First-order Policy Optimization for Robust Markov Decision Process

We consider the problem of solving robust Markov decision process (MDP), which involves a set of discounted, finite state, finite action space MDPs with uncertain transition kernels. The goal of planning is to find a robust policy that optimizes the worst-case values against the transition uncertainties, and thus encompasses the standard MDP planning as a special case. For $(\mathbf{s},\mathbf{a})$-rectangular uncertainty sets, we develop a policy-based first-order method, namely the robust policy mirror descent (RPMD), and establish an $\mathcal{O}(\log(1/\epsilon))$ and $\mathcal{O}(1/\epsilon)$ iteration complexity for finding an $\epsilon$-optimal policy, with two increasing-stepsize schemes. The prior convergence of RPMD is applicable to any Bregman divergence, provided the policy space has bounded radius measured by the divergence when centering at the initial policy. Moreover, when the Bregman divergence corresponds to the squared euclidean distance, we establish an $\mathcal{O}(\max \{1/\epsilon, 1/(\eta \epsilon^2)\})$ complexity of RPMD with any constant stepsize $\eta$. For a general class of Bregman divergences, a similar complexity is also established for RPMD with constant stepsizes, provided the uncertainty set satisfies the relative strong convexity. We further develop a stochastic variant, named SRPMD, when the first-order information is only available through online interactions with the nominal environment. For general Bregman divergences, we establish an $\mathcal{O}(1/\epsilon^2)$ and $\mathcal{O}(1/\epsilon^3)$ sample complexity with two increasing-stepsize schemes. For the euclidean Bregman divergence, we establish an $\mathcal{O}(1/\epsilon^3)$ sample complexity with constant stepsizes. To the best of our knowledge, all the aforementioned results appear to be new for policy-based first-order methods applied to the robust MDP problem

Prediabetes is associated with a higher serum neurofilament light chain level in adolescents

ObjectiveSerum neurofilament light chain (sNfL) level, which is a biomarker indicative of neuroaxonal damage and cognitive impairment, has been reported in several neurological diseases. There has been a lack of studies on the association between sNfL levels and prediabetes in adolescents. This study investigated whether sNfL levels were higher in adolescents with prediabetes undergoing elective orthopedic surgery.MethodsThe sNfL level was measured in 149 adolescents aged from 12 to 18 years who underwent elective orthopedic surgery at the Hunan Children’s Hospital (18 with and 131 without prediabetes). We evaluated the association between prediabetes and sNfL level after adjusting for age, sex, and triglycerides using a multivariable linear regression model.ResultsThe prevalence of prediabetes in adolescents was 12.08%. Univariate logistic regression analysis showed that prediabetes was related to sNfL. In multivariate logistic regression analysis, the association between prediabetes with sNfL levels remained significant after adjustment for age, sex, and triglyceride. The relationship between the two was further visualized by a smoothed curve.ConclusionsPrediabetes is associated with a higher sNfL. Further large-scale and prospective studies are needed to verify the clinical application of sNfL as a monitoring biomarker for adolescent prediabetes in adolescents and to evaluate the performance of sNfL in predicting the incidence of neuropathy and cognitive dysfunction in adolescents with prediabetes

Two new species of Craterellus (Cantharellales, Hydnaceae) with veined hymenophore from north-eastern China

In this contribution to the genus Craterellus in northern China, two new species are introduced: Craterellus connatus and C. striatus. These species and C. atrobrunneolus, initially described in south-western China, are highly similar and closely related. The species delimitation is molecularly supported by multigene phylogenetic analysis of the nr LSU and tef-1α region. Craterellus connatus is characterised by its medium-sized basidiomata, greyish-brown and smooth pileus with an off-white margin, the hymenophore with a strongly anastomosing vein, turning khaki upon drying, connate stipe, broad ellipsoid to ellipsoid basidiospores (6.1–7.8 × 4.8–5.9 μm), slender basidia with (2)4–6 sterigmata and the absence of clamp connection. Craterellus striatus is characterised by its small-sized basidiomata, fibrillose, greyish-brown to yellowish-brown, fully perforated pileus with a brown fringe, the hymenophore with a forking vein, the stipe inflated at the base, broad ellipsoid to ellipsoid basidiospores (6.8–8.0 × 5.1–6.0 μm), 2–6 spored basidia, encrusted hyphae and the absence of clamp connection. Detailed macroscopic and microscopic descriptions, accompanied by illustrations and a taxonomic discussion, are presented. A key to the Chinese Craterellus species is also provided

Development and validation of a predictive model for the risk of endocervical curettage positivity

ObjectiveThis study aimed to analyze the clinical characteristics of patients undergoing endocervical curettage (ECC), identify factors influencing ECC positivity, and develop a predictive model to assess the risk of positive ECC results. The goal was to assist clinicians in making ECC decisions and reduce missed diagnoses of cervical lesions.MethodsA retrospective analysis was performed on 953 patients who underwent colposcopically directed biopsy and ECC at the gynecology clinic of the First Affiliated Hospital of Xi’an Jiaotong University between October 2021 and September 2023 due to abnormal screening results. Univariate and multivariate logistic regression analyses were used to identify predictive factors for ECC positivity. An individualized prediction model for ECC positivity risk was developed using R Studio, and the model was subsequently evaluated and validated.ResultsAmong the 953 women, the ECC positive rate was 31.48% (300/953). Logistic regression analysis identified age (P<0.001), human papillomavirus (HPV) status (P<0.01), cytology results (P<0.05), acetowhite changes (P<0.01), Lugol staining (P<0.01), and colposcopic impression (P<0.01) as independent predictors of ECC positivity. These factors were incorporated into the prediction model for ECC positivity risk. The area under the receiver operating characteristic curve (AUC) of the model was 0.792 (95% CI:0.760–0.824). The Hosmer-Lemeshow test yielded a χ2 value of 10.489 (P=0.2324), and the calibration and clinical decision curves demonstrated that the model exhibited satisfactory calibration and clinical utility.ConclusionsThe clinical prediction model developed in this study demonstrated good discrimination, calibration, and clinical utility. It can be used to evaluate the risk of ECC positivity in patients undergoing colposcopy, reduce missed diagnoses of cervical lesions, and aid clinicians in making ECC decisions

Strategic Combination of Isocratic and Gradient Elution for Simultaneous Separation of Polar Compounds in Traditional Chinese Medicines by HPLC

A simple high-performance liquid chromatography (HPLC) method for the simultaneous separation of the highly polar and weakly polar components of traditional Chinese medicines was developed via a strategic combination of isocratic and gradient elution methods. Liu-Shen-Wan and Liu-Wei-Di-Huang-Wan were used as representative examples of traditional Chinese medicines. This is the first time that 6 components of varying degrees of polarity in Liu-Shen-Wan had been successfully resolved in a single chromatographic run using an ultraviolet-visible detector with a fixed wavelength of 296 nm. In contrast to conventional gradient separation methods, this novel method offered a viable route for separation of the highly and weakly polar fractions simultaneously, thus greatly reducing the time and cost of analysis. This method therefore provides a more efficient way to determine the polar components present in traditional Chinese medicines. It would find potential application in drug screening, drug authentication, and product quality control

Crystal structures of human caspase 6 reveal a new mechanism for intramolecular cleavage self‐activation

Dimeric effectors caspase 3 and caspase 7 are activated by initiator caspase processing. In this study, we report the crystal structures of effector caspase 6 (CASP6) zymogen and N-Acetyl-Val-Glu-Ile-Asp-al-inhibited CASP6. Both of these forms of CASP6 have a dimeric structure, and in CASP6 zymogen the intersubunit cleavage site (190)TEVD(193) is well structured and inserts into the active site. This positions residue Asp 193 to be easily attacked by the catalytic residue Cys 163. We demonstrate biochemically that intramolecular cleavage at Asp 193 is a prerequisite for CASP6 self-activation and that this activation mechanism is dependent on the length of the L2 loop. Our results indicate that CASP6 can be activated and regulated through intramolecular self-cleavage.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000283507900009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Biochemistry & Molecular BiologyCell BiologySCI(E)PubMed42ARTICLE11841-8471

A Genetic Variant of miR-34a Contributes to Susceptibility of Ischemic Stroke Among Chinese Population

miRNAs are small non-coding RNAs modulating gene expression, and variants in miRNA genes are involved in the pathogenesis of ischemic stroke (IS). However, the effect of miR-34a polymorphisms on IS susceptibility has rarely been reported. In the present study, we investigated the association between rs12128240, rs2666433, and rs6577555 of the miR-34a gene and IS susceptibility. Snapshot assay was used to detect miR-34a polymorphisms in 548 IS patients and 560 controls. Relative expression of miR-34a was measured by quantitative real-time PCR. We found that rs2666433 was associated with a significantly increased risk of IS (AA vs. GG: OR = 1.61, 95% CI = 1.05–2.52, P = 0.031; AA vs. GG+GA: OR = 1.58, 95% CI = 1.05–2.45, P = 0.026). For the IS subtypes, rs2666433 was associated with large artery atherosclerosis (AA vs. GG: OR = 2.09, 95% CI = 1.16–3.51, P = 0.007; AA vs. GG+GA: OR = 2.02, 95% CI = 1.15–3.33, P = 0.007; A vs. G: OR = 1.36, 95% CI = 1.07–1.81, P = 0.021). Additionally, the level of miR-34a was significantly up-regulated in IS patients compared to the controls (P < 0.001), and patients with rs2666433 AA genotype had a higher level of miR-34a than those with GG+GA genotypes (P < 0.001). Furthermore, increased level of homocysteine was observed in IS patients compared to the controls (P < 0.001), especially in patients carrying the rs2666433AA genotype compared to those carrying the rs2666433 GG+GA genotypes (P < 0.001). However, no significant association between rs12128240 or rs6577555 and IS was found. Collectively, our study found the association between miR-34a polymorphisms and the risk of IS among the Chinese population. The results may provide an explanation for etiology of IS and a potential biomarker or therapeutic target for IS. HIGHLIGHTS-MiR-34a rs2666433 polymorphism was associated with an increased risk of ischemic stroke.-The level of miR-34a was significantly up-regulated in ischemic stroke patients compared with controls, and patients with rs2666433 AA genotype had a higher level miR-34a than those with GG+GA genotypes.-Furthermore, increased level of homocysteine was showed in IS patients compared to controls, and in patients carrying the rs2666433AA compared to those carrying the rs2666433 GG+GA

Structure of the bifunctional methyltransferase YcbY (RlmKL) that adds the m7G2069 and m2G2445 modifications in Escherichia coli 23S rRNA

The 23S rRNA nucleotide m2G2445 is highly conserved in bacteria, and in Escherichia coli this modification is added by the enzyme YcbY. With lengths of around 700 amino acids, YcbY orthologs are the largest rRNA methyltransferases identified in Gram-negative bacteria, and they appear to be fusions from two separate proteins found in Gram-positives. The crystal structures described here show that both the N- and C-terminal halves of E. coli YcbY have a methyltransferase active site and their folding patterns respectively resemble the Streptococcus mutans proteins Smu472 and Smu776. Mass spectrometric analyses of 23S rRNAs showed that the N-terminal region of YcbY and Smu472 are functionally equivalent and add the m2G2445 modification, while the C-terminal region of YcbY is responsible for the m7G2069 methylation on the opposite side of the same helix (H74). Smu776 does not target G2069, and this nucleotide remains unmodified in Gram-positive rRNAs. The E.coli YcbY enzyme is the first example of a methyltransferase catalyzing two mechanistically different types of RNA modification, and has been renamed as the Ribosomal large subunit methyltransferase, RlmKL. Our structural and functional data provide insights into how this bifunctional enzyme evolved

Nucleotide excision repair-initiating proteins bind to oxidative DNA lesions in vivo

Base excision repair (BER) is the main repair pathway to eliminate abundant oxidative DNA lesions such as 8-oxo-7,8-dihydroguanine. Recent data suggest that the key transcription-coupled nucleotide excision repair factor (TC-NER) Cockayne syndrome group B (CSB) and the global genome NER-initiating factor XPC are implicated in the protection of cells against oxidative DNA damages. Our novel live-cell imaging approach revealed a strong and very rapid recruitment of XPC an CSB to sites of oxidative DNA lesions in living cells. The absence of detectable accumulation of downstrea NER factors at the site of local oxidative DNA damage provide the first in vivo indication of the involvement of CSB and XPC in the repair of oxidative DNA lesions independent of the remainder of the NER reaction. Interestingly, CSB exhibited different and transcription-dependent kinetics in the two compartments studied (nucleolus and nucleoplasm), suggesting a direct transcription-dependent involvement of CSB in the repair of oxidative lesions associated with different RNA polymerases but not involving other NER proteins