An artificially evolved gene for herbicide-resistant rice breeding.

Discovering and engineering herbicide-resistant genes is a crucial challenge in crop breeding. This study focuses on the 4-hydroxyphenylpyruvate dioxygenase Inhibitor Sensitive 1-Like (HSL) protein, prevalent in higher plants and exhibiting weak catalytic activity against many ß-triketone herbicides (ß-THs). The crystal structures of maize HSL1A complexed with ß-THs were elucidated, identifying four essential herbicide-binding residues and explaining the weak activity of HSL1A against the herbicides. Utilizing an artificial evolution approach, we developed a series of rice HSL1 mutants targeting the four residues. Then, these mutants were systematically evaluated, identifying the M10 variant as the most effective in modifying ß-THs. The initial active conformation of substrate binding in HSL1 was also revealed from these mutants. Furthermore, overexpression of M10 in rice significantly enhanced resistance to ß-THs, resulting in a notable 32-fold increase in resistance to methyl-benquitrione. In conclusion, the artificially evolved M10 gene shows great potential for the development of herbicide-resistant crops.

EGFR-mediated HSP70 phosphorylation facilitates PCNA association with chromatin and DNA replication.

Efficient DNA replication requires highly coordinated programs for the timely recruitment of protein complexes to DNA replication forks. Defects in this process result in replication stress, which in turn activates cell cycle checkpoints, suppresses cell proliferation and induces apoptosis. In response to persistent cell growth signals that speed up DNA replication processes, cells accelerate the recruitment of DNA replication proteins to avoid DNA replication stress. The mechanisms by which cell growth signals induce processes to facilitate the recruitment of DNA replication proteins onto the replication sites remain unclear. Here, we report that the epidermal growth factor receptor (EGFR) phosphorylates heat shock protein 70 (HSP70) for DNA replication. Such a modification promotes nuclear localization and chromatin association of HSP70, which interacts with the DNA replication coordinator, proliferating cell nuclear antigen (PCNA). HSP70 subsequently facilitates the loading of PCNA onto chromatin. Knockdown or chemical inhibition of HSP70 suppresses PCNA association with chromatin and impairs DNA synthesis and Okazaki fragment maturation, leading to replicative DNA double-strand breaks and apoptosis. Furthermore, chemical inhibition of HSP70 potentiates EGFR-tyrosine kinase inhibitor-induced tumor reduction in vivo. This work expands our understanding of oncogenesis-induced DNA replication processes and provides a foundation for improved treatments for EGFR-mutated lung cancer by simultaneously targeting HSP70.

Prediction of cytochrome P450-mediated bioactivation using machine learning models and in vitro validation.

Cytochrome P450 (P450)-mediated bioactivation, which can lead to the hepatotoxicity through the formation of reactive metabolites (RMs), has been regarded as the major problem of drug failures. Herein, we purposed to establish machine learning models to predict the bioactivation of P450. On the basis of the literature-derived bioactivation dataset, models for Benzene ring, Nitrogen heterocycle and Sulfur heterocycle were developed with machine learning methods, i.e., Random Forest, Random Subspace, SVM and Naïve Bayes. The models were assessed by metrics like "Precision", "Recall", "F-Measure", "AUC" (Area Under the Curve), etc. Random Forest algorithms illustrated the best predictability, with nice AUC values of 0.949, 0.973 and 0.958 for the test sets of Benzene ring, Nitrogen heterocycle and Sulfur heterocycle models, respectively. 2D descriptors like topological indices, 2D autocorrelations and Burden eigenvalues, etc. contributed most to the models. Furthermore, the models were applied to predict the occurrence of bioactivation of an external verification set. Drugs like selpercatinib, glafenine, encorafenib, etc. were predicted to undergo bioactivation into toxic RMs. In vitro, IC50 shift experiment was performed to assess the potential of bioactivation to validate the prediction. Encorafenib and tirbanibulin were observed of bioactivation potential with shifts of 3-6 folds or so. Overall, this study provided a reliable and robust strategy to predict the P450-mediated bioactivation, which will be helpful to the assessment of adverse drug reactions (ADRs) in clinic and the design of new candidates with lower toxicities.

Development of a risk estimation model for condomless sex among college students in Zhuhai, China: a cross-sectional study.

BACKGROUND: Condom use at last intercourse is an effective indicator for human immunodeficiency virus (HIV) prevention. To identify at-risk individuals and improve prevention strategies, this study explored factors associated with condomless sex at last intercourse in the last year and developed a risk estimation model to calculate the individual possibility of condomless sex among college students in Zhuhai, China. METHODS: A cross-sectional study was conducted among 1430 college students who had sex in the last year from six universities in Zhuhai. The least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to explore the predictors of condomless sex. The nomogram was constructed to calculate the individual possibility of condomless sex. Discrimination and calibration of the nomogram were evaluated using the area under the receiver-operator characteristic curve (AUROC) and the calibration curve. RESULTS: The proportion of students who had condomless sex at last intercourse was 18.2% (260/1430). Students who had experienced more types of intimate partner violence (aOR, 1.58; 95% CI, 1.31 ~ 1.92) and had anal sex (aOR, 1.75; 95% CI, 1.06 ~ 2.84) were more likely to have condomless sex. Students who had heterosexual intercourse (aOR, 0.37; 95% CI, 0.21 ~ 0.70), used condoms at first sex (aOR, 0.20; 95% CI, 0.14 ~ 0.27), had high attitudes towards condom use (aOR, 0.87; 95% CI, 0.80 ~ 0.95) and self-efficacy for condom use (aOR, 0.84; 95% CI, 0.78 ~ 0.90) were less likely to have condomless sex. The nomogram had high accuracy with an AUROC of 0.83 and good discrimination. CONCLUSIONS: Intimate partner violence, anal sex, condom use at first sex, attitude towards condom use, and self-efficacy for condom use were associated with condomless sex among college students. The nomogram was an effective and convenient tool for calculating the individualized possibility of condomless sex among college students. It could help to identify individuals at risk and help universities and colleges to formulate appropriate individualized interventions and sexual health education programs.

Factors associated with antiretroviral treatment adherence among people living with HIV in Guangdong Province, China: a cross sectional analysis.

BACKGROUND: Understanding factors associated with antiretroviral treatment (ART) adherence is crucial for ART success among people living with HIV (PLHIV) in the "test and treat" era. Multiple psychosocial factors tend to coexist and have a syndemic effect on ART adherence. We aimed to explore factors associated with ART adherence and the syndemic effect of multiple psychosocial factors on ART adherence among PLHIV newly starting ART in Guangdong Province, China. METHODS: Newly diagnosed PLHIV from six cities in Guangdong Province were recruited between May 2018 and June 2019, and then followed up from May 2019 to August 2020. Baseline and follow-up data were collected from a questionnaire and the national HIV surveillance system, the follow-up data of which were analyzed in this study. A Center for Adherence Support Evaluation (CASE) index > 10 points was defined as optimal ART adherence, which was measured via participants' self-reported adherence during follow-up survey. Multivariable logistic regression was used to identify factors associated with ART adherence. Exploratory factor analysis (EFA) and multi-order latent variable structural equation modeling (SEM) were performed to explore the syndemic effect of multiple psychosocial factors on ART adherence. RESULTS: A total of 734 (68.53%) follow-up participants were finally included in this study among the 1071 baseline participants, of whom 91.28% (670/734) had self-reported optimal ART adherence. Unemployment (aOR = 1.75, 95%CI: 1.01-3.02), no medication reminder (aOR = 2.28, 95%CI: 1.09-4.74), low medication self-efficacy (aOR = 2.28, 95%CI: 1.27-4.10), low social cohesion (aOR = 1.82, 95%CI: 1.03-3.19), no social participation (aOR = 5.65, 95%CI: 1.71-18.63), and ART side effects (aOR = 0.46, 95%CI: 0.26-0.81) were barriers to optimal ART adherence. The EFA and second-order latent variable SEM showed a linear relationship (standardized coefficient = 0.43, P < 0.001) between ART adherence and the latent psychosocial (syndemic) factor, which consisted of the three latent factors of medication beliefs and self-efficacy (standardized coefficient = 0.65, P < 0.001), supportive environment (standardized coefficient = 0.50, P < 0.001), and negative emotions (standardized coefficient=-0.38, P < 0.01). The latent factors of medication beliefs and self-efficacy, supportive environment, and negative emotions explained 42.3%, 25.3%, and 14.1% of the variance in the latent psychosocial factor, respectively. CONCLUSIONS: About nine out of ten PLHIV on ART in Guangdong Province self-reported optimal ART adherence. However, more efforts should be made to address barriers to optimal ART adherence.

Discovery of novel and potent CDK8 inhibitors for the treatment of acute myeloid leukaemia.

It has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 (3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide) showed the most potent inhibiting activity against CDK8 with an IC50 value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC50 = 0.02 ± 0.01 µM, MV4-11 GC50 = 0.03 ± 0.01 µM). Mechanistic studies revealed that this compound 12 could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound 12 showed relative good bioavailability (F = 38.80%) and low toxicity in vivo. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

Identification of RACK1 as a novel regulator of non-structural protein 4 of chikungunya virus.

Chikungunya virus (CHIKV) is a neglected arthropod-borne and anthropogenic alphavirus. Over the past two decades, the CHIKV distribution has undergone significant changes worldwide, from the original tropics and subtropics regions to temperate regions, which has attracted global attention. However, the interactions between CHIKV and its host remain insufficiently understood, which dampens the need for the development of an anti-CHIKV strategy. In this study, on the basis of the optimal overexpression of non-structural protein 4 (nsP4), we explore host interactions of CHIKV nsP4 using mass spectrometry-based protein-protein interaction approaches. The results reveal that some cellular proteins that interact with nsP4 are enriched in the ubiquitin-proteasome pathway. Specifically, the scaffold protein receptor for activated C kinase 1 (RACK1) is identified as a novel host interactor and regulator of CHIKV nsP4. The inhibition of the interaction between RACK1 and nsP4 by harringtonolide results in the reduction of nsP4, which is caused by the promotion of degradation but not the inhibition of nsP4 translation. Furthermore, the decrease in nsP4 triggered by the RACK1 inhibitor can be reversed by the proteasome inhibitor MG132, suggesting that RACK1 can protect nsP4 from degradation through the ubiquitin-proteasome pathway. This study reveals a novel mechanism by which the host factor RACK1 regulates CHIKV nsP4, which could be a potential target for developing drugs against CHIKV.

miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages.

Acute rejection (AR) is an important factor that leads to poor prognosis after liver transplantation (LT). Macrophage M1-polarization is an important mechanism in AR development. MicroRNAs play vital roles in disease regulation; however, their effects on macrophages and AR remain unclear. In this study, rat models of AR were established following LT, and macrophages and peripheral blood mononuclear cells were isolated from rats and humans, respectively. We found miR-449a expression to be significantly reduced in macrophages and peripheral blood mononuclear cells. Overexpression of miR-449a not only inhibited the M1-polarization of macrophages in vitro but also improved the AR of transplant in vivo. The mechanism involved inhibiting the noncanonical nuclear factor-kappaB (NF-κB) pathway. We identified procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 (PLOD1) as a target gene of miR-449a, which could reverse miR-449a's inhibition of macrophage M1-polarization, amelioration of AR, and inhibition of the NF-κB pathway. Overall, miR-449a inhibited the NF-κB pathway in macrophages through PLOD1 and also inhibited the M1-polarization of macrophages, thus attenuating AR after LT. In conclusion, miR-449a and PLOD1 may be new targets for the prevention and mitigation of AR.

Preference-Aware User Access Control Policy in Internet of Things.

There are multiple types of services in the Internet of Things, and existing access control methods do not consider situations wherein the same types of services have multiple access options. In order to ensure the QoS quality of user access and realize the reasonable utilization of Internet of Things network resources, it is necessary to consider the characteristics of different services to design applicable access control strategies. In this paper, a preference-aware user access control strategy in slices is proposed, which can increase the number of users in the system while balancing slice resource utilization. First, we establish the user QoS model and slice QoS index range according to the delay, rate and reliability requirements, and we select users with multiple access options. Secondly, a user preference matrix is established according to the user QoS requirements and the slice QoS index range. Finally, a preference matrix of the slice is built according to the optimization objective, and access control decisions are made for users through the resource utilization state of the slice and the preference matrix. The verification results show that the proposed strategy not only balances slice resource utilization but also increases the number of users who can access the system.

DPPA2/4 and SUMO E3 ligase PIAS4 opposingly regulate zygotic transcriptional program.

The molecular mechanism controlling the zygotic genome activation (ZGA) in mammals remains poorly understood. The 2-cell (2C)-like cells spontaneously emerging from cultures of mouse embryonic stem cells (ESCs) share some key transcriptional and epigenetic programs with 2C-stage embryos. By studying the transition of ESCs into 2C-like cells, we identified developmental pluripotency associated 2 and 4 (Dppa2/4) as important regulators controlling zygotic transcriptional program through directly up-regulating the expression of double homeobox (Dux). In addition, we found that DPPA2 protein is sumoylated and its activity is negatively regulated by small ubiquitin-like modifier (Sumo) E3 ligase protein inhibitor of activated STAT 4 (PIAS4). PIAS4 is down-regulated during ZGA process and during transitioning of ESCs into 2C-like cells. Depleting Pias4 or overexpressing Dppa2/4 is sufficient to activate 2C-like transcriptional program, whereas depleting Dppa2/4 or forced expression of Pias4 or Sumo2-Dppa2 inhibits 2C-like transcriptional program. Furthermore, ectopic expression of Pias4 or Sumo2-Dppa2 impairs early mouse embryo development. In summary, our study identifies key molecular rivals consisting of transcription factors and a Sumo2 E3 ligase that regulate zygotic transcriptional program upstream of Dux.

A mini-review on synthesis and antiviral activity of natural product oxetanocin A derivatives.

Oxetanocin A (Oxt-A), a novel oxetanosyl N-glycoside nucleoside, was isolated from Bacillus megaterium in 1986. It carries an oxetane ring on the sugar moiety of the nucleoside scaffold, which contributes to differences in its structure from those of common tetrahydrofuranyl-based nucleosides. In view of the unique 3D-spatial framework, the complete synthesis of Oxt-A has been achieved by multiple research groups. The pharmacological properties of this natural product have also been broadly investigated by pharmacists and chemists since its discovery. Notably, the potential antiviral effect of Oxt-A has captured attention of researchers in the field of antiviral agent development. Furthermore, epidemic outbreaks caused by viruses have been stimulating the preparation and modification of various Oxt-A analogs over the past few decades. However, none of the studies have overviewed the antiviral efficacies of this naturally occurring scaffold yet. Thus, the present review summarizes the synthesis, structural modification, and antiviral activities of Oxt-A and its derivatives. We believe that these comprehensive descriptions will provide a novel perspective for the discovery of antivirus drugs with well-improved performance and pave newer paths for combating sudden public health issues triggered by viruses in the future.

An Activity-Based Fluorogenic Probe Enables Cellular and in Vivo Profiling of Carboxylesterase Isozymes.

Carboxylesterases (CEs) exist as multiple types of isomers in humans, and two major types are CE1 and CE2. They are widely distributed in human tissues and well-known for their important roles in drug metabolism and pathology of various diseases. Thus, the detection of CEs in living systems could provide efficient proof in disease diagnostics, as well as important information regarding chemotherapeutic effects of antitumor drugs and prognosis. To develop a specific probe to discriminate CEs from other hydrolases, especially cholinesterases, is quite challenging due to their structural similarities and substrate specificity. To date, almost all of the fluorescent probes developed for CEs have been constructed with an acetyl group as the recognition unit. Herein we proposed a new design strategy of probe-cavity matching, which led to the identification of a new fluorogenic substrate (termed as HBT-CE) with high specificity toward both CE isomers and improved sensitivity, considering the higher binding affinity and catalysis efficiency. The promising capability of HBT-CE was further demonstrated for endogenous CEs imaging in living cells, zebrafish, and nude mice. In addition, HBT-CE was successfully applied in kinetically monitoring drug-induced CE regulation in cancer cells. All of these findings suggest that HBT-CE is a valuable tool for tracking and imaging endogenous CEs in complex biological systems.

Comprehensive analysis of differentially expressed profiles of lncRNAs, mRNAs, and miRNAs in laryngeal squamous cell carcinoma in order to construct a ceRNA network and identify potential biomarkers.

OBJECTIVE: This study aimed to uncover a regulatory network comprised of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in laryngeal squamous cell carcinoma (LSCC), to explore its underlying mechanisms and development, and to identify key genetic biomarkers for the prognosis of LSCC. METHODS: Here, we compared mRNA, lncRNA, and miRNA expression profiles between 111 LSCC and 12 adjacent normal tissues using RNA sequencing (RNA-Seq) data from the Cancer Genome Atlas (TCGA) database. Based on the interaction information obtained from miRcode, TargetScan, miRTarBase, and miRDB, a lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network was constructed using differentially expressed lncRNAs (DElncRNA), miRNAs (DEmiRNA), and mRNAs (DEmRNA). By assessing the functional enrichment of DEmRNAs in this network, the potential underlying mechanisms were explored. In addition, Kaplan-Meier survival analysis was used to assess genetic biomarkers related to the prognosis of LSCC patients. RESULTS: Upon comparing LSCC and control tissues, 1640 DElncRNAs, 75 DEmiRNAs, and 3217 DEmRNAs were identified. Based on the prediction between lncRNA-miRNA and miRNA-mRNA relationships, we constructed a ceRNA network comprised of 93 lncRNAs, nine miRNAs, and nine mRNAs. This network predicted that two lncRNAs (AC016773.1 and C00299), two mRNAs (DIO1 and STC2), and two miRNAs (hsa-mir-137 and hsa-mir-210) were significant biomarkers of LSCC prognosis according to thorough topological and survival analyses (P < .05). CONCLUSION: Through a ceRNA network analysis, our study identifies new lncRNAs, miRNAs, and mRNAs, which can be used as potential biomarkers of LSCC and as therapeutic targets for treating LSCC, thus laying a foundation for future clinical studies.

[Analysis on mechanisms and medication rules of herbal prescriptions for gout caused by heat-damp accumulation syndrome based on data mining and network pharmacology].

To mine the medication rules of herbal prescriptions for gout caused by heat-damp accumulation syndrome, and explore the possible mechanism of the core herbs, we collected the relevant literature of gout caused by heat-damp accumulation syndrome in CNKI, medication rules of herbal prescriptions are analyzed by using TCMISS(V2.5) software, and the compatibility of core drugs and new prescriptions were mined.KEGG pathway analysis was performed by BATMAN-TCM, an online analysis tool, and the potential signaling pathways of core drugs compatibility to treat gout caused by heat-damp accumulation syndrome were revealed. The results showed that six core drugs and three new prescriptions were found out of the 136 prescriptions. The core compatibility herbs in clinical treament of gout caused by heat-damp accumulation syndrome, Phellodendri Chinrnsis Cortex, Achyranthis Bidentatae Radix and Achyranthis Bidentatae Radix, which potential signaling pathways were purine metabolic pathway and neura activity ligand receptor interaction signaling pathway. Therefore, for gout caused by heat-damp accumulation syndrome, the mainly used therapies of TCM were clearing heat and drying dampness,inducing diuresis for removing edema, dispeling wind and eliminating dampness. The mechnisms of core compatibility herbs may be achieved through the intervention of purine metabolic pathway and neural activity ligand receptor interaction signaling pathway.

Vitamin C at high concentrations induces cytotoxicity in malignant melanoma but promotes tumor growth at low concentrations.

Vitamin C has been used in complementary and alternative medicine for cancers regardless of its ineffectiveness in clinical trials and the paradoxical effects antioxidants have on cancer. Vitamin C was found to induce cytotoxicity against cancers. However, the mechanisms of action have not been fully elucidated, and the effects of vitamin C on human malignant melanoma have not been examined. This study revealed that vitamin C at millimolar concentrations significantly reduced the cell viability as well as invasiveness, and induced apoptosis in human malignant melanoma cells. Vitamin C displayed stronger cytotoxicity against the Vemurafenib-resistance cell line A2058 compared with SK-MEL-28. In contrast, vitamin C at micromolar concentrations promoted cell growth, migration and cell cycle progression, and protected against mitochondrial stress. Vemurafenib paradoxically activated the RAS-RAF-MEK-ERK signaling pathway in the Vemurafenib-resistant A2058, however, vitamin C abolished the activations. Vitamin C displayed synergistic cytotoxicity with Vemurafenib against the Vemurafenib-resistant A2058. In vivo assay suggested that lower dosage (equivalent to 0.5 g/70 kg) of vitamin C administered orally increased the melanoma growth. Therefore, vitamin C may exert pro- or anti-melanoma effect depending on concentration. The combination of vitamin C at high dosage and Vemurafenib is promising in overcoming the action of drug resistance.

A comparative study of the vibro-impact capsule systems with one-sided and two-sided constraints.

This paper studies the dynamics of the vibro-impact capsule systems with one-sided and two-sided soft constraints under variations of various system and control parameters, including mass ratio, stiffness ratio, gap of contact, and amplitude and frequency of external excitation. The aim of this study is to optimise the progression speed and energy consumption of the capsule and minimise the required cabin length for prototype design used for engineering pipeline inspection. Our studies focus on three systems: the capsule with a right constraint, the capsule with a right and a weak left constraints, and the capsule with a right and a strong left constraints. Bifurcation analyses show that the behaviour of the capsule with one-sided constraint is mainly periodic, and the dynamic responses of the other two capsules with two-sided constraints become complex when the stiffness of the left constraint increases. Based on our extensive comparisons, the following optimisation strategies are recommended. When the capsule speed is paramount, one can employ the two-sided capsule with a weak left constraint under large amplitude of excitation. When energy consumption is taken into account, the one-sided capsule is preferable. When a miniaturized prototype is needed, the two-sided capsule with a strong left constraint is the best choice.

[A Simple but Effective Device to Avoid Objective Lens Overheating: An Air Blower Device].

The interior of the Earth is a high temperature and high pressure environment. High temperatures cause important changes in the physical and chemical properties of minerals. An increase in temperature leads to significant changes in the molecular and lattice vibrations, elasticity, and seismic velocity of minerals. The high temperature vibrational spectroscopy (infrared and Raman) used to study these changes can provide highly significant understanding of the Earth's interior. During high temperature spectroscopy, the heating device that is used to heat the sample can work at a very high temperature (e.g., 1 500 ℃) because it has a cooling device surrounding it that is used to prevent the temperature of its environments from getting too high. However, radiation from its heating elements is intense and this will shine on and heat the objective lens of the focusing system for the spectroscopic light source, and this would result in damage to the lens. Thus, to avoid damage to the objective lens, an upper limit is placed on the heater temperature. The significance of this work is that it presents a method to exceed the present instrument's temperature limit so that we can perform in situ spectroscopy on samples at higher temperatures. This work extended the temperature limit for the sample to a higher temperature by using an air blower around the objective lens to create a gas flow around it. The gas flow serves to remove heat from the objective lens by forced convection and its turbulent flow also served to increase the rate of heat transport from the lens to the moving gas stream, which together prevented overheating of the objective lens. Our results have shown that although this device is simple, it was highly effective: for a sample temperature of 1 000 ℃, the objective lens temperature was reduced from ～235 to ～68 ℃. Using this device, we performed in situ high temperature Raman spectroscopy of forsterite up to a sample temperature of 1 300 ℃. The results agreed well with previous studies and demonstrated that with our simple air blower device, we can perform in situ high temperature spectroscopy up to 1 300 ℃ without damaging the objective lens and without expensive components like a high temperature composite objective lens or a long focus objective lens.

[PPARs Mediate the Regulation of Energy Metabolism By Long-Chain Fatty Acids].

PPAR-alpha expressed primarily in liver is essential for metabolic adaptation to starvation by inducing genes for beta-oxidation and ketogenesis to increase the utility of LCFAs and fibroblast growth factor 21. PPAR-delta induces genes for LCFA oxidation during fasting and endurance exercise in skeletal muscle. PPAR-delta also regulates glucose metabolism and mitochondrial biogenesis by inducing FOXO1 and PGC1-alpha. PPAR-gamma can induces the pathways to store LCFAs as triglycerides in adipocytes. Adiponectin, another important target of PPAR-gamma may maintain insulin sensitivity between adipocytes. The present review summarize that PPARs mediate the regulation of energy metabolism by long-chain fatty acids.

Iron-Catalyzed Regioselective Transfer Hydrogenative Couplings of Unactivated Aldehydes with Simple Alkenes.

An FeBr3 -catalyzed reductive coupling of various aldehydes with alkenes that proceeds through a direct hydride transfer pathway has been developed. With (i) PrOH as the hydrogen donor under mild conditions, previously challenging coupling reactions of unactivated alkyl and aryl aldehydes with simple alkenes, such as styrene derivatives and α-olefins, proceeded smoothly to furnish a diverse range of functionalized alcohols with complete linear regioselectivity.

[Impact of CHA2DS2 VASc score on substrate for persistent atrial fibrillation and outcome post catheter ablation of atrial fibrillation].

OBJECTIVE: To explore if CHA2DS2 VASc score can predict substrate for persistent atrial fibrillation ( AF) and outcome post catheter ablation of AF. METHODS: From January 2011 to December 2012,116 patients underwent catheter ablation of persistent AF in our department and were enrolled in this study. CHA2DS2VASc score was calculated as follows: two points were assigned for a history of stroke or transient ischemic attack and age ≥ 75 and 1 point each was assigned for age ≥ 65, a history of hypertension, diabetes,recent cardiac failure, vessel disease, female. Left atrial geometry ( LA) was reconstructed with a 3.5 mm tip ablation catheter with fill-in threshold 10 in CARTO system. The mapping catheter was stabled at each endocardial location for at least 3 seconds for recording. The electrogram recordings at each endocardial location were analyzed with a custom software embedded in the CARTO mapping system. Interval confidence level (ICL) was used to characterize complex fractionated atrial electrograms (CFAEs) . As the default setting of the software, ICL more than or equal to 7 was considered sites with a highly repetitive CFAEs complex. CFAEs index was defined as the fraction of area of ICL more than or equal to 7 to the left atrial surface. The CFAEs index and outcome of catheter ablation among different CHA2DS2VASc groups were compared. RESULTS: Of the 116 patients, CHA2DS2VASc was 0 in 33 patients, 1 in 31 patients and ≥ 2 in 52 patients. Left atrial surface ((121.2 ± 18.9) cm2, (133.6 ± 23.8) cm2, (133.9 ± 16.1) cm2, P = 0.008), left atrial volume ((103.6 ± 24.8) ml, (118.3 ± 27.8) ml, (120.9 ± 20.9) ml, P = 0.005) and CFAEs index (44.6% ± 22.4%, 54.2% ± 22.2%, 58.7% ± 23.1%, P = 0.023) increased in proportion with increasing CHA2DS2VASc. ICLmax, ICLmin and CFAEs spatial distribution were similar among the three groups. During the mean follow-up of (13 ± 8) months, the recurrence rate were 36.4%, 35.5%, 55.8% among the three groups (P = 0.025). CONCLUSION: A high CHA2DS2VASc score is associated with extensive AF substrate and higher recurrence rate post catheter ablation of persistent AF.