Carbon starvation raises capacities in bacterial antibiotic resistance and viral auxiliary carbon metabolism in soils.

Organic carbon availability in soil is crucial for shaping microbial communities, yet, uncertainties persist concerning microbial adaptations to carbon levels and the ensuing ecological and evolutionary consequences. We investigated organic carbon metabolism, antibiotic resistance, and virus-host interactions in soils subjected to 40 y of chemical and organic fertilization that led to contrasting carbon availability: carbon-poor and carbon-rich soils, respectively. Carbon-poor soils drove the enrichment of putative genes involved in organic matter decomposition and exhibited specialization in utilizing complex organic compounds, reflecting scramble competition. This specialization confers a competitive advantage of microbial communities in carbon-poor soils but reduces their buffering capacity in terms of organic carbon metabolisms, making them more vulnerable to environmental fluctuations. Additionally, in carbon-poor soils, viral auxiliary metabolic genes linked to organic carbon metabolism increased host competitiveness and environmental adaptability through a strategy akin to "piggyback the winner." Furthermore, putative antibiotic resistance genes, particularly in low-abundance drug categories, were enriched in carbon-poor soils as an evolutionary consequence of chemical warfare (i.e., interference competition). This raises concerns about the potential dissemination of antibiotic resistance from conventional agriculture that relies on chemical-only fertilization. Consequently, carbon starvation resulting from long-term chemical-only fertilization increases microbial adaptations to competition, underscoring the importance of implementing sustainable agricultural practices to mitigate the emergence and spread of antimicrobial resistance and to increase soil carbon storage.

Pursuing sustainable productivity with millions of smallholder farmers.

Sustainably feeding a growing population is a grand challenge, and one that is particularly difficult in regions that are dominated by smallholder farming. Despite local successes, mobilizing vast smallholder communities with science- and evidence-based management practices to simultaneously address production and pollution problems has been infeasible. Here we report the outcome of concerted efforts in engaging millions of Chinese smallholder farmers to adopt enhanced management practices for greater yield and environmental performance. First, we conducted field trials across China's major agroecological zones to develop locally applicable recommendations using a comprehensive decision-support program. Engaging farmers to adopt those recommendations involved the collaboration of a core network of 1,152 researchers with numerous extension agents and agribusiness personnel. From 2005 to 2015, about 20.9 million farmers in 452 counties adopted enhanced management practices in fields with a total of 37.7 million cumulative hectares over the years. Average yields (maize, rice and wheat) increased by 10.8-11.5%, generating a net grain output of 33 million tonnes (Mt). At the same time, application of nitrogen decreased by 14.7-18.1%, saving 1.2 Mt of nitrogen fertilizers. The increased grain output and decreased nitrogen fertilizer use were equivalent to US$12.2 billion. Estimated reactive nitrogen losses averaged 4.5-4.7 kg nitrogen per Megagram (Mg) with the intervention compared to 6.0-6.4 kg nitrogen per Mg without. Greenhouse gas emissions were 328 kg, 812 kg and 434 kg CO2 equivalent per Mg of maize, rice and wheat produced, respectively, compared to 422 kg, 941 kg and 549 kg CO2 equivalent per Mg without the intervention. On the basis of a large-scale survey (8.6 million farmer participants) and scenario analyses, we further demonstrate the potential impacts of implementing the enhanced management practices on China's food security and sustainability outlook.

Large-scale exploration of nitrogen utilization efficiency in Asia region for rice crop: Variation patterns and determinants.

Improving rice nitrogen utilization efficiency (NUtE) is imperative to maximizing future food productivity while minimizing environmental threats, yet knowledge of its variation and the underlying regulatory factors is still lacking. Here, we integrated a dataset with 21,571 data compiled by available data from peer-reviewed literature and a large-scale field survey to address this knowledge gap. The overall results revealed great variations in rice NUtE, which were mainly associated with human activities, climate conditions, and rice variety. Specifically, N supply rate, temperature, and precipitation were the foremost determinants of rice NUtE, and NUtE responses to climatic change differed among rice varieties. Further prediction highlighted the improved rice NUtE with the increasing latitude or longitude. The indica and hybrid rice exhibited higher NUtE in low latitude regions compared to japonica and inbred rice, respectively. Collectively, our results evaluated the primary drivers of rice NUtE variations and predicted the geographic responses of NUtE in different varieties. Linking the global variations in rice NUtE with environmental factors and geographic adaptability provides valuable agronomic and ecological insights into the regulation of rice NUtE.

A neoadjuvant therapy compatible prognostic staging for resected pancreatic ductal adenocarcinoma.

OBJECTIVE: To improve prediction, the AJCC staging system was revised to be consistent with upfront surgery (UFS) and neoadjuvant therapy (NAT) for PDAC. BACKGROUND: The AJCC staging system was designed for patients who have had UFS for PDAC, and it has limited predictive power for patients receiving NAT. METHODS: We examined 146 PDAC patients who had resection after NAT and 1771 who had UFS at Changhai Hospital between 2012 and 2021. The clinicopathological factors were identified using Cox proportional regression analysis, and the Neoadjuvant Therapy Compatible Prognostic (NATCP) staging was developed based on these variables. Validation was carried out in the prospective NAT cohort and the SEER database. The staging approach was compared to the AJCC staging system regarding predictive accuracy. RESULTS: The NAT cohort's multivariate analysis showed that tumor differentiation and the number of positive lymph nodes independently predicted OS. The NATCP staging simplified the AJCC stages, added tumor differentiation, and restaged the disease based on the Kaplan-Meier curve survival differences. The median OS for NATCP stages IA, IB, II, and III was 31.7 months, 25.0 months, and 15.8 months in the NAT cohort and 30.1 months, 22.8 months, 18.3 months, and 14.1 months in the UFS cohort. Compared to the AJCC staging method, the NATCP staging system performed better and was verified in the validation cohort. CONCLUSIONS: Regardless of the use of NAT, NATCP staging demonstrated greater predictive abilities than the existing AJCC staging approach for resected PDAC and may facilitate clinical decision-making based on accurate prediction of patients' OS.

Large-cohort humanized NPI mice reconstituted with CD34+ hematopoietic stem cells are feasible for evaluating preclinical cancer immunotherapy.

Cancer immunotherapy has achieved impressive therapeutic effects in many cancers, while only a small subset of patients benefit from it and some patients even have experienced severe toxicity. It is urgent to develop a feasible large-cohort humanized mouse model to evaluate the pre-clinical efficacy and safety of cancer immunotherapy. Furthermore, developing potentially effective combination therapy between cancer immunotherapy and other therapies also needs humanized mouse model to adequately mimic clinical actual setting. Herein, we established a humanized mouse model engrafted with less human CD34+ HSCs than ever before and then evaluated reconstitution efficiency and the profiles of human immune cells in this humanized mouse model. Also, this humanized mouse model was used to evaluate the preclinical efficacy and safety of cancer immunotherapy. For each batch of CD34+ HSCs humanized mouse model, a relatively-large cohort with over 25% human CD45+ cells in peripheral blood was established. This humanized mouse model could efficiently reconstitute human innate and adaptive immune cells. This humanized mouse model supported patient-derived xenograft tumor growth and tumor infiltration of PD-1+ human T cells. Furthermore, therapeutic efficacy, re-activation of tumor-infiltrated T cells, and side effects of checkpoint blockade therapy could be monitored in this humanized mouse model. Human T cells from this humanized mouse model were successfully engineered with CD19-CAR. CD19 CAR-T cells could effectively deplete B cells and suppress tumor growth of acute lymphoblastic leukemia in vivo in this humanized mouse model. This humanized mouse model also could be used to demonstrate the efficacy of bispecific antibodies, such as anti-CD19/CD3. Overall, our work provides a feasible large-cohort humanized mouse model for evaluating a variety of cancer immunotherapy approaches including checkpoint inhibitors, adoptive cell therapy, and bispecific antibody therapy, and demonstrates that human T cells from this humanized mouse model possess anti-tumor activities in vitro and in vivo.

Chromatic aberration correction based on cross-channel information alignment in microscopy.

A microscope usually consists of dozens of complex lenses and requires careful assembly, alignment, and testing before use. Chromatic aberration correction is a significant step in the design of microscopes. Reducing chromatic aberration by improving optical design will inevitably increase the overall weight and size of the microscope, leading to more cost in manufacturing and maintenance. Nevertheless, the improvement in hardware can only achieve limited correction. In this paper, we propose an algorithm based on cross-channel information alignment to shift some of the correction tasks from optical design to post-processing. Additionally, a quantitative framework is established to evaluate the performance of the chromatic aberration algorithm. Our algorithm outperforms the other state-of-the-art methods in both visual appearance and objective assessments. The results indicate that the proposed algorithm can effectively obtain higher-quality images without changing the hardware or engaging the optical parameters.

Combined utility of Ki-67 index and tumor grade to stratify patients with pancreatic ductal adenocarcinoma who underwent upfront surgery.

OBJECTIVE: To investigate the prognostic prediction of a new indicator, combined by tumor grade and Ki-67, in patients with resected pancreatic ductal adenocarcinoma (PDAC). METHODS: Data were retrospectively collected from consecutive patients who underwent primary resection of pancreas from December 2012 to December 2017. Tumor grade and Ki-67 were reviewed from routine pathological reports. G-Ki67 was classified as three categories as I (G1/2 and Ki-67 < 40%), II (G1/2 and Ki-67 ≥ 40%), and III(G3/4 and all Ki-67). RESULTS: Cox regression analyses revealed that tumor stage (II vs. I: hazard ratio (HR), 3.781; 95% confidence index (CI), 2.844-5.025; P < 0.001; III vs. I: HR, 7.476; 95% CI, 5.481-10.20; P < 0.001) and G-Ki67 (II vs. I: HR, 1.299; 95% CI, 1.038-1.624; P = 0.022; III vs. I: HR, 1.942; 95% CI, 1.477-2.554; P < 0.001) were independent prognostic factors in the developing cohort. The result was rectified in the validation cohort. In subgroups analysis, G-Ki67 (II vs. I: HR, 1.866 ; 95% CI, 1.045-3.334; P = 0.035; III vs. I: HR, 2.333 ; 95% CI, 1.156-4.705; P = 0.018) also had a high differentiation for survival prediction. CONCLUSION: Our findings indicate that three-categories of G-Ki67 in resectable PDAC according to the routine pathological descriptions provided additional prognostic information complementary to the TNM staging system.

Determining optimal nitrogen management to improve rice yield, quality and nitrogen use efficiency based on multi-index decision analysis method.

BACKGROUND: Reasonable nitrogen (N) supply is critical for increasing rice yield while improving grain quality and nitrogen use efficiency (NUE). However, the trade-off relationship between yield, quality and NUE of rice under N management has not been well understood enough. In the present study, a 2-year field experiment was conducted to identify optimal N fertilizer management practices that resulted in high-yield, high-quality and high-NUE by using the technique for order preference by similarity to an ideal solution (TOPSIS) with entropy weight (EW) method. RESULTS: All the parameters of rice yield, quality and efficiency were remarkably affected by fertilization treatments. Compared with farmer's fertilization practice (FFP), optimizing N fertilizer treatment (OPT) and substituting 20% of N fertilizer with pig manure based on OPT treatment (OPTM) increased grain yield (2.87-6.62%) by maintaining higher 1000-grain weight and filled grains rate. The agronomic NUE (AE) and N partial factor productivity (PFP) under OPT and OPTM treatment were also remarkably increased by 32.81-43.01% and 28.59-33.28% with respect to the value under FFP treatment, respectively. Meanwhile, OPT and OPTM significantly improved the milling quality of rice by increasing brown rice rate (0.71-1.17%) and head rice rate (1.34-2.31%). OPT and OPTM significantly improved appearance quality by decreasing chalkiness and eating quality by reducing amylose content in 2020. The TOPSIS with EW showed that rice comprehensive evaluation could be maintained at a high level under OPT and OPTM. CONCLUSION: OPT and OPTM were nutrient management modes of high-yield, high-quality and high-efficiency, and promising practice to improve rice comprehensive productivity. This strategy is also highly-consistent with the United Nations Sustainable Development Goals. © 2023 Society of Chemical Industry.

Meta-analysis of diazotrophic signatures across terrestrial ecosystems at the continental scale.

Biological nitrogen fixation performed by diazotrophs forms a cornerstone of Earth's terrestrial ecosystem productivity. However, the composition, diversity and distribution of soil diazotrophs are poorly understood across different soil ecosystems. Furthermore, the biological potential of the key diazotroph species in relation to key environmental parameters is unknown. To address this, we used meta-analysis approach to merge together 39 independent diazotroph amplicon sequencing (nifH gene) datasets consisting of 1988 independent soil samples. We then employed multiple statistical analyses and machine-learning approaches to compare diazotroph community differences and indicator species between terrestrial ecosystems on a global scale. The distribution, composition and structure of diazotroph communities varied across seven different terrestrial ecosystems, with community composition exhibiting an especially clear effect. The Cyanobacteria were the most abundant taxa in crust ecosystems (accounting for ~45% of diazotrophs), while other terrestrial ecosystems were dominated by Proteobacteria, including Alpha-, Beta- and Gamma-Proteobacteria (accounting for ~70% of diazotrophs). Farmland ecosystems harboured the highest and crust ecosystems the lowest alpha and phylogenetic diversities. Azospirillum zeae, Skermanella aerolata and four Bradyrhizobium species were identified as key indicator species of potential diazotroph activity. Overall, diazotroph abundances and distribution were affected by multiple environmental parameters, including soil pH, nitrogen, organic carbon, C:N ratio and annual mean precipitation and temperature. Together, our findings suggest that based on the relative abundance and diversity of nifH marker gene, diazotrophs have adapted to a range of environmental niches globally.

Noninvasive detection of pancreatic ductal adenocarcinoma using the methylation signature of circulating tumour DNA.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has the lowest overall survival rate primarily due to the late onset of symptoms and rapid progression. Reliable and accurate tests for early detection are lacking. We aimed to develop a noninvasive test for early PDAC detection by capturing the circulating tumour DNA (ctDNA) methylation signature in blood. METHODS: Genome-wide methylation profiles were generated from PDAC and nonmalignant tissues and plasma. Methylation haplotype blocks (MHBs) were examined to discover de novo PDAC markers. They were combined with multiple cancer markers and screened for PDAC classification accuracy. The most accurate markers were used to develop PDACatch, a targeted methylation sequencing assay. PDACatch was applied to additional PDAC and healthy plasma cohorts to train, validate and independently test a PDAC-discriminating classifier. Finally, the classifier was compared and integrated with carbohydrate antigen 19-9 (CA19-9) to evaluate and maximize its accuracy and utility. RESULTS: In total, 90 tissues and 546 plasma samples were collected from 232 PDAC patients, 25 chronic pancreatitis (CP) patients and 323 healthy controls. Among 223 PDAC cases with known stage information, 43/119/38/23 cases were of Stage I/II/III/IV. A total of 171 de novo PDAC-specific markers and 595 multicancer markers were screened for PDAC classification accuracy. The top 185 markers were included in PDACatch, from which a 56-marker classifier for PDAC plasma was trained, validated and independently tested. It achieved an area under the curve (AUC) of 0.91 in both the validation (31 PDAC, 26 healthy; sensitivity = 84%, specificity = 89%) and independent tests (74 PDAC, 65 healthy; sensitivity = 82%, specificity = 88%). Importantly, the PDACatch classifier detected CA19-9-negative PDAC plasma at sensitivities of 75 and 100% during the validation and independent tests, respectively. It was more sensitive than CA19-9 in detecting Stage I (sensitivity = 80 and 68%, respectively) and early-stage (Stage I-IIa) PDAC (sensitivity = 76 and 70%, respectively). A combinatorial classifier integrating PDACatch and CA19-9 outperformed (AUC=0.94) either PDACatch (0.91) or CA19-9 (0.89) alone (p < 0.001). CONCLUSIONS: The PDACatch assay demonstrated high sensitivity for early PDAC plasma, providing potential utility for noninvasive detection of early PDAC and indicating the effectiveness of methylation haplotype analyses in discovering robust cancer markers.

Microbial generalist or specialist: Intraspecific variation and dormancy potential matter.

Microbial generalists and specialists coexist in the soil environment while having distinctive impacts on microbial community dynamics. In microbial ecology, the underlying mechanisms as to why a species is a generalist or a specialist remain ambiguous. Herein, we collected soils across a national scale and identified bacterial generalists and specialists according to niche breadth at the species level (OTU level), and the single-nucleotide differences in each species were measured to investigate intraspecific variation (at zero-radius OTU level). Compared with that of the specialists, the intraspecific variation of the generalists was much higher, which ensured their wider niche breadth and lower variability. The higher asynchrony and different niche preferences of conspecific individuals and the higher dormancy potential within the generalists further contributed to their stability in varying environments. Besides, generalists were less controlled by environmental filtering, which was indicated by the stronger signature of stochastic processes in their assembly, and had higher diversification and transition rates that allowed them to adapt to environmental changes to a greater extent than specialists. Overall, this study provides a new comprehensive understanding of the rules of assembly and the evolutionary roles of bacterial generalists and specialists. It also highlights the importance of intraspecific variation and the dormancy potential in the stability of species.

Rare Bacteria Assembly in Soils Is Mainly Driven by Deterministic Processes.

Rare species are crucial components of the highly diverse soil microbial pool and over-proportionally contribute to the soil functions. However, much remains unknown about their assembling rules. The biogeographic patterns and species aggregations of the rare bacterial biosphere were assessed using 140 soil samples from a gradient of 2000 km across the main tea-producing areas in China. About 96% OTUs with ~40% sequences were classified as rare taxa. The rare bacterial communities were significantly affected by geographical regions and showed distance-decay effects, indicating that the rare bacteria are not cosmopolitan, they displayed a pattern of limited dispersal and were restricted to certain sites. Variation partitioning analysis (VPA) revealed that environmental variation and spatial factors explained 12.5% and 6.4%, respectively, of the variance in rare bacterial community. The Mantel and partial Mantel tests also showed that the environmental factors had stronger (~3 times) impacts than spatial factors. The null model showed that deterministic processes contributed more than stochastic processes in rare bacterial assembly (75% vs. 25%). There is likely an enrichment in ecological functions within the rare biosphere, considering this high contribution of deterministic processes in the assembly. In addition, the assembly of rare taxa was found to be mainly driven by soil pH. Overall, this study revealed that rare bacteria were not cosmopolitan, and their assembly was more driven by deterministic processes. These findings provided a new comprehensive understanding of rare bacterial biogeographic patterns and assembly rules.

Use of Buried Guide Needle to Fix Inferior Eyelid Orbital Septum Fat for Tear Trough Depression Filling.

ABSTRACT: Fat fixation is a key step in filling tear trough depression with inferior eyelid orbital septum fat. The ideal position for inferior eyelid fat fixation is to cross the tear trough ligament causing tear trough depression and the orbicularis retaining ligament, with the distal end fixed at the farthest end of the dissected lacuna deep down the inferior orbicularis oculi muscle. Traditional suturing is difficult in the deep narrow lacunae, but a buried guide needle can be used to suture and fix the fat in the deepest lacuna. In this study, 264 patients who underwent tear trough filling using a buried guide needle to fix the released inferior eyelid orbital septum fat from 2017 to 2020 were followed up. The preoperative and postoperative imaging findings were compared to evaluate the effectiveness of the operation and postoperative complications. The inferior eyelid bulging, loose skin, and tear trough depression significantly improved than that before the operation. None of the patients had any severe complications, such as inferior eyelid ectropion, lagophthalmos, scar hyperplasia, and diplopia, in the long term (6 months) postoperatively. Five patients showed mild eyelid-eyeball separation and recovered in 1 month. Four patients had diplopia, and 3 patients had chemosis; all recovered in 7 days. The tear trough depression was not corrected completely in 2 patients. The operation showed satisfactory results in the improvement of tear trough depression in addition to alleviation of inferior eyelid bulging and loose inferior eyelid skin that is caused by the traditional inferior eyelid pouch removal.

Prognostic validity of the American joint committee on cancer eighth edition staging system for well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: The American Joint Committee on Cancer (AJCC) made improvements for staging pancreatic neuroendocrine tumors (pNETs) in its 8th Edition; however, multicenter studies were not included. METHODS: We collected multicenter datasets (n = 1,086, between 2004 and 2018) to validate the value of AJCC 8 and other coexisting staging systems through univariate and multivariate analysis for well-differentiated (G1/G2) pNETs. RESULTS: Compared to other coexisting staging systems, AJCC 7 only included 12 (1.1%) patients with stage III tumors. Patients with European Neuroendocrine Tumor Society (ENETS) stage IIB disease had a higher risk of death than patients with stage IIIA (hazard ratio [HR]: 4.376 vs. 4.322). For the modified ENETS staging system, patients with stage IIB disease had a higher risk of death than patients with stage III (HR: 6.078 vs. 5.341). According to AJCC 8, the proportions of patients with stage I, II, III, and IV were 25.7%, 40.3%, 23.6%, and 10.4%, respectively. As the stage advanced, the median survival time decreased (NA, 144.7, 100.8, 72.0 months, respectively), and the risk of death increased (HR: II = 3.145, III = 5.925, and IV = 8.762). CONCLUSION: These findings suggest that AJCC 8 had a more reasonable proportional distribution and the risk of death was better correlated with disease stage.

Seed-borne, endospheric and rhizospheric core microbiota as predictors of plant functional traits across rice cultivars are dominated by deterministic processes.

A host-plant and its associated microbiota depend on one another. However, the assembly process and the functioning of host-associated microbiota are poorly understood. Herein, rice was used as model plant to investigate the assemblage of bacterial microbiota, including those in the seed, root endosphere and rhizosphere. We also assessed the degree to which endosphere and rhizosphere communities were influenced by vertical transmission through seed and identified the core microbes that potentially associated with plant phenotypic properties. Plant microhabitat, rather than subspecies type, was the major driver shaping plant-associated bacterial microbiota. Deterministic processes were primarily responsible for community assembly in all microhabitats. The influence of vertical transmission from seed to root-associated bacterial communities appeared to be quite weak (endosphere) or even absent (rhizosphere). A core microbial community composed of 15 generalist species persisted across different microhabitats and represented key connectors in networks. Host-plant functional traits were linked to the relative abundance of these generalist core microbes and could be predicted from them using machine learning algorithms. Overall, bacterial microbiota is assembled by host-plant interactions in a deterministic-based manner. This study enhances our understanding of the driving mechanisms and associations of microbiota in various plant microhabitats and provides new perspectives to improve plant performance.

Nitrate mediated resistance against Fusarium infection in cucumber plants acts via photorespiration.

Fusarium wilt is one of the major biotic factors limiting cucumber (Cucumis sativus L.) growth and yield. The outcomes of cucumber-Fusarium interactions can be influenced by the form of nitrogen nutrition (nitrate [NO3- ] or ammonium [NH4+ ]); however, the physiological mechanisms of N-regulated cucumber disease resistance are still largely unclear. Here, we investigated the relationship between nitrogen forms and cucumber resistance to Fusarium infection. Our results showed that on Fusarium infection, NO3- feeding decreased the levels of the fungal toxin, fusaric acid, leaf membrane oxidative, organelle damage and disease-associated loss in photosynthesis. Metabolomic analysis and gas-exchange measurements linked NO3- mediated plant defence with enhanced leaf photorespiration rates. Cucumber plants sprayed with the photorespiration inhibitor isoniazid were more susceptible to Fusarium and there was a negative correlation between photorespiration rate and leaf membrane injury. However, there were positive correlations between photorespiration rate, NO3- assimilation and the tricarboxylic acid (TCA) cycle. This provides a potential electron sink or the peroxisomal H2 O2 catalysed by glycolate oxidase. We suggest that the NO3- nutrition enhanced cucumber resistance against Fusarium infection was associated with photorespiration. Our findings provide a novel insight into a mechanism involving the interaction of photorespiration with nitrogen forms to drive wider defence.

Comparison of 4- and 4 plus-courses S-1 administration as adjuvant chemotherapy for pancreatic ductal adenocarcinoma.

PURPOSE: The study aimed to investigate the potential benefit of more than 4 courses of S1 adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma (PDAC) after surgery. METHOD: Data were retrospectively collected from consecutive patients who underwent S-1 adjuvant chemotherapy following curative pancreatectomy between January 2016 and December 2018. Four-courses and > 4 courses cohorts were compared for overall survival (OS) as a primary outcome, and relapse-free survival (RFS) and adverse event incidence as secondary outcomes. RESULTS: Four-courses and > 4 courses cohorts comprised 99 patients and 64 ones, respectively. TNM stage (stage II vs. I: HR, 2.125; 95% CI, 1.164-4.213; P = 0.015), duration of S-1 administration (4 vs. > 4 courses: HR, 3.113; 95% CI, 1.531-6.327; P = 0.002) and tumor grade (G3 vs. G1/2: HR, 3.887; 95% CI, 1.922-7.861; P < 0.001) were independent prognostic factors. Under the condition of patients' survival time beyond 8 months, the OS of patients in > 4 courses cohort was significantly prolonged compared with that of 4 courses cohort (4 vs. > 4 courses: HR, 2.284; 95% CI, 1.197-4.358; P = 0.012), especially for patients in TNM stageII (4 vs. > 4 courses: HR, 2.906; 95% CI, 1.275-6.623; P = 0.011).RFS and adverse events incidence did not signifcantly difer between both cohorts. CONCLUSION: Prolonged duration of S-1 intake is beneficial to prognosis of patients with PDAC resection.

The cross-kingdom roles of mineral nutrient transporters in plant-microbe relations.

The regulation of plant physiology by plant mineral nutrient transporter (MNT) is well understood. Recently, the extensive characterization of beneficial and pathogenic plant-microbe interactions has defined the roles for MNTs in such relationships. In this review, we summarize the roles of diverse nutrient transporters in the symbiotic or pathogenic relationships between plants and microorganisms. In doing so, we highlight how MNTs of plants and microbes can act in a coordinated manner. In symbiotic relationships, MNTs play key roles in the establishment of the interaction between the host plant and rhizobium or mycorrhizae as well in the subsequent coordinated transport of nutrients. Additionally, MNTs may also regulate the colonization or degeneration of symbiotic microorganisms by reflecting the nutrient status of the plant and soil. This allows the host plant obtain nutrients from the soil in the most optimal manner. With pathogenic-interactions, MNTs influence pathogen proliferation, the efficacy of the host's biochemical defense and related signal transduction mechanisms. We classify the MNT effects in plant-pathogen interactions as either indirect by influencing the nutrient status and fitness of the pathogen, or direct by initiating host defense mechanisms. While such observations indicate the fundamental importance of MNTs in governing the interactions with a range of microorganisms, further work is needed to develop an integrative understanding of their functions.

Selectfluor facilitated bridging of indoles to bis(indolyl)methanes using methyl tert-butyl ether as a new methylene precursor.

A novel, green and efficient method is developed for the synthesis of methylene bridged bis(indolyl)methanes in good to excellent yields. The reaction employs methyl tert-butyl ether (MTBE) as the methylene source and selectfluor as an oxidizing agent. The scope and versatility of the methods have been successfully demonstrated with 48 examples. The metal-free transformation process is suitable for scale-up production. A selectfluor-promoted oxidative reaction mechanism is proposed based on the results of the experimental studies.

Amphiphilic branched polymer-nitroxides conjugate as a nanoscale agent for potential magnetic resonance imaging of multiple objects in vivo.

BACKGROUND: In order to address the potential toxicity of metal-based magnetic resonance imaging (MRI) contrast agents (CAs), a concept of non-metallic MRI CAs has emerged. Currently, paramagnetic nitroxides (such as (2,2,5,5-tetramethylpyrrolidine-1-oxyl, PROXYL), (2,2,6,6-tetramethylpiperidine-1-oxide, TEMPO), etc.) are being extensively studied because their good stability and imaging mechanism are similar to metal-based contrast agents (such as Gd3+ chelate-based clinical CAs). However, a lower relaxivity and rapid in vivo metabolism of nitroxides remain to be addressed. Previous studies have demonstrated that the construction of macromolecular nitroxides contrast agents (mORCAs) is a promising solution through macromolecularization of nitroxides (i.e., use of large molecules to carry nitroxides). Macromolecular effects not only increase the stability of nitroxides by limiting their exposure to reductive substances in the body, but also improve the overall 1H water relaxation by increasing the concentration of nitroxides and slowing the molecular rotation speed. RESULTS: Branched pDHPMA-mPEG-Ppa-PROXYL with a high molecular weight (MW = 160 kDa) and a nitroxides content (0.059 mmol/g) can form a nanoscale (~ 28 nm) self-assembled aggregate in a water environment and hydrophobic PROXYL can be protected by a hydrophilic outer layer to obtain strong reduction resistance in vivo. Compared with a small molecular CA (3-Carboxy-PROXYL (3-CP)), Branched pDHPMA-mPEG-Ppa-PROXYL displays three prominent features: (1) its longitudinal relaxivity (0.50 mM- 1 s- 1) is about three times that of 3-CP (0.17 mM- 1 s- 1); (2) the blood retention time of nitroxides is significantly increased from a few minutes of 3-CP to 6 h; (3) it provides long-term and significant enhancement in MR imaging of the tumor, liver, kidney and cardiovascular system (heart and aortaventralis), and this is the first report on nitroxides-based MRI CAs for imaging the cardiovascular system. CONCLUSIONS: As a safe and efficient candidate metal-free magnetic resonance contrast agent, Branched pDHPMA-mPEG-Ppa-PROXYL is expected to be used not only in imaging the tumor, liver and kidney, but also the cardiovascular system, which expands the application scope of these CAs.