Safe Offline Reinforcement Learning with Real-Time Budget Constraints

Aiming at promoting the safe real-world deployment of Reinforcement Learning (RL), research on safe RL has made significant progress in recent years. However, most existing works in the literature still focus on the online setting where risky violations of the safety budget are likely to be incurred during training. Besides, in many real-world applications, the learned policy is required to respond to dynamically determined safety budgets (i.e., constraint threshold) in real time. In this paper, we target at the above real-time budget constraint problem under the offline setting, and propose Trajectory-based REal-time Budget Inference (TREBI) as a novel solution that approaches this problem from the perspective of trajectory distribution. Theoretically, we prove an error bound of the estimation on the episodic reward and cost under the offline setting and thus provide a performance guarantee for TREBI. Empirical results on a wide range of simulation tasks and a real-world large-scale advertising application demonstrate the capability of TREBI in solving real-time budget constraint problems under offline settings.Comment: We propose a method to handle the constraint problem with dynamically determined safety budgets under the offline settin

A real-world pharmacovigilance study of polatuzumab vedotin based on the FDA adverse event reporting system (FAERS)

BackgroundPolatuzumab vedotin, the first FDA-approved antibody-drug conjugate (ADC) targeting CD79b, is utilized in the treatment of previously untreated diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL), as well as relapsed or refractory (R/R) DLBCL. Despite its approval, concerns persist regarding the long-term safety profile of polatuzumab vedotin. This study aims to evaluate the adverse events (AEs) associated with polatuzumab vedotin since its approval in 2019, utilizing data mining strategies applied to the FDA Adverse Event Reporting System (FAERS).MethodsSignal detection employed four methodologies, including reporting odds ratio (ROR), proportional reporting ratio (PRR), bayesian confidence propagation neural network (BCPNN), and multi-item gamma poisson shrinker (MGPS), to evaluate and quantify the signals of polatuzumab vedotin-associated AEs. Additionally, subgroup analyses based on patients age, gender, and fatal cases were conducted to investigate AEs occurrences in specific subpopulations.ResultsA total of 1,521 reports listing polatuzumab vedotin as a “principal suspect (PS)” drug were collected from the FAERS database. Through concurrent compliance with four algorithms, 19 significant Standardized MedDRA Query (SMQ) AEs and 92 significant Preferred Term (PT) AEs were detected. Subgroup analyses revealed a higher incidence of PTs in male patients compared to female patients, increased likelihood of polatuzumab vedotin-associated AEs in elder patients (>65 years), and AEs with a high risk of fatal cases include: blood lactate dehydrogenase increased, cytopenia, and hydronephrosis. The median time to AEs occurrence following polatuzumab vedotin initiation was 18.5 (5∼57.75) days, with 95% of AEs occurred within 162 days.ConclusionThis study identified various AEs associated with polatuzumab vedotin, offering critical insights for clinical monitoring and risk identification in patients receiving polatuzumab vedotin therapy

Variation and stability of rhizosphere bacterial communities of Cucumis crops in association with root-knot nematodes infestation

IntroductionRoot-knot nematodes (RKN) disease is a devastating disease in Cucumis crops production. Existing studies have shown that resistant and susceptible crops are enriched with different rhizosphere microorganisms, and microorganisms enriched in resistant crops can antagonize pathogenic bacteria. However, the characteristics of rhizosphere microbial communities of Cucumis crops after RKN infestation remain largely unknown.MethodsIn this study, we compared the changes in rhizosphere bacterial communities between highly RKN-resistant Cucumis metuliferus (cm3) and highly RKN-susceptible Cucumis sativus (cuc) after RKN infection through a pot experiment. ResultsThe results showed that the strongest response of rhizosphere bacterial communities of Cucumis crops to RKN infestation occurred during early growth, as evidenced by changes in species diversity and community composition. However, the more stable structure of the rhizosphere bacterial community in cm3 was reflected in less changes in species diversity and community composition after RKN infestation, forming a more complex and positively co-occurrence network than cuc. Moreover, we observed that both cm3 and cuc recruited bacteria after RKN infestation, but the bacteria enriched in cm3 were more abundant including beneficial bacteria Acidobacteria, Nocardioidaceae and Sphingomonadales. In addition, the cuc was enriched with beneficial bacteria Actinobacteria, Bacilli and Cyanobacteria. We also found that more antagonistic bacteria than cuc were screened in cm3 after RKN infestation and most of them were Pseudomonas (Proteobacteria, Pseudomonadaceae), and Proteobacteria were also enriched in cm3 after RKN infestation. We hypothesized that the cooperation between Pseudomonas and the beneficial bacteria in cm3 could inhibit the infestation of RKN.DiscussionThus, our results provide valuable insights into the role of rhizosphere bacterial communities on RKN diseases of Cucumis crops, and further studies are needed to clarify the bacterial communities that suppress RKN in Cucumis crops rhizosphere

Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis

Abnormal angiogenesis is associated with myriad human diseases including proliferative diabetic retinopathy. Signaling transduction via phosphoinositide 3-kinases (PI3Ks) plays a critical role in angiogenesis. Herein, we showed that p110δ, the catalytic subunit of PI3Kδ, was highly expressed in pathological retinal vascular endothelial cells (ECs) in a mouse model of oxygen-induced retinopathy (OIR) and in fibrovascular membranes from patients with proliferative diabetic retinopathy. To explore novel intervention with PI3Kδ expression, we developed a recombinant dual adeno-associated viral (rAAV) system for delivering CRISPR/Cas9 in which Streptococcus pyogenes (Sp) Cas9 expression was driven by an endothelial specific promoter of intercellular adhesion molecule 2 (pICAM2) to edit genomic Pik3cd, the gene encoding p110δ. We then demonstrated that infection of cultured mouse vascular endothelial cells with the dual rAAV1s of rAAV1-pICAM2-SpCas9 and rAAV1-SpGuide targeting genomic Pik3cd resulted in 80% DNA insertion/deletion in the locus of genomic Pik3cd and 70% depletion of p110δ expression. Furthermore, we showed that in the mouse model of OIR editing retinal Pik3cd with the dual rAAV1s resulted in not only a significant decrease in p110δ expression, and Akt activation, but also a dramatic reduction in pathological retinal angiogenesis. These findings reveal that Pik3cd editing is a novel approach to treating abnormal retinal angiogenesis

Correction to: Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis, by Wu et al. Hum Gene Ther 2023;34(1-2):30-41; doi: 10.1089/hum.2022.079

In the January 2023 issue of Human Gene Therapy (vol. 34, no. 1-2; 30–41), the article titled Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis, by Wu et al. requires correction. The author byline originally appeared with the 13th author's name incorrectly published as GuomingZhao Wenyi Wu,1,2,3 Gaoen Ma,4 Hui Qi,5 Lijun Dong,5 Fang Chen,6 Yun Wang,5 Xingxing Mao,5 Xiaoqing Guo,2,3 Jing Cui,7 Joanne Aiko Matsubara,7 Bart Vanhaesebroeck,8 Xiaohe Yan,5Guoming Zhao,5 Shaochong Zhang,5,* and Hetian Lei 5,* The correct spelling of the author's name is GuomingZhang The online version of the article has been corrected to reflect this. The authors apologize for the error

Comprehensive analysis of the WRKY gene family in Cucumis metuliferus and their expression profile in response to an early stage of root knot nematode infection

Root-knot nematode (RKN) is a major factor that limits the growth and productivity of important Cucumis crops, such as cucumber and melon, which lack RKN-resistance genes in their genome. Cucumis metuliferus is a wild Cucumis species that displays a high degree of RKN-resistance. WRKY transcription factors were involved in plant response to biotic stresses. However, little is known on the function of WRKY genes in response to RKN infection in Cucumis crops. In this study, Cucumis metuliferus 60 WRKY genes (CmWRKY) were identified in the C. metuliferus genome, and their conserved domains were classified into three main groups based on multiple sequence alignment and phylogenetic analysis. Synteny analysis indicated that the WRKY genes were highly conserved in Cucumis crops. Transcriptome data from of C. metuliferus roots inoculated with RKN revealed that 16 CmWRKY genes showed differential expression, of which 13 genes were upregulated and three genes were downregulated, indicating that these CmWRKY genes are important to C. metuliferus response to RKN infection. Two differentially expression CmWRKY genes (CmWRKY10 and CmWRKY28) were selected for further functional analysis. Both CmWRKY genes were localized in nucleus, indicating they may play roles in transcriptional regulation. This study provides a foundation for further research on the function of CmWRKY genes in RKN stress resistance and elucidation of the regulatory mechanism

Pervasive hybridization during evolutionary radiation of Rhododendron subgenus Hymenanthes in mountains of southwest China

Radiations are especially important for generating species biodiversity in mountainous ecosystems. The contribution of hybridization to such radiations has rarely been examined. Here, we use extensive genomic data to test whether hybridization was involved in evolutionary radiation within Rhododendron subgenus Hymenanthes, whose members show strong geographic isolation in the mountains of southwest China. We sequenced genomes for 143 species of this subgenus and 93 species of four other subgenera, and found that Hymenanthes was monophyletic and radiated during the late Oligocene to middle Miocene. Widespread hybridization events were inferred within and between the identified clades and subclades. This suggests that hybridization occurred both early and late during diversification of subgenus Hymenanthes, although the extent to which hybridization, speciation through mixing-isolation-mixing or hybrid speciation, accelerated the diversification needs further exploration. Cycles of isolation and contact in such and other montane ecosystems may have together promoted species radiation through hybridization between diverging populations and species. Similar radiation processes may apply to other montane floras in this region and elsewhere

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.This work was conducted on behalf of the CHIPGECS and The PRACTICAL consortia (see Supplementary Consortia). We acknowledge the contribution of doctors, nurses and postgraduate research students at the CHIPGENCS sample collecting centers. We thank Orchid and Rosetrees for funding support. This work was also supported by National Natural Science foundation of China for funding support to H Zhang (Grant No: 30671793 and 81072377), N Feng (Grant No: 81272831), X Zhang (Grant No: 30572139, 30872924 and 81072095), S Zhao (Grant No: 81072092 and 81328017), Y Yu (Grant No: 81172448) and Program for New Century Excellent Talents in University from Department of Education of China (NCET-08-0223) and the National High Technology Research and Development Program of China (863 Program 2012AA021101) to X Zhang.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.725

The complete chloroplast genome of Torreya parvifolia, a species with extremely small population in China

Torreya parvifolia (Torreya, Taxaceae) is endemic in Sichuan, China. It consisted of an extremely small population with less than 100 wild individuals. In this study, the complete chloroplast genome of T. parvifolia was assembled using the Illumina data. The complete chloroplast genome of T. parvifolia is 137,106 bp in length. The genome consists of 119 genes in total, including 82 protein-coding genes (PCGs), 4 ribosomal RNA (rRNA) genes, and 33 transfer RNA (tRNA) genes. Phylogenetic analysis indicated that T. parvifolia was closely related to T. fargesii, T. nucifera, and T. fargesii var. yunnanensis with strong support

Consistent Total Traction Torque-Oriented Coordinated Control of Multimotors with Input Saturation for Heavy-Haul Locomotives

In the coordinated control of multiple motors for heavy-haul locomotives, the input value for a motor often exceeds its maximum allowable input value, resulting in the saturation problem. A traction total-amount coordinated tracking control (TACTC) strategy is proposed to address the input saturation of heavy-haul locomotives driven by multiple motors. This strategy reduces control input and suppresses input saturation. First, a multimotor traction model with uncertain parameter perturbations and external disturbances was established. Next, a sliding-mode disturbance observer (SMDO) was designed to reduce the sliding-mode switching gain, thereby decreasing the control input. An auxiliary anti-windup (AW) system was used to weaken the effect of input saturation on tracking performance. Then, the observed value and auxiliary state were fed back to the sliding-mode controller to design a TACTC protocol and ensure that the total amount of traction torque follows the desired traction characteristic curve. Finally, the Matlab/Simulink simulation and RT-Lab semiphysical experiment results show that the proposed strategy can effectively suppress the input saturation problem of multimotor coordinated control