资源环境科技发展态势分析平台

Enhanced silicate rock weathering (ERW), deployable with croplands, has potential use for atmospheric carbon dioxide (CO2) removal (CDR), which is now necessary to mitigate anthropogenic climate change(1). ERW also has possible co-benefits for improved food and soil security, and reduced ocean acidification(2-4). Here we use an integrated performance modelling approach to make an initial techno-economic assessment for 2050, quantifying how CDR potential and costs vary among nations in relation to business-as-usual energy policies and policies consistent with limiting future warming to 2 degrees Celsius(5). China, India, the USA and Brazil have great potential to help achieve average global CDR goals of 0.5 to 2gigatonnes of carbon dioxide (CO2) per year with extraction costs of approximately US$80-180 per tonne of CO2. These goals and costs are robust, regardless of future energy policies. Deployment within existing croplands offers opportunities to align agriculture and climate policy. However, success will depend upon overcoming political and social inertia to develop regulatory and incentive frameworks. We discuss the challenges and opportunities of ERW deployment, including the potential for excess industrial silicate materials (basalt mine overburden, concrete, and iron and steel slag) to obviate the need for new mining, as well as uncertainties in soil weathering rates and land-ocean transfer of weathered products.

A microscopy system that enables simultaneous recording from hundreds of neurons in the mouse visual cortex reveals that the brain enhances its coding capacity by representing visual inputs in dimensions perpendicular to correlated noise.

Adipose tissue is an energy store and a dynamic endocrine organ(1,2). In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism(3,4). Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes(5,6). Regulatory T (T-reg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT(7-9). Here we uncover pronounced sexual dimorphism in T-reg cells in the VAT. Male VAT was enriched for T-reg cells compared with female VAT, and T-reg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T-reg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T-reg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T-reg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T-reg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.

Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.

ABBV-744, a selective inhibitor of the BD2 domains of BET family proteins, is effective against prostate cancer in mouse xenograft models, with lower toxicities than the dual-bromodomain BET inhibitor ABBV-075.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi(1-5). Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice(6), the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions(7-9) and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported(10,11), suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment(10-13). Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-075(14). Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.