HBI transcription factor-mediated ROS homeostasis regulates nitrate signal transduction.

Nitrate is both an important nutrient and a critical signaling molecule that regulates plant metabolism, growth, and development. Although several components of the nitrate signaling pathway have been identified, the molecular mechanism of nitrate signaling remains unclear. Here, we showed that the growth-related transcription factors HOMOLOG OF BRASSINOSTEROID ENHANCED EXPRESSION2 INTERACTING WITH IBH1 (HBI1) and its three closest homologs (HBIs) positively regulate nitrate signaling in Arabidopsis thaliana. HBI1 is rapidly induced by nitrate through NLP6 and NLP7, which are master regulators of nitrate signaling. Mutations in HBIs result in the reduced effects of nitrate on plant growth and ∼22% nitrate-responsive genes no longer to be regulated by nitrate. HBIs increase the expression levels of a set of antioxidant genes to reduce the accumulation of reactive oxygen species (ROS) in plants. Nitrate treatment induces the nuclear localization of NLP7, whereas such promoting effects of nitrate are significantly impaired in the hbi-q and cat2 cat3 mutants, which accumulate high levels of H2O2. These results demonstrate that HBI-mediated ROS homeostasis regulates nitrate signal transduction through modulating the nucleocytoplasmic shuttling of NLP7. Overall, our findings reveal that nitrate treatment reduces the accumulation of H2O2, and H2O2 inhibits nitrate signaling, thereby forming a feedback regulatory loop to regulate plant growth and development.

Giant and anisotropic many-body spin-orbit tunability in a strongly correlated kagome magnet.

Owing to the unusual geometry of kagome lattices-lattices made of corner-sharing triangles-their electrons are useful for studying the physics of frustrated, correlated and topological quantum electronic states1-9. In the presence of strong spin-orbit coupling, the magnetic and electronic structures of kagome lattices are further entangled, which can lead to hitherto unknown spin-orbit phenomena. Here we use a combination of vector-magnetic-field capability and scanning tunnelling microscopy to elucidate the spin-orbit nature of the kagome ferromagnet Fe3Sn2 and explore the associated exotic correlated phenomena. We discover that a many-body electronic state from the kagome lattice couples strongly to the vector field with three-dimensional anisotropy, exhibiting a magnetization-driven giant nematic (two-fold-symmetric) energy shift. Probing the fermionic quasi-particle interference reveals consistent spontaneous nematicity-a clear indication of electron correlation-and vector magnetization is capable of altering this state, thus controlling the many-body electronic symmetry. These spin-driven giant electronic responses go well beyond Zeeman physics and point to the realization of an underlying correlated magnetic topological phase. The tunability of this kagome magnet reveals a strong interplay between an externally applied field, electronic excitations and nematicity, providing new ways of controlling spin-orbit properties and exploring emergent phenomena in topological or quantum materials10-12.

TET1 is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Papillary Thyroid Cancer.

To investigate the function of ten-eleven translocation 1 (TET1) and its underlying mechanism in papillary thyroid cancer (PTC). Using the RNA-Seq data based on GDC TCGA, we analyzed the gene expression pattern of TET1 in PTC. Immunohistochemistry was carried out to assess the TET1 protein level. Then, its diagnostic and prognostic functions were determined by various bioinformatics approaches. Enrichment analysis was performed to explore the potential pathways in which TET1 is mainly involved. Finally, the immune cell infiltration analysis was conducted and the association of TET1 mRNA expression with the expression levels of immune checkpoints, tumor mutation burden (TMB) score, microsatellite instability (MSI) score, and cancer stem cells (CSC) score was examined. TET1 expression was lower in PTC tissues compared with that in normal tissues (P < 0.01). Besides, TET1 had a certain value in diagnosing PTC, and low-TET1 mRNA expression led to favorable disease-specific survival (DSS) (P < 0.01). The enrichment analysis revealed autoimmune thyroid disease and cytokine-cytokine receptor interaction were the consistent pathways in which TET1 participated. TET1 was negatively correlated with the Stromal score and Immune score. The different proportions of immune cell subtypes were observed between high- and low-TET1 expression groups. Interestingly, TET1 mRNA expression was inversely related to the expression levels of immune checkpoints, and TMB, MSI, and CSC scores. TET1 might be a robust diagnostic and prognostic biomarker for PTC. TET1 affected the DSS of PTC patients possibly through the regulation of immune-related pathways and tumor immunity.

Differentiation and immunosuppressive function of CD19+CD24hiCD27+ regulatory B cells are regulated through the miR-29a-3p/NFAT5 pathway.

BACKGROUND: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation. METHODS: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p. RESULTS: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19+ B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells. CONCLUSIONS: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation.

SUE4, a novel PIN1-interacting membrane protein, regulates acropetal auxin transport in response to sulfur deficiency.

Sulfur (S) is an essential macronutrient for plants and a signaling molecule in abiotic stress responses. It is known that S availability modulates root system architecture; however, the underlying molecular mechanisms are largely unknown. We previously reported an Arabidopsis gain-of-function mutant sulfate utilization efficiency4 (sue4) that could tolerate S deficiency during germination and early seedling growth with faster primary root elongation. Here, we report that SUE4, a novel plasma membrane-localized protein, interacts with the polar auxin transporter PIN1, resulting in reduced PIN1 protein levels and thus decreasing auxin transport to the root tips, which promotes primary root elongation. Moreover, SUE4 is induced by sulfate deficiency, consistent with its role in root elongation. Further analyses showed that the SUE4-PIN1 interaction decreased PIN1 levels, possibly through 26 S proteasome-mediated degradation. Taken together, our finding of SUE4-mediated root elongation is consistent with root adaptation to highly mobile sulfate in soil, thus revealing a novel component in the adaptive response of roots to S deficiency.

The OsNLP3/4-OsRFL module regulates nitrogen-promoted panicle architecture in rice.

Rice panicles, a major component of yield, are regulated by phytohormones and nutrients. How mineral nutrients promote panicle architecture remains largely unknown. Here, we report that NIN-LIKE PROTEIN3 and 4 (OsNLP3/4) are crucial positive regulators of rice panicle architecture in response to nitrogen (N). Loss-of-function mutants of either OsNLP3 or OsNLP4 produced smaller panicles with reduced primary and secondary branches and fewer grains than wild-type, whereas their overexpression plants showed the opposite phenotypes. The OsNLP3/4-regulated panicle architecture was positively correlated with N availability. OsNLP3/4 directly bind to the promoter of OsRFL and activate its expression to promote inflorescence meristem development. Furthermore, OsRFL activates OsMOC1 expression by binding to its promoter. Our findings reveal the novel N-responsive OsNLP3/4-OsRFL-OsMOC1 module that integrates N availability to regulate panicle architecture, shedding light on how N nutrient signals regulate panicle architecture and providing candidate targets for the improvement of crop yield.

Rapid shifts in thermal reaction norms and tolerance of brooded coral larvae following parental heat acclimation.

Thermal priming of reef corals can enhance their heat tolerance; however, the legacy effects of heat stress during parental brooding on larval resilience remain understudied. This study investigated whether preconditioning adult coral Pocillopora damicornis to high temperatures (29°C and 32°C) could better prepare their larvae for heat stress. Results showed that heat-acclimated adults brooded larvae with reduced symbiont density and shifted thermal performance curves. Reciprocal transplant experiments demonstrated higher bleaching resistance and better photosynthetic and autotrophic performance in heat-exposed larvae from acclimated adults compared to unacclimated adults. RNA-seq revealed strong cellular stress responses in larvae from heat-acclimated adults that could have been effective in rescuing host cells from stress, as evidenced by the widespread upregulation of genes involved in cell cycle and mitosis. For symbionts, a molecular coordination between light harvesting, photoprotection and carbon fixation was detected in larvae from heat-acclimated adults, which may help optimize photosynthetic activity and yield under high temperature. Furthermore, heat acclimation led to opposing regulations of symbiont catabolic and anabolic pathways and favoured nutrient translocation to the host and thus a functional symbiosis. Notwithstanding, the improved heat tolerance was paralleled by reduced light-enhanced dark respiration, indicating metabolic depression for energy saving. Our findings suggest that adult heat acclimation can rapidly shift thermal tolerance of brooded coral larvae and provide integrated physiological and molecular evidence for this adaptive plasticity, which could increase climate resilience. However, the metabolic depression may be maladaptive for long-term organismal performance, highlighting the importance of curbing carbon emissions to better protect corals.

Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

BACKGROUND AND AIMS: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. METHODS: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. RESULTS: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. CONCLUSIONS: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

Tree dissimilarity determines multi-dimensional beta-diversity of herbivores and carnivores via bottom-up effects.

Global biodiversity decline and its cascading effects through trophic interactions pose a severe threat to human society. Establishing the impacts of biodiversity decline requires a more thorough understanding of multi-trophic interactions and, more specifically, the effects that loss of diversity in primary producers has on multi-trophic community assembly. Within a synthetic conceptual framework for multi-trophic beta-diversity, we tested a series of hypotheses on neutral and niche-based bottom-up processes in assembling herbivore and carnivore communities in a subtropical forest using linear models, hieratical variance partitioning based on linear mixed-effects models (LMMs) and simulation. We found that the observed taxonomic, phylogenetic and functional beta-diversity of both herbivorous caterpillars and carnivorous spiders were significantly and positively related to tree dissimilarity. Linear models and variance partitioning for LMMs jointly suggested that as a result of bottom-up effects, producer dissimilarities were predominant in structuring consumer dissimilarity, the strength of which highly depended on the trophic dependencies on producers, the diversity facet examined, and data quality. Importantly, linear models for standardized beta-diversities against producer dissimilarities implied a transition between niche-based processes such as environmental filtering and competitive exclusion, which supports the role of bottom-up effect in determining consumer community assembly. These findings enrich our mechanistic understanding of the 'Diversity Begets Diversity' hypothesis and the complexity of higher-trophic community assembly, which is fundamental for sustainable biodiversity conservation and ecosystem management.

Is transoral endoscopic thyroidectomy safe for total thyroidectomy compared to open thyroidectomy? A propensity-score matched cohort study with papillary thyroid carcinoma.

BACKGROUND: Transoral endoscopic thyroidectomy via vestibular approach (TOETVA) has become increasingly popular in the treatment of papillary thyroid cancer (PTC). This study aimed to describe the safety and feasibility of total thyroidectomy between the TOETVA and open thyroidectomy (OT) approaches for the treatment of patients with PTC. METHODS: We retrospectively reviewed 780 consecutive patients suffering from PTC that had undergone total thyroidectomy using TOETVA (n = 107) and OT (n = 673) between April 2016 and December 2021 at our institute. Afterward, a total of 101 matched patients' surgical outcomes were compared using propensity score matching (PSM) analysis. RESULTS: Before PSM, the patients in the TOETVA group were younger (p < 0.001), had a lower body mass index (p < 0.001) and a greater female population (p < 0.001). After PSM, the TOETVA group was associated with significantly longer operative time (p < 0.001), greater blood loss (p < 0.001), total drainage amount (p < 0.001), higher C-reaction protein level (p < 0.001), better cosmetic satisfaction (p < 0.001) and quality of life (p < 0.001) and lower scar self-consciousness (p < 0.001). There was no statistical difference between the groups in the rate of parathyroid autotransplantation and bilateral lymph node dissection, the positivity of lymph node metastasis, number of dissected lymph nodes and positive lymph nodes, multifocality, postoperative level of blood calcium and parathyroid hormone (PTH), rate of PTH < 15 ng/mL, visual analog scale score, duration of hospital stay, complications, mean thyroid stimulating hormone (TSH)-stimulated Tg level before radioactive iodine, mean Tg level without TSH stimulation, and the proportion of serum Tg level of <1. CONCLUSION: TOETVA is a safe and feasible technique for better cosmetic effects and similar surgical outcomes compared to conventional open surgery for the studied patients that required total thyroidectomy.

lncRNA HOXA11-AS maintains the stemness of oral squamous cell carcinoma stem cells and reduces the radiosensitivity by targeting miR-518a-3p/PDK1.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is the most prevailing oral malignancy. The lncRNA HOXA11-AS shows prominent roles in OSCC. This study explored the effects of lncRNA HOXA11-AS on regulating OSCC stem cell stemness and radiosensitivity by targeting miR-518a-3p/PDK1. METHODS: Human OSCC cell lines SCC9 and SCC15 were selected. CD133+ cancer stem cells (CSCs) were sorted by immunomagnetic beads. CD133 expression in cells and HOXA11-AS expression in SCC9, SCC15, and CD133+ SCC9, CD133+ SCC15 cells were assessed by flow cytometry and RT-qPCR. HOXA11-AS was silenced/overexpressed in SCC9, SCC15, CD133+ SCC9, and CD133+ SCC15 cells. Cell proliferation, radiosensitivity, invasion, and stem cell sphere formation ability were examined by CCK-8, colony formation, Transwell, and stem cell sphere formation. The levels of stemness-related genes (Oct4, Nanog, Sox2), miR-518a-3p, epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, Vimentin, N-cadherin), and PDK1 were assessed by RT-qPCR and Western blot assay. RESULTS: HOXA11-AS was up-regulated in SCC9, SCC15, CD133+ SCC9, and CD133+ SCC15 cells. HOXA11-AS silencing inhibited OSCC proliferation and invasion and enhanced radiosensitivity. HOXA11-AS maintained CSC stemness in OSCC. HOXA11-AS silencing reduced CD133+ SCC9 and CD133+ SCC15 stem cell sphere formation ability, reduced stem cell stemness-related gene levels, and inhibited EMT. HOXA11-AS regulated OSCC stem cell stemness and radiosensitivity by targeting miR-518a-3p. PDK1 overexpression annulled the regulatory effects of HOXA11-AS silencing on OSCC cell stem cell stemness and radiosensitivity. CONCLUSION: In vitro lncRNA HOXA11-AS silencing inhibited OSCC stem cell stemness by targeting the miR-518a-3p/PDK1 axis, thus enhancing OSCC cell radiosensitivity.

Bond-breaking induced Lifshitz transition in robust Dirac semimetal VAI3.

Topological electrons in semimetals are usually vulnerable to chemical doping and environment change, which restricts their potential application in future electronic devices. In this paper, we report that the type-II Dirac semimetal [Formula: see text] hosts exceptional, robust topological electrons which can tolerate extreme change of chemical composition. The Dirac electrons remain intact, even after a substantial part of V atoms have been replaced in the [Formula: see text] solid solutions. This Dirac semimetal state ends at [Formula: see text], where a Lifshitz transition to p-type trivial metal occurs. The V-Al bond is completely broken in this transition as long as the bonding orbitals are fully depopulated by the holes donated from Ti substitution. In other words, the Dirac electrons in [Formula: see text] are protected by the V-Al bond, whose molecular orbital is their bonding gravity center. Our understanding on the interrelations among electron count, chemical bond, and electronic properties in topological semimetals suggests a rational approach to search robust, chemical-bond-protected topological materials.

Mechanism underlying the effect of MnO2 nanosheets for A549 cell chemodynamic therapy.

MnO2 nanosheets (MnO2NSs) were synthesized by one-step method, and MnO2NSs were applied to A549 cell chemodynamic Therapy (CDT). The cytotoxicity, redox ability, and reactive oxygen species production of MnO2NSs have been investigated, and differences in cell metabolism during CDT were determined using liquid chromatography-mass spectrometry (LC-MS/MS). In addition, the metabolites of A549 lung cancer cells affected by MnO2NSs treatment are identified; metabolite differences were identified by PCA, PLS-DA, orthogonal PLS-DA, and other methods; and these differences were analyzed using non-targeted metabolomics. We found that A549 cells which were treated by MnO2NSs have 17 different metabolites and 9 metabolic pathways that varied markedly. Owing to their unique composition, structure, and physicochemical properties, MnO2NSs and their composites have become a favored type of nanomaterial used for CDT in cancer therapy. This work provides insights into the mechanism underlying the effects of MnO2NSs on the tumor microenvironment of A549 lung cancer cells, effectively making up for the deficiency of the study on cellular mechanism of CDT-induced apoptosis of cancer cells. It could aid the development of cancer CDT treatment strategies and help improve the use of nanomaterials in the clinical field.

Numerical simulation analysis of heat and mass transfer of saline wastewater in a falling film evaporation tube based on different inlet modes.

Falling film evaporation technology is widely used in the treatment of salt-containing wastewater in coal chemical industry. However, there is still a lack of research on the inlet method of vertical falling film evaporation tubes. In this paper, the heat and mass transfer processes of saline wastewater under vertical and tangential inlets were investigated using numerical simulations. On this basis, the differences in flow and heat transfer processes between saline wastewater and pure water under tangential inlet were investigated. The results showed that the flow velocity of saline wastewater with a falling film evaporation tube in a tangential inlet mode was larger. Meanwhile, the turbulence in this way was more intense and the fluid temperature in the vertical tube was higher. Saline wastewater has higher temperature and smaller liquid volume fraction than pure water liquid membrane in the range of 193-1,000 mm from the inlet. The use of tangential inlet method to treat salt-containing wastewater has higher evaporation efficiency and is a very effective way to guide the improvement of heat transfer efficiency.

Single Molecule-Level Detection via Liposome-Based Signal Amplification Mass Spectrometry Counting Assay.

Because of the low atomization and/or ionization efficiencies of many biological macromolecules, the application of mass spectrometry to the direct quantitative detection of low-abundance proteins and nucleic acids remains a significant challenge. Herein, we report mass spectrum tags (MS-tags) based upon gold nanoparticle (AuNP)-templated phosphatidylcholine phospholipid (DSPC) liposomes, which exhibit high and reliable signals via electrospray ionization (ESI). Using these MS-tags, we constructed a liposome signal amplification-based mass spectrometric (LSAMS) "digital" counting assay to enable ultrasensitive detection of target nucleic acids. The LSAMS system consists of liposomes modified with a gold nanoparticle core and surface-anchored photocleavable DNA. In the presence of target nucleic acids, the modified liposome and a magnetic bead simultaneously hybridize with the target nucleic acid. After magnetic separation and photolysis, the MS-tag is released and can be analyzed by ESI-MS. At very low target concentrations, one liposome particle corresponds to one target molecule; thus, the concentration of the target can be estimated by counting the number of liposomes. With this assay, hepatitis C (HCV) virus RNA was successfully analyzed in clinical samples.

GAF domain is essential for nitrate-dependent AtNLP7 function.

Nitrate is an essential nutrient and an important signaling molecule in plants. However, the molecular mechanisms by which plants perceive nitrate deficiency signaling are still not well understood. Here we report that AtNLP7 protein transport from the nucleus to the cytoplasm in response to nitrate deficiency is dependent on the N-terminal GAF domain. With the deletion of the GAF domain, AtNLP7ΔGAF always remains in the nucleus regardless of nitrate availability. AtNLP7 ΔGAF also shows reduced activation of nitrate-induced genes due to its impaired binding to the nitrate-responsive cis-element (NRE) as well as decreased growth like nlp7-1 mutant. In addition, AtNLP7ΔGAF is unable to mediate the reduction of reactive oxygen species (ROS) accumulation upon nitrate treatment. Our investigation shows that the GAF domain of AtNLP7 plays a critical role in the sensing of nitrate deficiency signal and in the nitrate-triggered ROS signaling process.

Highly Dispersed Ru-Co Nanoparticles Interfaced With Nitrogen-Doped Carbon Polyhedron for High Efficiency Reversible Li-O2 Battery.

The lithium-oxygen (Li-O2 ) battery with high energy density of 3860 Wh kg-1 represents one of the most promising new secondary batteries for future electric vehicles and mobile electronic devices. However, slow oxygen reduction/oxygen evolution (ORR/OER) reaction efficiency and unstable cycling performance restrain the practical applications of the Li-O2 battery. Herein, Ru-modified nitrogen-doped porous carbon-encapsulated Co nanoparticles (Ru/Co@CoNx -C) are synthesized through reduction of Ru on metal-organic framework (MOFs) pyrolyzed derivatives strategies. Porous carbon polyhedra provide channels for reactive species and stable structure ensures the cyclic stability of the catalyst; abundant Co-Nx sites and high specific surface area (353 m2 g-1 ) provide more catalytically active sites and deposition sites for reaction products. Theoretical calculations further verify that Ru/Co@CoNx -C can regulate the growth of Li2 O2 to improve reversibility of Li-O2 batteries. Li-O2 batteries with Ru/Co@CoNx -C as cathode catalyst achieve small voltage gaps of 1.08 V, exhibit excellent cycle stability (205 cycles), and deliver high discharge specific capacity (17050 mAh g-1 ). Furthermore, pouch-type Li-O2 batteries that maintain stable electrochemical performance output even under conditions of bending deformation and corner cutting are successfully assembled. This study demonstrates Ru/Co@CoNx -C catalyst's great application potential in Li-O2 batteries.

Rice NIN-LIKE PROTEIN 3 modulates nitrogen use efficiency and grain yield under nitrate-sufficient conditions.

Nitrogen (N) is an essential macronutrient for crop growth and yield. Improving the N use efficiency (NUE) of crops is important to agriculture. However, the molecular mechanisms underlying NUE regulation remain largely elusive. Here we report that the OsNLP3 (NIN-like protein 3) regulates NUE and grain yield in rice under N sufficient conditions. OsNLP3 transcript level is significantly induced by N starvation and its protein nucleocytosolic shuttling is specifically regulated by nitrate. Loss-of-function of OsNLP3 reduces plant growth, grain yield, and NUE under sufficient nitrate conditions, whereas under low nitrate or different ammonium conditions, osnlp3 mutants show no clear difference from the wild type. Importantly, under sufficient N conditions in the field, OsNLP3 overexpression lines display improved grain yield and NUE compared with the wild type. OsNLP3 orchestrates the expression of multiple N uptake and assimilation genes by directly binding to the nitrate-responsive cis-elements in their promoters. Overall, our study demonstrates that OsNLP3, together with OsNLP1 and OsNLP4, plays overlapping and differential roles in N acquisition and NUE, and modulates NUE and the grain yield increase promoted by N fertilizer. Therefore, OsNLP3 is a promising candidate gene for the genetic improvement of grain yield and NUE in rice.

Procurement of medicines to treat cancer, 2015-2020, China.

Objective: To assess the procurement of medicines to treat cancer in China. Methods: We conducted a descriptive analysis of the national procurement data for 20 anti-cancer medicines in China from 2015 to 2020. We estimated the number of defined daily doses procured per year in three areas of China for essential medicines and medicines for targeted therapies. We adjusted the data by the number of cancer patients in each region for each year. Findings: Between 2015 and 2020, the number of defined daily doses per patient decreased from 40.87 to 35.86 (-12.27%) for essential medicines, while the number increased from 0.85 to 12.52 (1381.15%) for target medicines. The procurement of three out of 10 essential medicines decreased, whereas procurement of all 10 targeted medicines increased. In 2020, the eastern area procured the most essential medicines (44.98 doses per patient) and targeted medicines (16.55 doses per patient), but had the smallest relative change in procurement of both essential medicines (-22.76%) and targeted medicines (978.16%). The central area had the largest increase in procurement of both essential medicines (9.64%; from 25.25 to 27.68 doses per patient) and targeted medicines (4587.81%; from 0.23 to 10.64 doses per patient). Conclusion: Procurement of anti-cancer medicines varied across regions. Specific policies are needed at the national level to eliminate inequalities in access to these medicines. Two issues that need attention are the lower access to many essential anti-cancer medicines in some provinces and the increase in use of targeted medicines.

Development and validation of a gradient boosting machine to predict prognosis after liver resection for intrahepatic cholangiocarcinoma.

BACKGROUND: Accurate prognosis assessment is essential for surgically resected intrahepatic cholangiocarcinoma (ICC) while published prognostic tools are limited by modest performance. We therefore aimed to establish a novel model to predict survival in resected ICC based on readily-available clinical parameters using machine learning technique. METHODS: A gradient boosting machine (GBM) was trained and validated to predict the likelihood of cancer-specific survival (CSS) on data from a Chinese hospital-based database using nested cross-validation, and then tested on the Surveillance, Epidemiology, and End Results (SEER) database. The performance of GBM model was compared with that of proposed prognostic score and staging system. RESULTS: A total of 1050 ICC patients (401 from China and 649 from SEER) treated with resection were included. Seven covariates were identified and entered into the GBM model: age, tumor size, tumor number, vascular invasion, number of regional lymph node metastasis, histological grade, and type of surgery. The GBM model predicted CSS with C-Statistics ≥ 0.72 and outperformed proposed prognostic score or system across study cohorts, even in sub-cohort with missing data. Calibration plots of predicted probabilities against observed survival rates indicated excellent concordance. Decision curve analysis demonstrated that the model had high clinical utility. The GBM model was able to stratify 5-year CSS ranging from over 54% in low-risk subset to 0% in high-risk subset. CONCLUSIONS: We trained and validated a GBM model that allows a more accurate estimation of patient survival after resection compared with other prognostic indices. Such a model is readily integrated into a decision-support electronic health record system, and may improve therapeutic strategies for patients with resected ICC.