Lead contamination alters enzyme activities and microbial composition in the rhizosphere soil of the hyperaccumulator Pogonatherum crinitum

Pogonatherum crinitum is a promising lead (Pb) hyperaccumulator; however, the effects of Pb contamination on P. crinitum rhizosphere soil enzymatic activities and microbial composition remain largely unexplored. Thus, an indoor experiment was conducted by cultivating P. crinitum seedlings and exposing them to four Pb concentrations (0, 1,000, 2000 and 3000 mg/kg Pb). Protease, urease, acid phosphatase and invertase activities were determined using standard methods while soil bacterial composition was determined by 16 S rDNA sequencing. The results showed that rhizosphere soil acid phosphatase activity significantly increased with increasing Pb concentration, while urease activity was significantly greater in rhizosphere soil contaminated with 1000 and 2000 mg/kg than in the control. There was a clear shift in bacterial composition during phytoremediation by P. crinitum. Compared to the control, Bacteroidetes was more abundant in all Pb-contaminated soils, Actinobacteria was more abundant in 1000 mg/kg Pb-treated soil, and Firmicutes was more abundant in 3000 mg/kg Pb-treated soil. Positive correlations were observed between dominant bacterial phyla and soil enzyme activities. Metabolic pathways, such as ABC transporter, quinine reductase, and ATP-binding protein were significantly increased in rhizosphere soil bacteria with Pb contamination. In conclusion, Pb contamination differentially influenced the activities of rhizosphere soil enzymes, specifically increasing acid phosphatase and urease activities, and alters the dominance of soil bacteria through up-regulation of genes related to some metabolic pathways. The strong correlations between dominant bacterial phyla and enzymatic activities suggest synergetic effects on the growth of P. crinitum during Pb contamination

A broad-spectrum substrate for the human UDP-glucuronosyltransferases and its use for investigating glucuronidation inhibitors

Strong inhibition of the human UDP-glucuronosyltransferase enzymes (UGTs) may lead to undesirable effects, including hyperbilirubinaemia and drugiherb-drug interactions. Currently, there is no good way to examine the inhibitory effects and specificities of compounds toward all the important human UGTs, side-by-side and under identical conditions. Herein, we report a new, broad-spectrum substrate for human UGTs and its uses in screening and characterizing of UGT inhibitors. Following screening a variety of phenolic compound(s), we have found that methylophiopogonanone A (MOA) can be readily O-glucuronidated by all tested human UGTs, including the typical N-glucuronidating enzymes UGT1A4 and UGT2B10. MOA-O-glucuronidation yielded a single mono-O-glucuronide that was biosynthesized and purified for structural characterization and for constructing an LC-UV based MOA-O-glucuronidation activity assay, which was then used for investigating MOA-O-glucuronidation kinetics in recombinant human UGTs. The derived K-m values were crucial for selecting the most suitable assay conditions for assessing inhibitory potentials and specificity of test compound(s). Furthermore, the inhibitory effects and specificities of four known UGT inhibitors were reinvestigated by using MOA as the substrate for all tested UGTs. Collectively, MOA is a broad-spectrum substrate for the human UGTs, which offers a new and practical tool for assessing inhibitory effects and specificities of UGT inhibitors. (C) 2021 Elsevier B.V. All rights reserved.Peer reviewe

An ultra-sensitive and easy-to-use assay for sensing human UGT1A1 activities in biological systems

The human UDP-glucuronosyltransferase 1A1 (UGT1A1), one of the most essential conjugative enzymes, is responsible for the metabolism and detoxification of bilirubin and other endogenous substances, as well as many different xenobiotic compounds. Deciphering UGT1A1 relevance to human diseases and characterizing the effects of small molecules on the activities of UGT1A1 requires reliable tools for probing the function of this key enzyme in complex biological matrices. Herein, an easy-to-use assay for highly-selective and sensitive monitoring of UGT1A1 activities in various biological matrices, using liquid chromatography with fluorescence detection (LC-FD), has been developed and validated. The newly developed LC-FD based assay has been confirmed in terms of sensitivity, specificity, precision, quantitative linear range and stability. One of its main advantages is lowering the limits of detection and quantification by about 100-fold in comparison to the previous assay that used the same probe substrate, enabling reliable quantification of lower amounts of active enzyme than any other method. The precision test demonstrated that both intra- and inter-day variations for this assay were less than 5.5%. Furthermore, the newly developed assay has also been successfully used to screen and characterize the regulatory effects of small molecules on the expression level of UGT1A1 in living cells. Overall, an easy-to-use LC-FD based assay has been developed for ultra-sensitive UGT1A1 activities measurements in various biological systems, providing an inexpensive and practical approach for exploring the role of UGT1A1 in human diseases, interactions with xenobiotics, and characterization modulatory effects of small molecules on this conjugative enzyme. (c) 2020 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Peer reviewe

COIN: Chance-Constrained Imitation Learning for Uncertainty-aware Adaptive Resource Oversubscription Policy

We address the challenge of learning safe and robust decision policies in presence of uncertainty in context of the real scientific problem of adaptive resource oversubscription to enhance resource efficiency while ensuring safety against resource congestion risk. Traditional supervised prediction or forecasting models are ineffective in learning adaptive policies whereas standard online optimization or reinforcement learning is difficult to deploy on real systems. Offline methods such as imitation learning (IL) are ideal since we can directly leverage historical resource usage telemetry. But, the underlying aleatoric uncertainty in such telemetry is a critical bottleneck. We solve this with our proposed novel chance-constrained imitation learning framework, which ensures implicit safety against uncertainty in a principled manner via a combination of stochastic (chance) constraints on resource congestion risk and ensemble value functions. This leads to substantial ($\approx 3-4\times$) improvement in resource efficiency and safety in many oversubscription scenarios, including resource management in cloud services.Comment: 9 pages, 4 figure

IgA-Targeted Lactobacillus jensenii Modulated Gut Barrier and Microbiota in High-Fat Diet-Fed Mice

IgA-coated Lactobacillus live in the mucous layer of the human or mammalian intestine in close proximity to epithelial cells. They act as potential probiotics for functional food development, but their physiological regulation has not yet been studied. We isolated IgA-targeted (Lactobacillus jensenii IgA21) and lumen lactic acid bacterial strains (Pediococcus acidilactici FS1) from the fecal microbiota of a healthy woman. C57BL/6 mice were fed a normal (CON) or high fat diet (HFD) for 6 weeks and then treated with IgA21 or FS1 for 4 weeks. HFD caused dyslipidemia, mucosal barrier damage, and intestinal microbiota abnormalities. Only IgA21 significantly inhibited dyslipidemia and gut barrier damage. This was related to significant up-regulation of mucin-2, PIgR mRNA expression, and colonic butyrate production (P < 0.05 vs. HFD). Unlike IgA21, FS1 caused a more pronounced gut dybiosis than did HFD, and, in particular, it induced a significant decrease in the Bacteroidales S24-7 group and an increase in Desulfovibrionaceae (P < 0.05 vs. CON). In conclusion, IgA-coated and non-coated lactic acid bacteria of gut have been demonstrated to differentially affect the intestinal barrier and serum lipids. This indicates that IgA-bound bacteria possess the potential to more easily interact with the host gut to regulate homeostasis

Study on SnO2/graphene composites with superior electrochemical performance for lithium-ion batteries

NSFC [U1305246, 21321062]; Xiamen city [3502Z20121002]; Quanzhou "Tong-Jiang Scholar" program; Fujian "Min-Jiang Scholar" program; program for New Century Excellent Talents in University [NCET-13-0879]; Education and Scientific Research Foundation (Class A) for Young Teachers of Education Bureau of Fujian Province, China [JA13263]; National Natural Science Foundation of China [21353001]In this study, the in situ growth of tin dioxide (SnO2) nanoparticles on reduced graphene oxide (rGO) has been realized using a hydrothermal method. The size of the SnO2 nanoparticles in the SnO2/rGO composites prepared by three different procedures is about 5 nm, and they are well dispersed on rGO. When applied as anode materials for lithium-ion batteries, we found that the composites synthesized from the stannous oxalate precursor showed the best rate performance and highest cyclic stability. The surface status of the composites, including interactions between SnO2 and rGO and surface chemical components, was investigated in detail in order to understand why the composites prepared using different procedures displayed vastly different electrochemical performances. The results presented here describe a new approach for the synthesis of uniform and nanosized metal-oxide/rGO composites with excellent electrochemical performance

Polyethyleneimine-coated MXene quantum dots improve cotton tolerance to Verticillium dahliae by maintaining ROS homeostasis

Verticillium dahliae is a soil-borne hemibiotrophic fungal pathogen that threatens cotton production worldwide. In this study, we assemble the genomes of two V. dahliae isolates: the more virulence and defoliating isolate V991 and nondefoliating isolate 1cd3-2. Transcriptome and comparative genomics analyses show that genes associated with pathogen virulence are mostly induced at the late stage of infection (Stage II), accompanied by a burst of reactive oxygen species (ROS), with upregulation of more genes involved in defense response in cotton. We identify the V991-specific virulence gene SP3 that is highly expressed during the infection Stage II. V. dahliae SP3 knock-out strain shows attenuated virulence and triggers less ROS production in cotton plants. To control the disease, we employ polyethyleneimine-coated MXene quantum dots (PEI-MQDs) that possess the ability to remove ROS. Cotton seedlings treated with PEI-MQDs are capable of maintaining ROS homeostasis with enhanced peroxidase, catalase, and glutathione peroxidase activities and exhibit improved tolerance to V. dahliae. These results suggest that V. dahliae trigger ROS production to promote infection and scavenging ROS is an effective way to manage this disease. This study reveals a virulence mechanism of V. dahliae and provides a means for V. dahliae resistance that benefits cotton production

Secrets of RLHF in Large Language Models Part I: PPO

Large language models (LLMs) have formulated a blueprint for the advancement of artificial general intelligence. Its primary objective is to function as a human-centric (helpful, honest, and harmless) assistant. Alignment with humans assumes paramount significance, and reinforcement learning with human feedback (RLHF) emerges as the pivotal technological paradigm underpinning this pursuit. Current technical routes usually include \textbf{reward models} to measure human preferences, \textbf{Proximal Policy Optimization} (PPO) to optimize policy model outputs, and \textbf{process supervision} to improve step-by-step reasoning capabilities. However, due to the challenges of reward design, environment interaction, and agent training, coupled with huge trial and error cost of large language models, there is a significant barrier for AI researchers to motivate the development of technical alignment and safe landing of LLMs. The stable training of RLHF has still been a puzzle. In the first report, we dissect the framework of RLHF, re-evaluate the inner workings of PPO, and explore how the parts comprising PPO algorithms impact policy agent training. We identify policy constraints being the key factor for the effective implementation of the PPO algorithm. Therefore, we explore the PPO-max, an advanced version of PPO algorithm, to efficiently improve the training stability of the policy model. Based on our main results, we perform a comprehensive analysis of RLHF abilities compared with SFT models and ChatGPT. The absence of open-source implementations has posed significant challenges to the investigation of LLMs alignment. Therefore, we are eager to release technical reports, reward models and PPO code

Evidence of cure for extranodal nasal-type natural killer/T-cell lymphoma with current treatment: an analysis of the CLCG database

Survival from extranodal nasal-type NK/T-cell lymphoma (ENKTCL) has substantially improved over the last decade. However, there is little consensus as to whether a population of patients with ENKTCL can be considered “cured” of the disease. We aimed to evaluate the statistical “cure” of ENKTCL in the modern treatment era. This retrospective multicentric study reviewed the clinical data of 1,955 patients with ENKTCL treated with non-anthracycline-based chemotherapy and/or radiotherapy in the China Lymphoma Collaborative Group multicenter database between 2008 and 2016. A non-mixture cure model with incorporation of background mortality was fitted to estimate cure fractions, median survival times and cure time points. The relative survival curves attained plateau for the entire cohort and most subsets, indicating that the notion of cure was robust. The overall cure fraction was 71.9%. The median survival was 1.1 years in uncured patients. The cure time was 4.5 years, indicating that beyond this time, mortality in ENKTCL patients was statistically equivalent to that in the general population. Cure probability was associated with B symptoms, stage, performance status, lactate dehydrogenase, primary tumor invasion, and primary upper aerodigestive tract site. Elderly patients (>60 years) had a similar cure fraction to that of younger patients. The 5-year overall survival rate correlated well with the cure fraction across risk-stratified groups. Thus, statistical cure is possible in ENKTCL patients receiving current treatment strategies. Overall probability of cure is favorable, though it is affected by the presence of risk factors. These findings have a high potential impact on clinical practice and patients’ perspective