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Neuroendocrine tumors (NETs) are rare, heterogeneous, often indolent tumors that predominantly originate in the lungs and gastrointestinal tract. An understanding of the biology and tumor microenvironment of NETs has led to the development of molecularly targeted treatment options including somatostatin analogs, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors and peptide receptor radionuclide therapy. Although increases in progression-free survival have been demonstrated, most currently approved NET therapies are limited by the development of tumor resistance. Surufatinib (HMPL-012, previously known as sulfatinib) is a new, oral, small-molecule tyrosine kinase inhibitor that potently inhibits vascular endothelial growth-factor receptor 1–3, fibroblast growth-factor receptor 1, and colony-stimulating-factor-1 receptor. This unique combination of molecular activities inhibits tumor angiogenesis, regulates tumor-immune evasion, and may decrease tumor resistance. Surufatinib demonstrated statistically significant, clinically meaningful antitumor activity, including tumor shrinkage, in two phase III studies recently completed in China in advanced pancreatic NETs and advanced extrapancreatic NETs. The safety profile of surufatinib in neuroendocrine tumors studies was consistent with previous surufatinib clinical studies. In an ongoing study in United States (US) patients with NETs of pancreatic origin and NETs of extrapancreatic origin previously treated with everolimus or sunitinib, surufatinib has also demonstrated promising efficacy. Furthermore, the pharmacokinetic and safety profile of surufatinib in US patients is similar to data collected in studies done in China. These positive phase III results support the efficacy of surufatinib in patients with advanced, progressive, well-differentiated NETs regardless of tumor origin.

This article reviews the molecular structure, expression pattern, physiological function, pathological roles and mo- lecular mechanisms of Twistl in development, genetic disease and cancer. Twistl is a basic helix-loop-helix domain- containing transcription factor. It forms homo- or hetero-dimers in order to bind the Ndel E-box element and acti- vate or repress its target genes. During development, Twistl is essential for mesoderm specification and differentia- tion. Heterozygous loss-of-function mutations of the human Twistl gene cause several diseases including the Saethre- Chotzen syndrome. The Twistl-null mouse embryos die with unclosed cranial neural tubes and defective head mesen- chyme, somites and limb buds. Twistl is expressed in breast, liver, prostate, gastric and other types of cancers, and its expression is usually associated with invasive and metastatic cancer phenotypes. In cancer cells, Twistl is upregulated by multiple factors including SRC-1, STAT3, MSX2, HIF-la, integrin-linked kinase and NF-κB. Twistl significantly enhances epithelial-mesenchymal transition （EMT） and cancer cell migration and invasion, hence promoting cancer metastasis. Twistl promotes EMT in part by directly repressing E-cadherin expression by recruiting the nucleosome remodeling and deacetylase complex for gene repression and by upregulating Bmil, AKT2, YB-1, etc. Emerging evi- dence also suggests that Twistl plays a role in expansion and chemotherapeutic resistance of cancer stem cells. Fur- ther understanding of the mechanisms by which Twistl promotes metastasis and identification of Twistl functional modulators may hold promise for developing new strategies to inhibit EMT and cancer metastasis.

The relationship between metallic micronutrients and soil microorganisms, and thereby soil functioning, has been little explored. Here, we investigate the relationship between metallic micronutrients (Fe, Mn, Cu, Zn, Mo and Ni) and the abundance, diversity and function of soil microbiomes. In a survey across 180 sites in China, covering a wide range of soil conditions the structure and function of the soil microbiome are highly correlated with metallic micronutrients, especially Fe, followed by Mn, Cu and Zn. These results are robust to controlling for soil pH, which is often reported as the most important predictor of the soil microbiome. An incubation experiment with Fe and Zn additions for five different soil types also shows that increased micronutrient concentration affects microbial community composition and functional genes. In addition, structural equation models indicate that micronutrients positively contribute to the ecosystem productivity, both directly (micronutrient availability to plants) and, to a lesser extent, indirectly (via affecting the microbiome). Our findings highlight the importance of micronutrients in explaining soil microbiome structure and ecosystem functioning. Soil micronutrients may be important for belowground biota and associated functions. Here, the authors identify the relationships between metallic micronutrients and soil microbial communities and functions across 180 sites, and validate them in a soil incubation experiment.

Background and aims Soil microbiome is the key driver mediating soil P transformation in agroecosystems. However, the underlying genomic information related to soil P cycling in response to organic C inputs is largely unknown. Methods By using metagenomic sequencing, we investigated the effect of P fertilization and C input ( i.e. , glucose and lignin) on functional profiles of microbial genes related to P cycling in bulk and rhizosphere soils. Maize plants were grown for 47 days in Ultisols with or without P-fertilizer history. Results Glucose decreased rhizosphere H 2 O-P i concentrations in soil with P history, increased that in soil without P history; while lignin increased that in both soils. Ogranic C inputs increased the relative abundances of phnGHIJLMNP and pit genes by 17–138% and 2.3–31%, decreased those of phoB , phoR and pstABCS genes by 3.6–18%, 12–31% and 11–26%, respectively, in rhizosphere soils irrespective of P history. In the rhizosphere rather than bulk soil, the proportion of P starvation regulation-related genes was higher in lignin treated-soils without than with P history. Proteobacteria (10–89%) and Acidobacteria (0.41–57%) were the dominant phyla and main contributors to soil P transformation-related genes ( e.g. , appA , phoAD , gcd ). Elevated soil pH induced by organic C inputs also diversified the composition of genes involved in P transformation. Conclusions Organic C altered P cycling-related gene composition irrespective of soil P status, which facilitated P transformation. Proteobacteria and Acidobacteria were vital in mediating C and P metabolisms.

Air quality forecasting is crucial to reducing air pollution in China, which has detrimental effects on human health. Atmospheric chemical-transport models can provide air pollutant forecasts with high temporal and spatial resolution and are widely used for routine air quality predictions (e.g., 1–3 days in advance). However, the model’s performance is limited by uncertainties in the emission inventory and biases in the initial and boundary conditions, as well as deficiencies in the current chemical and physical schemes. As a result, experimentation with several new methods, such as machine learning, is occurring in the field of air quality forecasting. This study combined hourly PM 2.5 mass concentration forecasts from an operational air quality numerical prediction system (WRF-Chem) at the Shanghai Meteorological Service (SMS) with comprehensive near-surface measurements of air pollutants and meteorological conditions to develop a machine learning model that estimates the daily PM 2.5 mass concentration in Shanghai, China. With correlation coefficients that are higher by 50–100% and a standard deviation that is lower by 14–24 µg m –3 , the machine learning model provides significantly better daily forecasting of PM 2.5 than the WRF-Chem model. Thus, this research offers a new technique for enhancing air quality forecasting in China.

Cropland is a main source of global nitrogen pollution 1 , 2 . Mitigating nitrogen pollution from global croplands is a grand challenge because of the nature of non-point-source pollution from millions of farms and the constraints to implementing pollution-reduction measures, such as lack of financial resources and limited nitrogen-management knowledge of farmers 3 . Here we synthesize 1,521 field observations worldwide and identify 11 key measures that can reduce nitrogen losses from croplands to air and water by 30–70%, while increasing crop yield and nitrogen use efficiency (NUE) by 10–30% and 10–80%, respectively. Overall, adoption of this package of measures on global croplands would allow the production of 17 ± 3 Tg (10 12  g) more crop nitrogen (20% increase) with 22 ± 4 Tg less nitrogen fertilizer used (21% reduction) and 26 ± 5 Tg less nitrogen pollution (32% reduction) to the environment for the considered base year of 2015. These changes could gain a global societal benefit of 476 ± 123 billion US dollars (USD) for food supply, human health, ecosystems and climate, with net mitigation costs of only 19 ± 5 billion USD, of which 15 ± 4 billion USD fertilizer saving offsets 44% of the gross mitigation cost. To mitigate nitrogen pollution from croplands in the future, innovative policies such as a nitrogen credit system (NCS) could be implemented to select, incentivize and, where necessary, subsidize the adoption of these measures. A meta-analysis of 1,521 field observations from the past two decades led to the identification of 11 key measures to cost-effectively mitigate nitrogen pollution from global croplands.

Halving nitrogen pollution is crucial for achieving Sustainable Development Goals (SDGs). However, how to reduce nitrogen pollution from multiple sources remains challenging. Here we show that reactive nitrogen (Nr) pollution could be roughly halved by managed urban development in China by 2050, with NH 3 , NO x and N 2 O atmospheric emissions declining by 44%, 30% and 33%, respectively, and Nr to water bodies by 53%. While rural-urban migration increases point-source nitrogen emissions in metropolitan areas, it promotes large-scale farming, reducing rural sewage and agricultural non-point-source pollution, potentially improving national air and water quality. An investment of approximately US$ 61 billion in waste treatment, land consolidation, and livestock relocation yields an overall benefit of US$ 245 billion. This underscores the feasibility and cost-effectiveness of halving Nr pollution through urbanization, contributing significantly to SDG1 (No poverty), SDG2 (Zero hunger), SDG6 (Clean water), SDG12 (Responsible consumption and production), SDG14 (Climate Action), and so on. Here the authors demonstrate how managed urbanization in China could halve reactive nitrogen pollution to both the atmosphere and water resources. Investing 61 billion USD could provide 245 billion USD in benefits, while contributing to multiple SDG goals.

Soil harbors a vast expanse of unidentified microbes, termed as microbial dark matter, presenting an untapped reservoir of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conduct a large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalogue) from 3304 soil metagenomes. We identify 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which expand archaeal and bacterial diversity across the tree of life. We also illustrate the pivotal role of uSGBs in augmenting soil microbiome’s functional landscape and intra-species genome diversity, providing large proportions of the 43,169 biosynthetic gene clusters and 8545 CRISPR-Cas genes. Additionally, we determine that uSGBs contributed 84.6% of previously unexplored viral-host associations from the SMAG catalogue. The SMAG catalogue provides an useful genomic resource for further studies investigating soil microbial biodiversity and genetic resources. Soil conceals a vast realm of unexplored microbes, often referred to as the “microbial dark matter.” This hidden universe boasts a rich tapestry of microbial and genetic biodiversity. Here, the authors introduce the SMAG catalogue, comprising of 40,039 metagenome-assembled genomes from 3304 soil metagenomes, and uncovering 21,077 species-level genome bins.

Human epidermal growth factor receptor 2 ( HER2 , also known as ERBB2 ) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas 1 – 3 . More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours 4 . Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer 5 , there are preclinical 6 – 19 and clinical 20 , 21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma 22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate. Interim analysis of a phase III clinical trial of HER2-positive gastric adenocarinoma shows pembrolizumab plus trastuzumab and chemotherapy improves response rates compared with trastuzumab and chemotherapy alone.

Heavy metal contamination poses an escalating global challenge to soil ecosystems, with hyperaccumulators playing a crucial role in environmental remediation and resource recovery. The enrichment of diazotrophs and resulting nitrogen accumulation promoted hyperaccumulator growth and facilitated phytoremediation. Nonetheless, the regulatory mechanism of hyperaccumulator biological nitrogen fixation has remained elusive. Here, we report the mechanism by which arsenic regulates biological nitrogen fixation in the arsenic-hyperaccumulator Pteris vittata . Field investigations and greenhouse experiments, based on multi-omics approaches, reveal that elevated arsenic stress induces an enrichment of key diazotrophs, enhances plant nitrogen acquisition, and thus improves plant growth. Metabolomic analysis and microfluidic experiments further demonstrate that the upregulation of specific root metabolites plays a crucial role in recruiting key diazotrophic bacteria. These findings highlight the pivotal role of nitrogen-acquisition mechanisms in the arsenic hyperaccumulation of Pteris vittata , and provide valuable insights into the plant stress resistance. Elevated arsenic is found to enhance plant nitrogen acquisition and plant growth of the arsenic hyperaccumulator Pteris vittate . Multi-omics analysis reveals the interaction between root metabolites and key diazotrophs underlying this effect.