Estimating tree-based dynamic treatment regimes using observational data with restricted treatment sequences

A dynamic treatment regime (DTR) is a sequence of decision rules that provide guidance on how to treat individuals based on their static and time-varying status. Existing observational data are often used to generate hypotheses about effective DTRs. A common challenge with observational data, however, is the need for analysts to consider “restrictions” on the treatment sequences. Such restrictions may be necessary for settings where (1) one or more treatment sequences that were offered to individuals when the data were collected are no longer considered viable in practice, (2) specific treatment sequences are no longer available, or (3) the scientific focus of the analysis concerns a specific type of treatment sequences (eg, “stepped-up” treatments). To address this challenge, we propose a restricted tree–based reinforcement learning (RT-RL) method that searches for an interpretable DTR with the maximum expected outcome, given a (set of) user-specified restriction(s), which specifies treatment options (at each stage) that ought not to be considered as part of the estimated tree-based DTR. In simulations, we evaluate the performance of RT-RL versus the standard approach of ignoring the partial data for individuals not following the (set of) restriction(s). The method is illustrated using an observational data set to estimate a two-stage stepped-up DTR for guiding the level of care placement for adolescents with substance use disorder.     

Sub-Cellular Distribution of Zinc in Different Vegetative Organs and Their Contribution to Grains Zinc Accumulation in Rice Under Different Nitrogen and Zinc Supply

Journal of Plant Growth Regulation - Zinc is an important micronutrient for the growth and development of human body and plants. Proper use of nitrogen fertilizer and foliar application of Zn have...     

铜对大鳞泥鳅幼鱼的毒性

本文用流水和换水式试验,在水硬度为115mg/L(以CaCO_3计)条件下研究了铜对大鳞泥鳅幼鱼生长和存活的影响。试验从刚孵出的幼鱼开始,流水式试验持续30d,换水式试验历时16d。结果表明,在流水条件下铜对泥鳅幼鱼存活有明显影响的可观察效应浓度最低是41.2μg/L,而无可观察效应浓度则为25.2μg/L。根据对现存量的影响,用换水式试验测得铜的最低可观察效应浓度为38μg/L,无可观察效应浓度是19μg/L。     

LDL的氧化修饰和氧化修饰LDL的组成和结构变化

与低密度脂蛋白(LDL)相比,氧化修饰LDL(O-LDL)的组成、结构和生物学特性发生了深刻的变化,而组成和结构的改变是生物学特性改变的基础.本文根据最近文献资料.结合我们实验室的工作.对LDL的氧化修饰、O-LDL的组成、结构改变,以及它们的机理作一简要综述.     

玻璃体内注射清栓酶治疗实验性玻璃体积血

清栓酶可促进玻璃体内纤维蛋白凝血块溶解,我们制作新鲜及陈旧性兔眼玻璃体积血模型,将清栓酶、尿激酶及注射用水分别注入玻璃体腔内,观察眼底、测定玻璃体出血指数、FDP含量、进行3P 试验,结果发现清栓酶有治疗效果,同对照组相比统计学上有显著差异,同尿激酶相比无差异,且未发现有毒副作用。     

Insights into circular RNAs: Biogenesis,function and their regulatory roles in cardiovascular disease

As a distinctive member of the noncoding RNA family, circular RNAs (circRNAs) are generated from single-stranded, covalently closed structures and are ubiquitous in mammalian cells and tissues. Due to its atypical circular architecture, it was conventionally deemed insignificant dark matter for a prolonged duration. Nevertheless, studies conducted over the last decade have demonstrated that this abundant, structurally stable and tissue-specific RNA has been increasingly relevant in diverse diseases, including cancer, neurological disorders, diabetes mellitus and cardiovascular diseases (CVDs). Therefore, regulatory pathways controlled by circRNAs are widely involved in the occurrence and pathological processes of CVDs through their function as miRNA sponges, protein sponges and protein scaffolds. To better understand the role of circRNAs and their complex regulatory networks in CVDs, we summarize current knowledge of their biogenesis and function and the latest research on circRNAs in CVDs, with the hope of paving the way for the identification of promising biomarkers and therapeutic strategies for CVDs.     

Pan-Cancer analyses of Necroptosis-Related genes as a potential target to predict immunotherapeutic outcome

Necroptosis is a unique programmed death mechanism of necrotic cells. However, its role and specific mechanism in cancer remain unclear, and a systematic pan-cancer analysis of necroptosis is yet to be conducted. Thus, we performed a specific pan-cancer analysis using The Cancer Genome Atlas and Genotype-Tissue Expression databases to analyse necroptosis expression in terms of cancer prognosis, DNA methylation status, tumour mutative burden, microsatellite instability, immune cell infiltration in different types of cancer and molecular mechanisms. For the first time, we explored the correlation between necroptosis and immunotherapy prognosis. Thus, our study provides a relatively comprehensive understanding of the carcinogenicity of necroptosis in different types of cancer. It is suggested that necroptosis can be used to evaluate the sensitivity of different patients to immunotherapy and may become a potential target for tumour immunotherapy.     

First chromosome scale genomes of ithomiine butterflies (Nymphalidae: Ithomiini): Comparative models for mimicry genetic studies

The ithomiine butterflies (Nymphalidae: Danainae) represent the largest known radiation of Müllerian mimetic butterflies. They dominate by number the mimetic butterfly communities, which include species such as the iconic neotropical Heliconius genus. Recent studies on the ecology and genetics of speciation in Ithomiini have suggested that sexual pheromones, colour pattern and perhaps hostplant could drive reproductive isolation. However, no reference genome was available for Ithomiini, which has hindered further exploration on the genetic architecture of these candidate traits, and more generally on the genomic patterns of divergence. Here, we generated high-quality, chromosome-scale genome assemblies for two Melinaea species, M. marsaeus and M. menophilus, and a draft genome of the species Ithomia salapia. We obtained genomes with a size ranging from 396 to 503 Mb across the three species and scaffold N50 of 40.5 and 23.2 Mb for the two chromosome-scale assemblies. Using collinearity analyses we identified massive rearrangements between the two closely related Melinaea species. An annotation of transposable elements and gene content was performed, as well as a specialist annotation to target chemosensory genes, which is crucial for host plant detection and mate recognition in mimetic species. A comparative genomic approach revealed independent gene expansions in ithomiines and particularly in gustatory receptor genes. These first three genomes of ithomiine mimetic butterflies constitute a valuable addition and a welcome comparison to existing biological models such as Heliconius, and will enable further understanding of the mechanisms of adaptation in butterflies.     

Effects of serotonin (5HT) and complement C3 on the synthesis of the surface membrane precursors of adult Schistosoma mansoni

The syncytial surface epithelium of Schistosoma mansoni plays an important role in immune evasion. This syncytium is covered by an unusual double-membrane complex consisting of an apical plasma membrane (APM) and an overlying envelope (En) that have been shown to have different rates of synthesis and turnover. It has been suggested that discoid bodies (DBs) and multilamellar bodies (MLBs), the major syncytial inclusion bodies of schistosomes, may be the precursors of the APM and En, respectively. In this ultrastructural study, we examined the effects of serotonin (5HT) and complement C3, which have been shown to stimulate synthesis and turnover of the APM and En, respectively, on the synthesis of DBs and MLBs in vitro. With short-time incubations (20 or 40 min), 5HT stimulated the synthesis of the DBs by 2-fold, whereas C3 accelerated synthesis of the MLBs by 2-fold. Furthermore, when microtubules within the cytoplasmic connections between the syncytium and the underlying cell bodies (the site of membrane synthesis) were disrupted with colchicine, the DBs and MLBs synthesized in response to 5HT or C3 accumulated in the cell bodies. This suggests that the transport of the organelles to the syncytium is dependent upon the microtubules but not the signaling mechanism in response to 5HT or C3. These observations also support the suggestion that the DBs and MLBs are synthesized in subsyncytial cell bodies and serve as precursors of the APM and En, respectively. The rapid synthetic response to 5HT and C3 is also consistent with rapid synthesis and turnover of the APM/En, as suggested by previous studies.     

Total chemical synthesis and NMR characterization of the glycopeptide tx5a, a heavily post-translationally modified conotoxin, reveals that the glycan structure is alpha-D-Gal-(1-->3)-alpha-D-GalNAc.

The 13-amino acid glycopeptide tx5a (Gla-Cys-Cys-Gla-Asp-Gly-Trp*-Cys-Cys-Thr*-Ala-Ala-Hyp-OH, where Trp* = 6-bromotryptophan and Thr* = Gal-GalNAc-threonine), isolated from Conus textile, causes hyperactivity and spasticity when injected intracerebral ventricularly into mice. It contains nine post-translationally modified residues: four cysteine residues, two gamma-carboxyglutamic acid residues, and one residue each of 6-bromotryptophan, 4-trans-hydroxyproline and glycosylated threonine. The chemical nature of each of these has been determined with the exception of the glycan linkage pattern on threonine and the stereochemistry of the 6-bromotryptophan residue. Previous investigations have demonstrated that tx5a contains a disaccharide composed of N-acetylgalactosamine (GalNAc) and galactose (Gal), but the interresidue linkage was not characterized. We hypothesized that tx5a contained the T-antigen, beta-D-Gal-(1-->3)-alpha-D-GalNAc, one of the most common O-linked glycan structures, identified previously in another Conus glycopeptide, contalukin-G. We therefore utilized the peracetylated form of this glycan attached to Fmoc-threonine in an attempted synthesis. While the result-ing synthetic peptide (Gla-Cys-Cys-Gla-Asp-Gly-Trp*-Cys-Cys-Thr*-Ala-Ala-Hyp-OH, where Trp* =6-bromotryptophan and Thr* = beta-D-Gal-(1-->3)-alpha-D-GalNAc-threonine) and the native peptide had almost identical mass spectra, a comparison of their RP-HPLC chromatograms suggested that the two forms were not identical. Two-dimensional 1H homonuclear and 13C-1H heteronuclear NMR spectroscopy of native tx5a isolated from Conus textile was then used to determine that the glycan present on tx5a indeed is not the aforementioned T-antigen, but rather alpha-D-Gal-(1-->3)-alpha-D-GalNAc.