Development and validation of a nomogram for arterial stiffness.

Even though as a gold standard for noninvasive measurement of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV) is not widely used in primary healthcare institutions due to time-consuming and unavailable equipment. The aim of this study was to develop a convenient and low-cost nomogram model for arterial stiffness screening. A cross-sectional study was undertaken in the department of general practice, the First Affiliated Hospital of Fujian Medical University. Arterial stiffness was defined as cfPWV ≥ 10 m/s. A total of 2717 participants were recruited to construct the nomogram using the least absolute shrinkage and selection operator and logistic regressions. Receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis, clinical impact curve were used to evaluate the performance of the model. The model was validated internally and externally (399 participants) by bootstrap method. Arterial stiffness was identified in 913 participants (33.60%). Age, sex, waist to hip ratio, systolic blood pressure, duration of diabetes, heart rate were selected to construct the nomogram model. Good discrimination and accuracy were exhibited with area under curve of 0.820 (95% CI 0.803-0.837) in ROC curve and mean absolute error = 0.005 in calibration curve. A positive net benefit was shown in decision curve analysis and clinical impact curve. A satisfactory agreement was displayed in internal validation and external validation. The low cost and user-friendly nomogram is suitable for arterial stiffness screening in primary healthcare institutions.

Increased Plasma Homocysteine Levels Are Associated with Left Ventricular Hypertrophy in Hypertensive Patients with Normal Renal Function.

INTRODUCTION: Renal function has an important bearing on plasma homocysteine levels. Plasma homocysteine is related to left ventricular hypertrophy (LVH). However, it remains unclear whether the association between plasma homocysteine levels and LVH is influenced by renal function. This study aimed to investigate relationships among left ventricular mass index (LVMI), plasma homocysteine levels, and renal function in a population from southern China. METHODS: A cross-sectional study was performed in 2,464 patients from June 2016 to July 2021. Patients were divided into three groups based on gender-specific tertiles of homocysteine levels. LVMI ≥115 g/m2 for man or ≥95 g/m2 for woman was defined as LVH. RESULTS: LVMI and the percentage of LVH were increased, while estimated glomerular filtration rate (eGFR) was decreased with the increase in homocysteine levels, both significantly. Multivariate stepwise regression analysis showed that eGFR and homocysteine were independently associated with LVMI in patients with hypertension. No correlation was observed between homocysteine and LVMI in patients without hypertension. Stratified by eGFR, further analysis confirmed homocysteine was independently associated with LVMI (ß = 0.126, t = 4.333, p < 0.001) only in hypertensive patients with eGFR ≥90 mL/(min·1.73 m2), not with 60≤ eGFR <90 mL/(min·1.73 m2). Multivariate logistic regression indicated that in hypertensive patients with eGFR ≥90 mL/(min·1.73 m2), the patients in high tertile of homocysteine levels had a nearly twofold increased risk of occurring LVH compared with those in low tertile (high tertile: OR = 2.780, 95% CI: 1.945-3.975, p < 0.001). CONCLUSION: Plasma homocysteine levels were independently associated with LVMI in hypertensive patients with normal eGFR.

Dual-target nucleic acid sequences responsive electrochemiluminescence biosensor using single type carbon dots as probe for SARS-CoV-2 detection based on series catalytic hairpin assembly amplification.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is rampant all over the world, and rapid and effective virus detection is the best auxiliary to curb the spread of the epidemic. A diagnosis can only be made if two or more different nucleic acid sequences are confirmed at the same time, and in most of traditional detection technologies, these target sequences have been detected separately. In this work, an electrochemiluminescent (ECL) biosensor employing a single ECL probe as signal output and responding to dual-target simultaneously is proposed for the first time. Taking the two sequences located in ORF 1ab region and N region of SARS-CoV-2 gene sequence as the model target and nitrogen doped carbon quantum dots (CDs) as ECL beacon, supplemented with catalytic hairpin assembly (CHA) reaction for signal amplification, the presented strategy has been successfully applied to the rapid detection of SARS-CoV-2. The developed SARS-CoV-2 biosensor based on the series CHA systems can realize the quantitative determination of SARS-CoV-2 in the range of 50 fM to 200 pM within 40 min. Moreover, the clinical validity of this method has been verified by the high consistency between the detection results of using this method and those using RT-qPCR for seven clinical pharyngeal swab samples.

Association of homocysteine with carotid atherosclerosis in hypertension.

Information on the association between homocysteine (HCY) levels and carotid atherosclerosis (CAS) in hypertension (HTN) is limited. A cross-sectional study was performed to examine the relationship of plasma HCY concentration with CAS in 1700 hypertensives (61.62 ± 12.16 year). The prevalence of CAS and carotid intima-media thickness (CIMT) progressively increased across quartiles of HCY levels (P < 0.001). Correlation analysis showed significantly positive correlation between HCY and CAS (r = 0.261, P < 0.001). In a logistic regression, HCY independently predicted the presence of CAS (OR 1.284, 95% CI 1.163-1.418). Further investigation revealed that interaction effect of HCY was substantial for gender (P for interaction 0.023), age (P for interaction <0.001) and smoking (P for interaction 0.025) on CAS. Thus, in hypertensives, those of male, aged ≥55 year and current smokers, in which HCY ≥ 13.49 µmol/L were more likely to suffer CAS, suggesting a role of HCY in the development and progression of CAS in these patients, and HCY determination should be recommended to better stratify the cardiovascular risk.

Defect Detection Method of Carbon Fiber Sucker Rod Based on Multi-Sensor Information Fusion and DBN Model.

Because of its unique characteristics of small specific gravity, high strength, and corrosion resistance, the carbon fiber sucker rod has been widely used in petroleum production. However, there is still a lack of corresponding online testing methods to detect its integrity during the process of manufacturing. Ultrasonic nondestructive testing has become one of the most accepted methods for inspection of homogeneous and fixed-thickness composites, or layered and fixed-interface-shape composites, but a carbon fiber sucker rod with multi-layered structures and irregular interlayer interfaces increases the difficulty of testing. In this paper, a novel defect detection method based on multi-sensor information fusion and a deep belief network (DBN) model was proposed to identify online its defects. A water-immersed ultrasonic array with 32 ultrasonic probes was designed to realize the online and full-coverage scanning of carbon fiber rods in radial and axial positions. Then, a multi-sensor information fusion method was proposed to integrate amplitudes and times-of-flight of the received ultrasonic pulse-echo signals with the spatial angle information of each probe into defect images with obvious defects including small cracks, transverse cracks, holes, and chapped cracks. Three geometric features and two texture features from the defect images characterizing the four types of defects were extracted. Finally, a DBN-based defect identification model was constructed and trained to identify the four types of defects of the carbon fiber rods. The testing results showed that the defect identification accuracy of the proposed method was 95.11%.

The association between orthostatic blood pressure changes and arterial stiffness.

OBJECTIVE: Although orthostatic hypotension (OH) and orthostatic hypertension (OHT) can independently predict cardiovascular events, the underlying mechanisms remain controversial. Our study aimed to examine the relationships between orthostatic blood pressure (BP) changes and arterial stiffness. METHODS: In this cross-sectional analysis, 1820 participants were divided into three groups according to BP changes within 3 min of orthostatism: the OH group had a decrease of >20 mmHg in SBP or >10 mmHg in DBP, the OHT group had an increase of ≥20 mmHg in SBP, and the orthostatic normotensive (ONT) group had normal changes. Arterial stiffness was assessed by measuring the carotid-femoral pulse wave velocity (cfPWV). RESULTS: OH and OHT were observed in 257 (14.1%) and 62 (3.4%) participants, respectively. Subjects in the OH group were significantly older, were more likely to have hypertension and diabetes, and had higher cfPWV than those in the ONT group ( P < 0.05); however, no differences were found between the ONT and OHT groups. Stepwise multiple regression analysis of the subgroups stratified by hypertension and diabetes revealed that age was related to increased cfPWV in all stratifications, and the change in SBP was significantly positively correlated with cfPWV in hypertensive subjects; however, this association was not observed in nonhypertensive subjects. CONCLUSION: We found that arterial stiffness was closely related to OH but not to OHT. In addition to expanding current knowledge of the relationship between orthostatic BP changes and arterial stiffness, our study underlines the importance of age, SBP changes, and hypertension in evaluating arterial stiffness.

Relationship between lactate dehydrogenase and albuminuria in Chinese hypertensive patients.

Lactate dehydrogenase (LDH) has been reported to be positively correlated with albuminuria assessed by urinary albumin-to-creatinine ratio (UACR) in patients with sickle cell disease; both LDH and albuminuria are positively associated with the severity of hypertension (HTN). Here, a cross-sectional study was performed to investigate the association between LDH and albuminuria in Chinese hypertensives. A total of 1169 Chinese individuals (aged 58.0 ± 11.5 years, 60.4% male), who were admitted to our hospital, were included in this study. Based on the level of LDH, all hypertensives (n = 802) were divided into three groups: HTN1 (lowest tertile of LDH, n = 264), HTN2 (mediate tertile of LDH, n = 268), and HTN3 (highest tertile of LDH, n = 270). Hypertensives with hyperhomocysteinemia were defined as hypertensives with homocysteine ≥15µmol/L. Meanwhile, 367 normotensives served as controls. Compared with normotensives, the levels of LDH and UACR were significantly higher in hypertensives (p < .05). There was an increasing trend of albuminuria (UACR ≥30 mg/g) from control, HTN1, HTN2 to HTN3 group (4% vs. 12.1% vs. 14.9% vs. 19.6%, χ2  = 38.886, p < .001). Stepwise multiple regression analysis showed an independent association between LDH and UACR in patients with HTN (ß = 0.085, p < .05), but not in normotensives. After further stratification in hypertensive patients, this correlation remained in the male (ß = 0.161, p < .001), elderly (age ≥65 years, ß = 0.174, p < .001) and especially hypertensives with hyperhomocysteinemia (ß = 0.402, p < .001). LDH combined with white blood cell (WBC) counts was observed to have better discrimination for albuminuria than creatinine united with cystatin C in hypertensives according to receiver operation characteristic curves (area under curve: 0.637 vs. 0.535, z = 2.563, p = .0104). In conclusion, the level of LDH was associated with albuminuria in Chinese patients with HTN, particularly in hypertensives with hyperhomocysteinemia. LDH combined with WBC provided better prediction of albuminuria than routine renal function assessment in hypertensives. Further studies are needed to confirm LDH as an early marker for the risk of kidney involvement among hypertensives.

VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions.

Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation ßGlu6 → ßVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action-as elucidated through crystallographic and biological studies-is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate.

Electrochemiluminescence biosensor for miRNA-21 based on toehold-mediated strand displacement amplification with Ru(phen)32+ loaded DNA nanoclews as signal tags.

A novel electrochemiluminescence (ECL) biosensor was developed for high sensitive and selective detection of miRNA-21 based on the efficient and specific toehold-mediated strand displacement (TMSD) amplification with Ru(phen)32+ loaded DNA nanoclews (NCs-Ru(phen)32+) as signal tags. The stable DNA nanoclews, synthesized by a simple rolling circle amplification reaction, were employed to load with Ru(phen)32+ efficiently as ECL signal tags to amplify the signals. As for TMSD, the substrate strand (Sub) was initially hybridized with P1 and P2 to form DNA duplex structures with a toehold 1. miRNA-21 could hybridize with the toehold 1 and trigger the TMSD amplification with the help of assist strand, releasing lots of P1 stands from DNA duplex structures. The TMSD technique realized the converting and amplification of the single miRNA-21 input to lots of output DNA (namely P1) with good selectivity, simultaneously. Output P1 were designed to expand the stem-locked region of HP, which were immobilized on the Au electrodes firstly. Subsequently, the opened HP could hybridize with the Ru(phen)32+, capturing the ECL signal tags closed to the sensing surface. The ECL intensity of the system had a linear relationship with the logarithm of the miRNA-21 concentration in the range of 1.0 fM to 100 pM with a limit of detection of 0.65 fM. The strategy was further applied to detect miRNA-21 in complex samples, and the result was consistent with the qRT-PCR.

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway.

The overall survival rate of patients with hepatocellular carcinoma (HCC) has remained unchanged over the last several decades. Therefore, novel drugs and therapies are required for HCC treatment. Isoliquiritigenin (ISL), a natural flavonoid predominantly isolated from the traditional Chinese medicine Glycyrrhizae Radix (Licorice), has a high anticancer potential and broad application value in various cancers. Here, we aimed to investigate the anticancer role of ISL in the HCC cell line Hep3B. Functional analysis revealed that ISL inhibited the proliferation of Hep3B cells by causing G1/S cell cycle arrest in vitro. Meanwhile, the inhibitory effect of ISL on proliferation was also observed in vivo. Further analysis revealed that ISL could suppress the migration and metastasis of Hep3B cells in vitro and in vivo. Mechanistic analysis revealed that ISL inhibited cyclin D1 and up-regulated the proteins P21, P27 that negatively regulate the cell cycle. Furthermore, ISL induced apoptosis while inhibiting cell cycle transition. In addition, phosphatidylinositol 3'-kinase/protein kinase B (PI3K/AKT) signal pathway was suppressed by ISL treatment, and the epithelial marker E-cadherin was up-regulated when the mesenchymal markers Vimentin and N-cadherin were down-regulated. In brief, our findings suggest that ISL could be a promising agent for preventing HCC tumorigenesis and metastasis.

Association of homocysteine with carotid-femoral pulse wave velocity in a southern Chinese population.

This study aimed to investigate whether plasma homocysteine levels were associated with carotid-femoral pulse wave velocity (cfPWV), a golden standard of arterial stiffness, in a population from southern China. A cross-sectional study was conducted on 713 patients admitted to the First Affiliated Hospital of Fujian Medical University from February 2016 to August 2017. They were divided into four groups based on gender-specific quartile of homocysteine levels. Age, cfPWV, uric acid levels, and percentage of hypertension increased with ascending quartiles. The duration of hypertension and systolic blood pressure were higher in the highest quartile than in the lowest quartile. Pearson's correlation analysis and multivariate regression showed a correlation of homocysteine levels with cfPWV. A nearly twofold increased risk of cfPWV ≥10 m/s was observed in the highest quartile compared with the lowest quartile (in the highest quartile: odds ratio = 2.917, 95% confidence interval: 1.635-5.202, P < 0.001). After stratification, this correlation was present in both sexes, in patients aged over 65 years, and those with hypertension. The plasma homocysteine levels were independently associated with cfPWV in the population from southern China, especially in the elderly and those with hypertension.

Structure and activity of lipid bilayer within a membrane-protein transporter.

Membrane proteins function in native cell membranes, but extraction into isolated particles is needed for many biochemical and structural analyses. Commonly used detergent-extraction methods destroy naturally associated lipid bilayers. Here, we devised a detergent-free method for preparing cell-membrane nanoparticles to study the multidrug exporter AcrB, by cryo-EM at 3.2-Å resolution. We discovered a remarkably well-organized lipid-bilayer structure associated with transmembrane domains of the AcrB trimer. This bilayer patch comprises 24 lipid molecules; inner leaflet chains are packed in a hexagonal array, whereas the outer leaflet has highly irregular but ordered packing. Protein side chains interact with both leaflets and participate in the hexagonal pattern. We suggest that the lipid bilayer supports and harmonizes peristaltic motions through AcrB trimers. In AcrB D407A, a putative proton-relay mutant, lipid bilayer buttresses protein interactions lost in crystal structures after detergent-solubilization. Our detergent-free system preserves lipid-protein interactions for visualization and should be broadly applicable.

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease.

Candidate drugs to counter intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) continue to represent a promising approach to mitigating the primary cause of the pathophysiology associated with sickle cell disease (SCD). One such compound is the naturally occurring antisickling agent, 5-hydroxymethyl-2-furfural (5-HMF), which has been studied in the clinic for the treatment of SCD. As part of our efforts to develop novel efficacious drugs with improved pharmacologic properties, we structurally modified 5-HMF into 12 ether and ester derivatives. The choice of 5-HMF as a pharmacophore was influenced by a combination of its demonstrated attractive hemoglobin modifying and antisickling properties, well-known safety profiles, and its reported nontoxic major metabolites. The derivatives were investigated for their time- and/or dose-dependent effects on important antisickling parameters, such as modification of hemoglobin, corresponding changes in oxygen affinity, and inhibition of red blood cell sickling. The novel test compounds bound and modified Hb and concomitantly increased the protein affinity for oxygen. Five of the derivatives exhibited 1.5- to 4.0-fold higher antisickling effects than 5-HMF. The binding mode of the compounds with Hb was confirmed by X-ray crystallography and, in part, helps explain their observed biochemical properties. Our findings, in addition to the potential therapeutic application, provide valuable insights and potential guidance for further modifications of these (and similar) compounds to enhance their pharmacologic properties.

The association of two polymorphisms in adiponectin-encoding gene with hypertension risk and the changes of circulating adiponectin and blood pressure: A meta-analysis.

OBJECTIVES: This meta-analysis was prepared to synthesize published data on the association of two polymorphisms (T45G and G276T) in adiponectin-encoding gene (ADIPOQ) with hypertension risk and the changes of circulating adiponectin and blood pressure. Methodology and Major Findings: Data were collected and corrected by two authors, and were managed with Stata software. In total, 12 articles were synthesized, including 12 studies (3358 cases and 5121 controls) for the association of two study polymorphisms with hypertension risk and 11 studies (3053 subjects) for the between-genotype changes of adiponectin and/or blood pressure. Based on all qualified studies, the risk prediction for hypertension was nonsignificant for both polymorphisms, with significant heterogeneity for G276T polymorphism (I2 = 53.8%). Overall changes in adiponectin and blood pressure were also nonsignificant for T45G, while contrastingly 276GT genotype was associated with significantly higher levels of adiponectin (weighted mean difference [WMD] = 0.72 µg/mL, 95% confidence interval [CI]: 0.04 to 1.41, P = 0.038), systolic (WMD = 5.15 mm Hg, 95% CI: 0.98 to 9.32, P = 0.016) and diastolic (WMD = 3.45 mm Hg, 95% CI: 0.37 to 6.53, P = 0.028) blood pressure with evident heterogeneity (I2 = 72.0%, 78.3% and 80.0%, respectively), and these associations were more obvious in hypertensive patients. Publication bias was a low probability event for overall comparisons. CONCLUSIONS: Our findings suggested that in spite of the nonsignificant association between ADIPOQ T45G or G276T polymorphism and hypertension, the heterozygous mutation of G276T was observed to account for increased levels of circulating adiponectin and blood pressure, especially in hypertensive patients.

Nanoconjugated NAP as a Potent and Periphery Selective Mu Opioid Receptor Modulator To Treat Opioid-Induced Constipation.

Opioids are the mainstay for cancer and noncancer pain management. However, their use is often associated with multiple adverse effects. Among them, the most common and persistent one is probably opioid-induced constipation (OIC). Periphery selective opioid antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. Recently our laboratories have identified one novel lead compound, 17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-[(4'-pyridyl)acetamido]morphinan (NAP), as a peripherally selective mu opioid receptor ligand carrying subnanomolar affinity to the mu opioid receptor and over 100-folds of selectivity over both the delta and kappa opioid receptors, with reasonable oral availability and half-life, and potential to treat OIC. Nanoparticle-based drug delivery systems are now widely considered due to their technological advantages such as good stability, high carrier capacity, low therapeutic side effects, etc. Herein we report nanoparticle supported NAP as a potential candidate for OIC treatment with improved peripheral selectivity over the original lead compound NAP.

Investigation of the disposal of dead pigs by pig farmers in mainland China by simulation experiment.

Dead pigs are a major waste by-product of pig farming. Thus, safe disposal of dead pigs is important to the protection of consumer health and the ecological environment by preventing marketing of slaughtered and processed dead pigs and improper dumping of dead pigs. In this study, a probability model was constructed for the disposal of dead pigs by pig farmers by selecting factors affecting disposal. To that end, we drew on the definition and meaning of behavior probability based on survey data collected from 654 pig farmers in Funing County, Jiangsu Province, China. Moreover, the role of influencing factors in pig farmers' behavioral choices regarding the disposal of dead pigs was simulated by simulation experiment. The results indicated that years of farming had a positive impact on pig farmers' choice of negative disposal of dead pigs. Moreover, there was not a simple linear relationship between scale of farming and pig farmers' behavioral choices related to the disposal of dead pigs. The probability for farmers to choose the safe disposal of dead pigs increased with the improvement of their knowledge of government policies and relevant laws and regulations. Pig farmers' behavioral choice about the disposal of dead pigs was also affected by government subsidy policies, regulation, and punishment. Government regulation and punishment were more effective than subsidy. The findings of our simulation experiment provide important decision-making support for the governance in preventing the marketing of dead pigs at the source.

Influential impacts of combined government policies for safe disposal of dead pigs on farmer behavior.

Improper disposal of dead pigs by pig farmers may have an adverse impact on the ecological environment and food safety. In this paper, disposal of dead pigs by pig farmers in four main pig production provinces in China (Jiangsu, Anhui, Hubei, and Hunan) was empirically investigated. Then, pig farmers' awareness and evaluation of current combined government policies for the safe disposal of dead pigs were analyzed. Furthermore, the influential effects of combined government policies on the disposal of dead pigs by pig farmers were examined using Decision-Making Trial and Evaluation Laboratory (DEMATEL). Results indicated that the issue of disposal of dead pigs by farmers was very complex and was influenced by the combination of subsidy and compensation, facility and technology, and supervision and punishment policies. The findings also indicated that the different types of policies had different effects and interacted with each other. Among these three combinations, supervision and punishment policies were the most influential policies and facility and technology policies were in most urgent need to improve for regulating the current state of the disposal of dead pigs by farmers. These findings have implications for sustainable pig production.

Carnitine palmitoyltransferase 1A functions to repress FoxO transcription factors to allow cell cycle progression in ovarian cancer.

Cancer cells rely on hyperactive de novo lipid synthesis for maintaining malignancy. Recent studies suggest involvement in cancer of fatty acid oxidation, a process functionally opposite to lipogenesis. A mechanistic link from lipid catabolism to oncogenic processes is yet to be established. Carnitine palmitoyltransferase 1 (CPT1) is a rate-limiting enzyme of fatty acid ß-oxidation (FAO) that catalyzes the transfer of long-chain acyl group of the acyl-CoA ester to carnitine, thereby shuttling fatty acids into the mitochondrial matrix for ß-oxidation. In the present study, we demonstrated that CPT1A was highly expressed in most ovarian cancer cell lines and primary ovarian serous carcinomas. Overexpression of CPT1A correlated with a poor overall survival of ovarian cancer patients. Inactivation of CPT1A decreased cellular ATP levels and induced cell cycle arrest at G0/G1, suggesting that ovarian cancer cells depend on or are addicted to CPT1A-mediated FAO for cell cycle progression. CPT1A deficiency also suppressed anchorage-independent growth and formation of xenografts from ovarian cancer cell lines. The cyclin-dependent kinase inhibitor p21WAF1 (p21) was identified as most consistently and robustly induced cell cycle regulator upon inactivation of CPT1A. Furthermore, p21 was transcriptionally upregulated by the FoxO transcription factors, which were in turn phosphorylated and activated by AMP-activated protein kinase and the mitogen-activated protein kinases JNK and p38. Our results established the oncogenic relevance of CPT1A and a mechanistic link from lipid catabolism to cell cycle regulation, suggesting that CPT1A could be a prognostic biomarker and rational target for therapeutic intervention of cancer.

Identifying critical factors influencing the disposal of dead pigs by farmers in China.

Disposal of dead pigs by pig farmers may have a direct impact on pork safety, public health, and the ecological environment in China. Drawing on the existing literature, this study analyzed and summarized the main factors that could affect the disposal of dead pigs by pig farmers by conducting a survey of 654 pig farmers in Funing County, Jiangsu Province, China. The purpose of this analysis was to investigate the disposal of dead pigs in China and provide useful regulatory strategies for the government. The interrelationships among dimensions and factors that affect the disposal of dead pigs by farmers were analyzed, and critical factors were identified by a hybrid multi-criteria decision-making method, which is a combination of decision-making trial and evaluation laboratory (DEMATEL) and analytic network process (ANP). Our results demonstrated that production characteristics were the most important dimensions and that costs and profits, scale of farming, pattern of farming, knowledge of relevant laws and regulations, and knowledge of pig disease and prevention were the five most critical factors affecting the disposal of dead pigs by farmers in China at this stage. The significance of this study lies in further discussing some management policies for the Chinese government regarding strengthen regulation of disposing dead pigs.

Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin-NO Biochemistry.

We have developed novel nitric oxide (NO)-releasing prodrugs of efaproxiral (RSR13) for their potential therapeutic applications in a variety of diseases with underlying ischemia. RSR13 is an allosteric effector of hemoglobin (Hb) that decreases the protein's affinity for oxygen, thereby increasing tissue oxygenation. NO, because of its vasodilatory property, in the form of ester prodrugs has been found to be useful in managing several cardiovascular diseases by increasing blood flow and oxygenation in ischemic tissues. We synthesized three NO-donor ester derivatives of RSR13 (DD-1, DD-2, and DD-3) by attaching the NO-releasing moieties nitrooxyethyl, nitrooxypropyl, and 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, respectively, to the carboxylate of RSR13. In vitro studies demonstrated that the compounds released NO in a time-dependent manner upon being incubated with l-cysteine (1.8-9.3%) or human serum (2.3-52.5%) and also reduced the affinity of Hb for oxygen in whole blood (ΔP50 of 4.9-21.7 mmHg vs ΔP50 of 25.4-32.1 mmHg for RSR13). Crystallographic studies showed RSR13, the hydrolysis product of the reaction between DD-1 and deoxygenated Hb, bound to the central water cavity of Hb. Also, the hydrolysis product, NO, was observed exclusively bound to the two α hemes, the first such HbNO structure to be reported, capturing the previously proposed physiological bis-ligated nitrosylHb species. Finally, nitrate was observed bound to ßHis97. Ultraperformance liquid chromatography-mass spectrometry analysis of the compounds incubated with matrices used for the various studies demonstrated the presence of the predicted reaction products. Our findings, beyond the potential therapeutic application, provide valuable insights into the biotransformation of NO-releasing prodrugs and their mechanism of action and into hemoglobin-NO biochemistry at the molecular level.