilometres per year (2 standard deviations) of deltaic land. Not all deltas lose land in response to river damming: deltas transitioning towards tide dominance are currently gaining land, probably through channel infilling. With expected accelerated sea-level rise(5), however, recent land gains are unlikely to be sustained throughout the twenty-first century. Understanding the redistribution of sediments by waves and tides will be critical for successfully predicting human-driven change to deltas, both locally and globally.

A global study of river deltas shows a net increase in delta area by about 54 km(2) yr(-1) over the past 30 years, in part due to deforestation-induced sediment delivery increase.

In a mouse model of glioblastoma, treatment with VEGF-C increases lymphatic drainage in the central nervous system and improves the immune response, suggesting that modulating meningeal lymphatics could enhance checkpoint inhibitor therapy.

Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain(1-3). Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours.