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A stereodivergent Pd/Cu catalyst system for asymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed, which was successfully applied to the asymmetric synthesis of β-h...

Background: Sleep disorders can cause a wide variety of diseases, however, his relationship with cholelithiasis has not been proven. The importance of this study is further indicated by the fact that the population of insomnia is on the rise every year. Aims: By understanding the causal relationship between sleep disorders and cholelithiasis through a Mendelian randomization method, we can better guide human work and rest to improve the quality of human life. Methods: We use exposure factors from UK Biobank and FinnGen consortia as well as outcome variables using Multivariate Univariate as well as Multivariate Multifactor Mendelian randomization methods to analyze the causal relationship between insomnia and cholelithiasis. Results: The results show that Nap during the day can increase the risk of cholelith (OR = 1.55 (1.10, 2.18), P = 0.011, P FDR = 0.078)and broad cholelith(OR = 1.54 (1.09, 2.17), P = 0.012, P FDR = 0.085). And, after further tests of multi-factor Mendelian randomization, the same results were still obtained (Cholelith P =0.04,Broad Cholelith P=0.04). Conclusions: Nap during the day can increase the risk of gallstone disease. This result was obtained by Mendelian randomization, and the present study was proved to be solid by sensitivity analysis.

Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of ALS caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing with historically superior potency in which short interfering RNAs (siRNAs) guide the RNA-induced silencing complex (RISC) to cleave complementary transcripts. However, delivery to extrahepatic tissues like the central nerve system (CNS) has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 (hSOD1) in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enables durable and potent activity in CNS tissues. Local delivery via intracerebroventricular (ICV) or intrathecal (IT) injection into SOD1G93Amice delayed disease progression and extended animal survival with superior efficacy compared to an ASO compound resembling Tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (i.e., siRNA-ACO) represents a novel modality for delivery of RNAi to the CNS in which we aim to pursue ALS as an exemplary indication for clinical development.

Concurrent treatment of tumor recurrence and bone defects after surgical resection of osteosarcoma remains a clinical challenge. Combination therapy based on local drug delivery systems shows great promise in the...

Inflammation is the key driver of liver fibrosis progression in nonalcoholic fatty liver disease (NAFLD). Unfortunately, it is often challenging to assess inflammation in NAFLD due to its dynamic nature and poor correlation with liver biochemical markers. Liver histology keeps its role as the standard tool, yet it is well-known for substantial sampling, intraobserver and interobserver variability. Serum proinflammatory cytokines and apoptotic markers namely cytokeratin-18 (CK-18) are well studied with reasonable accuracy; whereas serum metabolomics and lipidomics have been adopted in some commercially available diagnostic models. Ultrasound and computed tomography (CT) imaging techniques are attractive because of their wide availability; yet their accuracies may not be comparable with magnetic resonance imaging (MRI)-based tools. Machine learning and deep learning models, be they supervised or unsupervised learning, are promising tools to identify various subtypes of NAFLD, including those with dominating liver inflammation, contributing to sustainable care pathways for NAFLD.

Bladder cancer (BC) is among the most common malignant tumors of the genitourinary system worldwide. In recent years, the rate of BC incidence has increased, and the recurrence rate is high, resulting in poor quality of life for patients. Therefore, how to develop an effective method to achieve synchronous precise diagnoses and BC therapies is a difficult problem to solve clinically. Previous reports usually focus on the role of nanomaterials as drug delivery carriers, while a summary of the functional design and application of nanomaterials is lacking. Summarizing the application of functional nanomaterials in high-sensitivity diagnosis and multimodality therapy of BC is urgently needed. This review summarizes the application of nanotechnology in BC diagnosis, including the application of nanotechnology in the sensoring of BC biomarkers and their role in monitoring BC. In addition, conventional and combination therapies strategy in potential BC therapy are analyzed. Moreover, different kinds of nanomaterials in BC multimodal therapy according to pathological features of BC are also outlined. The goal of this review is to present an overview of the application of nanomaterials in the theranostics of BC to provide guidance for the application of functional nanomaterials to precisely diagnose and treat BC.

Canada goldenrod (Solidago canadensis L.) is considered one of the most deleterious and invasive species worldwide, and invasion of riparian wetlands by S. canadensis can reduce vegetation diversity and alter soil nutrient cycling. However, little is known about how S. canadensis invasion affects soil carbon cycle processes, such as soil respiration, in a riparian wetland. This study was conducted to investigate the effects of different degrees of S. canadensis invasion on soil respiration under different moisture conditions. Soil respiration rate (heterotrophic and autotrophic respiration) was measured using a closed-chamber method. S. canadensis invasion considerably reduced soil respiration under all moisture conditions. The inhibition effect on autotrophic respiration was higher than that on heterotrophic respiration. The water level gradient affects the soil autotrophic respiration, thereby affecting the soil respiration rate. The changes in soil respiration may be related to the alteration in the effective substrate of the soil substrate induced by the invasion of S. canadensis. While the effects of S. canadensis invasion were regulated by the fluctuation in moisture conditions. Our results implied that S. canadensis invasion could reduce the soil respiration, which further potentially affect the carbon sequestration in the riparian wetlands. Thus, the present study provided a reference for predicting the dynamics of carbon cycling during S. canadensis invasion and constituted a scientific basis for the sustainable development and management of riparian wetlands invaded by alien plants.

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa-miR-59 (miR-59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model (Lmna

Background: A number of protein biomarkers have been proposed for the assessment of non-alcoholic fatty liver disease (NAFLD), but few have been externally validated and directly compared. The aim of this study was to compare the diagnostic accuracies of 13 protein biomarkers and develop a biomarker-based machine learning algorithm to predict at-risk non-alcoholic steatohepatitis (NASH) in patients with NAFLD. Methods: 281 NAFLD patients had blood biomarker tested within one week before liver biopsy. We used three machine learning methods to select biomarkers in training (70%) and testing (30%) datasets, and then input selected features into a logistic regression model to predict at-risk NASH (NAFLD activity score ≥4 with at least 1 point in each component and fibrosis stage ≥2). Results: Among 13 protein biomarkers tested, growth differentiation factor-15 (GDF-15) and Pro-C3 had the highest accuracy for at-risk NASH and advanced fibrosis (F3-4), respectively. All three machine learning models selected GDF-15, Pro-C3, and tissue inhibitor matrix metalloproteinase 1 as the best predictors of at-risk NASH, and the logistic regression FibNASH-3 model had an area under receiver-operating characteristics curve of 0.784. Using LSM ≥8kPa as the first step, the sequential model had a 79.2% positive predictive value for at-risk NASH. During a mean follow-up of 9.7 years, 3% and 16.7% of patients with low and high sequential model score developed hepatocellular carcinoma and cirrhotic complications, respectively (PConclusions: The study provides a head-to-head comparison of 13 protein biomarkers. FibNASH-3 has the ability to accurately identify at-risk NASH in NAFLD patients and predict the development of liver-related events.

Parts with the complex curved surface are commonly-used in high-end equipment. The machining quality of the complex curved surface parts is important for the property of high-end equipment. With position control of the main spindle i.e. C axis, the slow tool servo (STS) turning is a very promising technique to effectively machine complex curved surface parts. However, the turning machining quality is restricted by the cutting force fluctuation in finishing turning. Hence, the STS turning toolpath generation approach with the constraint of the cutting force fluctuation is proposed in this study. As the cutting force is proportionate to the cutting area, the cutting area for turning complex curved surfaces is analyzed and calculated. Then the functional relation between the cutting force fluctuation and the feed rate is derived. Based on the geometrical characteristic of the first revolution of toolpath, the feed rate is optimized with small cutting force fluctuation to derive the cutter contact points (CCPs) of toolpath in the cylindrical coordinate system. Then the cutter location points (CLPs) of STS turning toolpath are calculated with tool nose radius compensation. From the validation experiment results, it can be seen that the cutting force fluctuation, the profile tolerance and the surface roughness of parts are effectively reduced, and the surface roughness of the part machined with the proposed toolpath planning method is 17.625 nm. Thus, this study provides guidance for toolpath generation with constraint of the fluctuation of the cutting force in STS turning for a complex curved surface.

Bacterial viruses, that is ‘bacteriophage’ or ‘phage’, can infect and lyse their bacterial hosts, releasing new viral progeny. In addition to the lytic pathway, certain bacteriophage (i.e. ‘temperate’ bacteriophage) can also initiate lysogeny, a latent mode of infection in which the viral genome is integrated into and replicated with the bacterial chromosome. Subsequently, the integrated viral genome, that is the ‘prophage’, can induce and restart the lytic pathway. Here, we explore the relationship among infection mode, ecological context, and viral fitness, in essence asking: when should viruses be temperate? To do so, we use network loop analysis to quantify fitness in terms of network paths through the life history of an infectious pathogen that start and end with infected cells. This analysis reveals that temperate strategies, particularly those with direct benefits to cellular fitness, should be favored at low host abundances. This finding applies to a spectrum of mechanistic models of phage–bacteria dynamics spanning both explicit and implicit representations of intra-cellular infection dynamics. However, the same analysis reveals that temperate strategies, in and of themselves, do not provide an advantage when infection imposes a cost to cellular fitness. Hence, we use evolutionary invasion analysis to explore when temperate phage can invade microbial communities with circulating lytic phage. We find that lytic phage can drive down niche competition amongst microbial cells, facilitating the subsequent invasion of latent strategies that increase cellular resistance and/or immunity to infection by lytic viruses—notably this finding holds even when the prophage comes at a direct fitness cost to cellular reproduction. Altogether, our analysis identifies broad ecological conditions that favor latency and provide a principled framework for exploring the impacts of ecological context on both the short- and long-term benefits of being temperate.

Bimetallic catalysis has emerged as an efficient strategy for the development of new chemical reactions. Importantly, this strategy also provides a simple and powerful platform for stereodivergent synthesis, whereby all the possible stereoisomers of products bearing two stereocenters can be easily prepared from the same set of starting materials. In this Minireview, the development of stereodivergent allylic substitution, propargylic substitution, hydrofunctionalization, and annulation based on bimetallic catalysis has been summarized. It is expected that more bimetallic catalytic systems will be developed and applied for the stereodivergent synthesis of valuable molecules.

Background The spatiotemporal variation of observed trace gases (NO2, SO2, O3) and particulate matter (PM2.5, PM10) were investigated over cities of Yangtze River Delta (YRD) region including Nanjing, Hefei, Shanghai and Hangzhou. Furthermore, the characteristics of different pollution episodes, i.e., haze events (visibility 2.5 > 40 µg/m3) and complex pollution episodes (PM2.5 > 35 µg/m3 and O3 > 160 µg/m3) were studied over the cities of the YRD region. The impact of China clean air action plan on concentration of aerosols and trace gases is examined. The impacts of trans-boundary pollution and different meteorological conditions were also examined. Results The highest annual mean concentrations of PM2.5, PM10, NO2 and O3 were found for 2019 over all the cities. The annual mean concentrations of PM2.5, PM10, and NO2 showed continuous declines from 2019 to 2021 due to emission control measures and implementation of the Clean Air Action plan over all the cities of the YRD region. The annual mean O3 levels showed a decline in 2020 over all the cities of YRD region, which is unprecedented since the beginning of the China’s National environmental monitoring program since 2013. However, a slight increase in annual O3 was observed in 2021. The highest overall means of PM2.5, PM10, SO2, and NO2 were observed over Hefei, whereas the highest O3 levels were found in Nanjing. Despite the strict control measures, PM2.5 and PM10 concentrations exceeded the Grade-1 National Ambient Air Quality Standards (NAAQS) and WHO (World Health Organization) guidelines over all the cities of the YRD region. The number of haze days was higher in Hefei and Nanjing, whereas the complex pollution episodes or concurrent occurrence of O3 and PM2.5 pollution days were higher in Hangzhou and Shanghai. The in situ data for SO2 and NO2 showed strong correlation with Tropospheric Monitoring Instrument (TROPOMI) satellite data. Conclusions Despite the observed reductions in primary pollutants concentrations, the secondary pollutants formation is still a concern for major metropolises. The increase in temperature and lower relative humidity favors the accumulation of O3, while low temperature, low wind speeds and lower relative humidity favor the accumulation of primary pollutants. This study depicts different air pollution problems for different cities inside a region. Therefore, there is a dire need to continuous monitoring and analysis of air quality parameters and design city-specific policies and action plans to effectively deal with the metropolitan pollution.

Alien plant invasion and residual soil microplastics (MPs) are growing threats to agricultural crop production. This study determined the adverse effects of Canadian goldenrod (Solidago canadensis L.) invasion and residual soil MPs on rice growth and development. The biomass, phenological indices, photosynthetic parameters, and antioxidant enzyme activities of rice were measured on the 50th and 80th day of post-plantation. Biomass and phenotypic results indicated the more harmful effects of the combination of S. canadensis invasion and residual soil MPs compared to S. canadensis invasion or residual soil MPs effects alone. Moreover, the interaction effect of S. canadensis invasion and residual soil MPs markedly reduced the ascorbate peroxidase and catalase belowground, while they increased in the aboveground parts of the rice. However, the S. canadensis invasion and residual soil MPs interactive treatments lowered the superoxide dismutase concentrations in the belowground parts of the rice plants while elevating the peroxidase and reactive oxygen species concentrations in both the belowground and aboveground parts compared to the other treatments. Among all treatments, S. canadensis invasion alone had the most negligible negative impact on rice biomass and growth indices. Our study suggests that soil MPs could negatively affect crop production with invasive alien plants, and the combined effects were more harmful than either of the single factors. Our findings will lay the groundwork for analyzing the impacts of invasive alien plants on rice crops.

3,3-Disubstituted oxindoles bearing quaternary and tertiary stereogenic centers are privileged structural motifs, which widely exist in pharmaceutical and natural products. Herein, a highly regio-, enantio-, and diastereoselective allylic alkylation of 3-alkyl oxindoles through synergistic iridium and copper catalysis is described, which provides a series of 3,3-disubstituted oxindole derivatives containing adjacent quaternary and tertiary stereogenic centers in excellent yields, enantiomeric excess, and diastereomeric ratio (for 30 examples, up to 97 % yield, >99 % ee, and >20 : 1 dr). This method provides exclusive branched selectivity, excellent enantio- and diastereoselectivities, and good functional compatibility. Control experiments suggested that the chiral copper catalyst is required for achieving high reactivities and diastereoselectivities under mild reaction conditions.

In order to prepare insulin-like growth factor 1 (IGF-1) more economically and efficiently, the structure prediction and molecular docking of three IGF-1 fusion proteins were performed by computer simulation. The most suitable expression form of IGF-1 fusion protein was screened out. A prokaryotic expression vector of IGF-1 fusion protein was constructed and transformed into

ABSTRACT: During well shut in after hydraulic fracturing, a large amount of fracturing fluid enters the formation through imbibition, which significantly reduces the recovery of injected water. However, the capillary pressure of fractures is usually ignored, and the effect of fracture aperture on this process is not clear. We examined the imbibition characteristics between fractures and matrix in the capillary-controlled gas-water flow. The focus is on the flow behavior and effects caused by capillary pressure of fractures. The imbibition experiments were carried out under different fracture apertures (50-950 μm). The results show that fractures within a certain opening range accelerate water imbibition by providing a plane source. The water flows rapidly in the fractures, then being absorbed by the matrix on both sides. The water imbibition rate of fractures is mainly affected by the fractures aperture, which controls the fracture capillary pressure and permeability. The overall trend is that the imbibition rate is inversely proportional to the fracture aperture. This indicates that the small aperture fractures without proppants can quickly transport water to the interior of the matrix. The research is significant to understand the law of fracturing fluid imbibition in the formation. 1. INTRODUCTION Horizontal wells with multistage hydraulic fracturing are an important technical means for developing unconventional gas reservoirs (Fazelipour, 2011; Yu and Sepehrnoori, 2013; Lei et al., 2022). A large volume of water-based fracturing fluid such as slick water is injected into the formation to form a complex fracture network (Barati and Liang, 2014; Cai et al., 2017). Field practice shows that the flowback rate of fracturing fluid is generally low (Alkouh and Wattenbarger, 2013; Osselin et al., 2018). Spontaneous water imbibition is considered to be one of the main reasons for this phenomenon (Almulhim et al., 2014; Ge et al., 2015; Al-Ameri et al., 2018). The fracturing fluid spontaneously imbibes into the matrix from fractures, which could increase water saturation and reduce the gas phase relative permeability, affecting the production of gas reservoirs (Saini et al., 2021). The study of spontaneous imbibition mostly focuses on the capillary pressure of matrix pores and related problems (Makhanov et al., 2012; Dehghanpour et al., 2013; Roychaudhuri et al., 2013; Sadjadi and Rieger, 2013; Mason and Morrow, 2013; Shi et al., 2018). But spontaneous imbibition in unsaturated water fractures also deserves attention. There are different scales of fractures in the complex fracture network formed by artificial and natural fractures (Yushi et al., 2016). Studying the effect of fracture aperture on fracturing fluid imbibition into gas-saturated rocks has significance for improving fracturing technology and enhancing recovery.

It is unclear if the leading causes of death in patients with NAFLD differ by age. We aimed to investigate if the relative importance of liver-related deaths is lower and overshadowed by cardiovascular and cancer-related deaths in the elderly population.We conducted a territory-wide retrospective cohort study of adult patients with NAFLD between 2000 and 2021 in Hong Kong. The outcomes of interest were all-cause and cause-specific mortality. Age groups at death were studied at 10-year intervals. During 662,471 person-years of follow-up of 30,943 patients with NAFLD, there were 2097 deaths. The top three causes of death were pneumonia, extrahepatic cancer, and cardiovascular diseases. Liver disease was the sixth leading cause of death in patients aged 70-79 and 80-89 years, accounting for 5.1% and 5.9% of deaths, respectively, but only accounted for 3% or fewer of the deaths in the other age groups. Nonetheless, liver disease was the leading cause of death in patients with NAFLD-related cirrhosis, accounting for 36.8% of all deaths. The incidence of liver-related death was higher in men younger than age 70 but higher in women afterwards. The incidence of liver-related death in women increased from 0.62 to 7.14 per 10,000 person-years from age 60-69 to 70-79 years.The relative importance of liver-related death increases with age in patients with NAFLD, especially among women. In patients with cirrhosis, liver disease is the leading cause of death.

Cloud is complicated due to its various types and distribution on different layers. Various classification principles and overlapping of clouds on multiple layers make it difficult to classify clou...

Purpose The purpose of this paper is to study the mechanical property of three-dimensional (3D) Printed photopolymer (Vero Yellow and Tango Black) with different constant strain rate. According to the experimental results, three constitutive models are used to describe the stress-strain and stress-time relation in the tension and stress relaxation process. Design/methodology/approach The Stratasys Objet 260 was used to prepare the four groups of samples with different photopolymers (Vero Yellow and Tango Black). The stress-strain and stress-time relations are obtained by the uniaxial tensile tests and relaxation tests performed at room temperature with different constant strain rates. The generalized Kelvin model (GKM), standard linearized model (SLM) and fractional order model (FOM) are used to describe experimental data by means of the curve-fitting approach. Findings Experimental results show that the tension stress increases faster at a higher strain-rate for tensile tests. Relaxation stress is influenced by the preload strain-rate for relaxation tests. For the theoretical fitting, the error comparison between three constitutive models and experimental data are calculated to demonstrate the high accuracy in describing the stress-strain relationship for tension. For stress relaxation, the error comparison confirms higher accuracy of FOM with the largest error within 3%, while the error of GKM and SLM up to 10%. Originality/value The paper confirms the viscous-elastic mechanical property of 3D printed photopolymer composites (Vero Yellow and Tango Black) for Stratasys PolyJet. As FOM shows high accuracy both in describing stress-strain and stress-time relation for tension and stress relaxation process, it can be directly used as a constitutive model to predict mechanical properties for engineering application.

Machines translation (MT) is an essential task in natural language processing or even in artificial intelligence. Statistical machine translation has been the dominant approach to MT for decades, but recently neural machine translation achieves increasing interest because of its appealing model architecture and impressive translation performance. In neural machine translation, an attention model is used to identify the aligned source words for the next target word, i.e., target foresight word, to select translation context. However, it does not make use of any information about this target foresight word at all. Previous work proposed an approach to improve the attention model by explicitly accessing this target foresight word and demonstrating substantial alignment tasks. However, this approach cannot be applied in machine translation tasks where the target foresight word is unavailable. This paper proposes several novel enhanced attention models by introducing hidden information (such as part-of-speech) of the target foresight word for the translation task. We incorporate the novel enhanced attention employing hidden information about the target foresight word into both recurrent and self-attention-based neural translation models and theoretically justify that such hidden information can make translation prediction easier. Empirical experiments on four datasets further verify that the proposed attention models deliver significant improvements in translation quality.

The first asymmetric Ni/Cu cocatalyzed benzylation of aldimine esters is reported. A series of benzyl-substituted α-quaternary amino acids could be synthesized in high yield and with high levels of enantioselectivity (up to 90 % yield and 99 % ee). The experimental and theoretical calculation results suggested that the strong electrophilicity of the η

The COVID-19 pandemic has precipitated a global crisis, with more than 690,000 confirmed cases and more than 33,000 confirmed deaths globally as of March 30, 2020 [1-4]. At present two central public health control strategies have emerged: mitigation and suppression (e.g, [5]). Both strategies focus on reducing new infections by reducing interactions (and both raise questions of sustainability and long-term tactics). Complementary to those approaches, here we develop and analyze an epidemiological intervention model that leverages serological tests [6, 7] to identify and deploy recovered individuals as focal points for sustaining safer interactions via interaction substitution, i.e., to develop what we term 'shield immunity' at the population scale. Recovered individuals, in the present context, represent those who have developed protective, antibodies to SARS-CoV-2 and are no longer shedding virus [8]. The objective of a shield immunity strategy is to help sustain the interactions necessary for the functioning of essential goods and services (including but not limited to tending to the elderly [9], hospital care, schools, and food supply) while decreasing the probability of transmission during such essential interactions. We show that a shield immunity approach may significantly reduce the length and reduce the overall burden of an outbreak, and can work synergistically with social distancing. The present model highlights the value of serological testing as part of intervention strategies, in addition to its well recognized roles in estimating prevalence [10, 11] and in the potential development of plasma-based therapies [12-15].

The present study examined microbial substrate utilization by community level physiological profiling and carbon-cycling enzyme assays (cellobiohydrolase, β-xylosidase, and oxidases) in three Japan...

In this paper, a novel quadratic boost converter is presented. The input current of the converter is non-pulsating and the currents of the inductors are relatively low. The operating principle and the mathematical model of the converter in continuous conduction mode (CCM) are given. The steady-state of the converter is calculated and the power loss of the converter is analyzed. Then the small-signal model of the converter is derived based on the state space averaging method. The inductor current and the voltage stress of the proposed converter arelow, which can improve the efficiency of the converter. The simulations and the circuit experiments are presented to verify the good performance of the converter.