Relative Entropy of Correct Proximal Policy Optimization Algorithms with Modified Penalty Factor in Complex Environment.

In the field of reinforcement learning, we propose a Correct Proximal Policy Optimization (CPPO) algorithm based on the modified penalty factor ß and relative entropy in order to solve the robustness and stationarity of traditional algorithms. Firstly, In the process of reinforcement learning, this paper establishes a strategy evaluation mechanism through the policy distribution function. Secondly, the state space function is quantified by introducing entropy, whereby the approximation policy is used to approximate the real policy distribution, and the kernel function estimation and calculation of relative entropy is used to fit the reward function based on complex problem. Finally, through the comparative analysis on the classic test cases, we demonstrated that our proposed algorithm is effective, has a faster convergence speed and better performance than the traditional PPO algorithm, and the measure of the relative entropy can show the differences. In addition, it can more efficiently use the information of complex environment to learn policies. At the same time, not only can our paper explain the rationality of the policy distribution theory, the proposed framework can also balance between iteration steps, computational complexity and convergence speed, and we also introduced an effective measure of performance using the relative entropy concept.

Fe2 N/S/N Codecorated Hierarchical Porous Carbon Nanosheets for Trifunctional Electrocatalysis.

Construction of multifunctional highly active earth-abundant electrocatalysts on a large scale is a great challenge due to poor control over nanostructural features and limited active sites. Here, a simple methodology to tailor metal-organic frameworks (MOFs) to extract highly active multifunctional electrocatalysts on a large scale for oxygen reduction (ORR), oxygen evolution (OER), and hydrogen evolution reaction (HER) is presented. The N, S codoped Fe2 N decorated highly porous and defect-rich carbon nanosheets are grown using MOF xerogels, melamine, and polyvinylpyrollidone. The resulting catalyst exhibits excellent activity for ORR with an onset (0.92 V) and half-wave (0.81 V) potential similar to state-of-the-art Pt/C catalysts. The catalyst also shows outstanding OER and HER activities with a small overpotential of 360 mV in 1 m KOH and -123 mV in 0.5 m H2 SO4 at a current density of 10 mA cm-2 , respectively. Excellent catalytic properties are further supported by theoretical calculations where relevant models are built and various possible activation sites are identified by first-principles calculations. The results suggest that the carbon atoms adjacent to heteroatoms as well as Fe2 -N sites present the active sites for improved catalytic response, which is in agreement with the experimental results.

Impact of biological manure substitution on grain yield, nitrogen recovery efficiency, and soil biochemical properties.

Fertilization plays a crucial role in ensuring global food security and ecological balance. This study investigated the impact of substituting innovative biological manure for chemical fertilization on rice (Oryza sativa L) productivity and soil biochemical properties based on a three-year experiment. Our results suggested rice yield and straw weight were increased under manure addition treatment. Specifically, 70% of total nitrogen (N) fertilizer substituted by biological manure derived from straw, animal waste and microbiome, led to a substantial 13.6% increase in rice yield and a remarkable 34.2% boost in straw weight. In comparison to the conventional local farmer practice of applying 165 kg N ha-1, adopting 70% of total N plus biological manure demonstrated superior outcomes, particularly in enhancing yield components and spike morphology. Fertilization treatments led to elevated levels of soil microbial biomass carbon and N. However, a nuanced comparison with local practices indicated that applying biological manure alongside urea resulted in a slight reduction in N content in vegetative and economic organs, along with decreases of 10.4%, 11.2%, and 6.1% in N recovery efficiency (NRE), respectively. Prudent N management through the judicious application of partial biological manure fertilizer in rice systems could be imperative for sustaining productivity and soil fertility in southern China.

Study on disinfection effect of a 222-nm UVC excimer lamp on object surface.

Effective disinfection of contaminated surfaces is essential for preventing the transmission of pathogens. In this study, we investigated the UV irradiance and wavelength distribution of a 222-nm ultraviolet C (UVC) excimer lamp and its disinfection efficacy against microorganisms in laboratory conditions. By using a carrier quantitative germicidal test with stainless steel sheets as carriers, we examined the disinfection effect of the 222-nm UVC lamp on three standard strains-Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We tested the disinfection efficacy under different conditions by adjusting irradiation time, as well as the state and temperature of the stainless steel carriers. Our results indicated that a bacterial suspension in PBS and not-dried stainless steel carriers yielded better disinfection than in TSB and dried carriers. Additionally, carrier temperature had no significant impact on disinfection efficacy. When utilizing a bacterial suspension in PBS and non-dried carriers at a temperature of 20 °C, the three bacteria were eliminated by 222-nm UVC excimer lamp irradiation in just 15 s. In contrast, when using a bacterial suspension in TSB and dried carriers at temperatures of 20 °C, 4 °C, or - 20 °C, the three bacteria were eradicated by 222-nm UVC excimer lamp irradiation in 60 s. Comparatively, the LPM lamp required more than 10 min to achieve the same disinfection effect. Our data demonstrate that the 222-nm UVC excimer lamp has higher irradiance and a more potent microbial disinfection effect than the LPM lamp, requiring significantly less irradiation time to achieve the same disinfection effect under identical conditions. Furthermore, the 222-nm UVC excimer lamp exhibited a substantial disinfection effect on bacterial propagules at low temperatures. Our findings support the optimization of "tunnel-type" cold-chain goods disinfection devices, providing an alternative, highly efficient, and practical tool to combat the spread of SARS-CoV-2 through cold-chain systems.

Pima Indians diabetes mellitus classification based on machine learning (ML) algorithms.

This paper proposes an e-diagnosis system based on machine learning (ML) algorithms to be implemented on the Internet of Medical Things (IoMT) environment, particularly for diagnosing diabetes mellitus (type 2 diabetes). However, the ML applications tend to be mistrusted because of their inability to show the internal decision-making process, resulting in slow uptake by end-users within certain healthcare sectors. This research delineates the use of three interpretable supervised ML models: Naïve Bayes classifier, random forest classifier, and J48 decision tree models to be trained and tested using the Pima Indians diabetes dataset in R programming language. The performance of each algorithm is analyzed to determine the one with the best accuracy, precision, sensitivity, and specificity. An assessment of the decision process is also made to improve the model. It can be concluded that a Naïve Bayes model works well with a more fine-tuned selection of features for binary classification, while random forest works better with more features.

Antiviral efficacy upon administration of a HepDirect prodrug of 2'-C-methylcytidine to hepatitis C virus-infected chimpanzees.

Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in ~50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3'-valyl ester prodrug of 2'-C-methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol. 46[Suppl. 1]:S5, 2007; N. Afdhal et al., J. Hepatol. 44[Suppl. 2]:S19, 2006). One approach to increase the antiviral efficacy of 2'-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5'-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2'-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ~1.4 log(10) IU/ml and by >3.6 log(10) IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.

Investigating the stress corrosion cracking of a biodegradable Zn-0.8 wt%Li alloy in simulated body fluid.

Stress corrosion cracking (SCC) may lead to brittle, unexpected failure of medical devices. However, available researches are limited to Mg-based biodegradable metals (BM) and pure Zn. The stress corrosion behaviors of newly-developed Zn alloys remain unclear. In the present work, we conducted slow strain rate testing (SSRT) and constant-load immersion test on a promising Zn-0.8 wt%Li alloy in order to investigate its SCC susceptibility and examine its feasibility as BM with pure Zn as control group. We observed that Zn-0.8 wt%Li alloy exhibited low SCC susceptibility. This was attributed to variations in microstructure and deformation mechanism after alloying with Li. In addition, both pure Zn and Zn-0.8 wt%Li alloy did not fracture over a period of 28 days during constant-load immersion test. The magnitude of applied stress was close to physiological condition and thus, we proved the feasibility of both materials as BM.

Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B.

Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.

Liver-targeted prodrugs of 2'-C-methyladenosine for therapy of hepatitis C virus infection.

2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.

Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-beta-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma.

Cytotoxic nucleosides have proven to be ineffective for the treatment of hepatocellular carcinoma (HCC) due, in part, to their inadequate conversion to their active nucleoside triphosphates (NTP) in the liver tumor and high conversion in other tissues. These characteristics lead to poor efficacy, high toxicity, and a drug class associated with an unacceptable therapeutic index. Cyclic 1-aryl-1,3-propanyl phosphate prodrugs selectively release the monophosphate of a nucleoside (NMP) into CYP3A4-expressing cells, such as hepatocytes, while leaving the prodrug intact in plasma and extrahepatic tissues. This prodrug strategy was applied to the monophosphate of the well-known cytotoxic nucleoside cytosine-1-beta-D-arabinofuranoside (cytarabine, araC). Compound 19S (MB07133), in mice, achieves good liver targeting compared to araC, generating >19-fold higher cytarabine triphosphate (araCTP) levels in the liver than levels of araC in the plasma and >12-fold higher araCTP levels in the liver than in the bone marrow, representing a >120-fold and >28-fold improvement, respectively, over araC administration.

Fatigue behaviors of HP-Mg, Mg-Ca and Mg-Zn-Ca biodegradable metals in air and simulated body fluid.

UNLABELLED: The dynamic loading in human body, along with the corrosive body fluid, presents a great challenge for the practical use of biodegradable magnesium implants. In this study, a high purity magnesium (99.99wt.%) and two typical promising biodegradable magnesium alloys (binary Mg-1Ca and ternary Mg-2Zn-0.2Ca) were chosen as the experimental materials. Their dynamic mechanical performances were comparatively evaluated by carrying out fatigue tests in air and in simulated body fluid (SBF). The fatigue strengths of HP-Mg, Mg-1Ca and Mg-2Zn-0.2Ca were all around 90MPa in air, however, they decreased to 52MPa, 70MPa and 68MPa in SBF at 4×10(6)cycles, respectively. The fatigue cracks initiated from the microstructural defects when tested in air, but nucleated from surface corrosion pits when tested in SBF. Cyclic loading significantly increased the corrosion rates of all the experimental materials compared to that in static SBF. Moreover, based on our findings, the fatigue failure processes and interactions between material, corrosion and cyclic loading were systematically discussed. STATEMENT OF SIGNIFICANCE: Fatigue strength and life are vital parameters to the design of metallic implant devices. For the corrosion fatigue of biomedical magnesium alloys, we reported the corrosion fatigue behavior of AZ91D and WE43 in SBF (Acta Biomaterialia, 6 (2010) 4605-4613), and till now there is no other reports to our knowledge. We spent 3years to finish the fatigue testing and get S-N curves for three more magnesium biomaterials, and our significant finding is that the fatigue strengths of HP-Mg, Mg-1Ca and Mg-2Zn-0.2Ca are all around 90MPa in air but 52MPa, 70MPa and 68MPa in SBF at 4×10(6)cycles, which will provide the first-hand data for the future magnesium implants design.

Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1,6-bisphosphatase.

Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.

A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis.

AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 µM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.