Paeonolum protects against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting 2% of the population aged over 65 years old. Mitochondrial defects and oxidative stress actively participate in degeneration of dopaminergic (DA) neurons in PD. Paeonolum, a main component isolated from Moutan cortex, has potent antioxidant ability. Here, we have examined the effects of paeonolum against MPP(+)-induced neurotoxicity in zebrafish and PC12 cells. METHODS: The overall viability and neurodegeneration of DA neurons was assessed in ETvmat2:green fluorescent protein (GFP) transgenic zebrafish, in which most monoaminergic neurons are labeled by GFP. Damage to PC12 cells was measured using a cell viability assay and assessment of nuclear morphology. Intracellular reactive oxygen species (ROS) and the level of total GSH were assessed. The mitochondrial cell death pathway including mitochondrial membrane potential, cytochrome C release and caspase-3 activity were also examined in PC12 cells. RESULTS: Paeonolum protected against MPP(+)-induced DA neurodegeneration and locomotor dysfunction in zebrafish in a concentration-dependent manner. Similar neuroprotection was replicated in the PC12 cellular model of MPP(+) toxicity. Paeonolum attenuated MPP(+)-induced intracellular ROS accumulation and restored the level of total GSH in PC12 cells. Furthermore, paeonolum significantly inhibited the mitochondrial cell death pathway induced by MPP(+). CONCLUSIONS: Collectively, the present study demonstrates that paeonolum protects zebrafish and PC12 cells against MPP(+)-induced neurotoxicity.

Identification of marine neuroactive molecules in behaviour-based screens in the larval zebrafish.

High-throughput behavior-based screen in zebrafish is a powerful approach for the discovery of novel neuroactive small molecules for treatment of nervous system diseases such as epilepsy. To identify neuroactive small molecules, we first screened 36 compounds (1-36) derived from marine natural products xyloketals and marine isoprenyl phenyl ether obtained from the mangrove fungus. Compound 1 demonstrated the most potent inhibition on the locomotor activity in larval zebrafish. Compounds 37-42 were further synthesized and their potential anti-epilepsy action was then examined in a PTZ-induced epilepsy model in zebrafish. Compound 1 and compounds 39, 40 and 41 could significantly attenuate PTZ-induced locomotor hyperactivity and elevation of c-fos mRNA in larval zebrafish. Compound 40 showed the most potent inhibitory action against PTZ-induced hyperactivity. The structure-activity analysis showed that the OH group at 12-position played a critical role and the substituents at the 13-position were well tolerated in the inhibitory activity of xyloketal derivatives. Thus, these derivatives may provide some novel drug candidates for the treatment of epilepsy.

Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish.

We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here investigated whether xyloketal B exhibits its antioxidant activity through induction of HO-1. In human umbilical vein endothelial cells (HUVECs), xyloketal B significantly induced HO-1 gene expression and translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) in a concentration- and time-dependent manner. The protection of xyloketal B against angiotensin II-induced apoptosis and reactive oxygen species (ROS) production could be abrogated by the HO-1 specific inhibitor, tin protoporphyrin-IX (SnPP). Consistently, the suppressive effects of xyloketal B on NADPH oxidase activity could be reversed by SnPP in zebrafish embryos. In addition, xyloketal B induced Akt and Erk1/2 phosphorylation in a concentration- and time-dependent manner. Furthermore, PI3K inhibitor LY294002 and Erk1/2 inhibitor U0126 suppressed the induction of HO-1 and translocation of Nrf-2 by xyloketal B, whereas P38 inhibitor SB203580 did not. In conclusion, xyloketal B can induce HO-1 expression via PI3K/Akt/Nrf-2 pathways, and the induction of HO-1 is mainly responsible for the antioxidant and antiapoptotic actions of xyloketal B.

dl-3n-Butylphthalide promotes angiogenesis via the extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3-kinase/Akt-endothelial nitric oxide synthase signaling pathways.

We have previously demonstrated that dl-3n-butylphthalide (NBP) has a potential angiogenic activity. In this study, we investigated the angiogenic effect of NBP and the molecular mechanisms underlying NBP-mediated angiogenesis. Zebrafish embryos and human umbilical vein endothelial cells were treated with various doses of NBP and several signaling pathway inhibitors. NBP induced ectopic subintestinal vessel production in zebrafish embryos and induced invasion, migration, and endothelial cell tube formation of human umbilical vein endothelial cells in a dose-dependent manner. These NBP-induced angiogenic effects were partially suppressed by SU5402, a fibroblast growth factor receptor 1 inhibitor; U0126, an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor; LY294002, a phosphatidylinositol 3-kinase inhibitor; 1L6-hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerocarbonate, an Akt inhibitor; cavtratin, an endothelial nitric oxide synthase (eNOS) inhibitor and completely inhibited by a combination of U0126 and LY294002. NBP enhanced phosphorylation of ERK1/2 and fibroblast growth factor receptor 2 expression, which were inhibited by U0126. NBP increased the phosphorylation of Akt and eNOS at serine 1177, which was blocked by LY294002. NBP-stimulated nitric oxide production, which was reduced by LY294002. Our data demonstrated that (1) NBP promoted angiogenesis and (2) the angiogenic effects of NBP were mediated by the ERK1/2 and phosphatidylinositol 3-kinase/Akt-eNOS signaling pathways. Our findings suggest that NBP could be a novel agent for therapeutic angiogenesis in ischemic diseases.

Melatonin protects against rotenone-induced cell injury via inhibition of Omi and Bax-mediated autophagy in Hela cells.

Parkinson's disease is the second most common neurodegenerative disease, and environmental toxins such as rotenone play an important role in causing degeneration of dopaminergic neurons. Melatonin, a major secretory product of pineal, is recently reported to protect against rotenone-induced cell death in animal models. Yet, the mechanism involved in this protection needs to be elucidated. Here, we report that rotenone treatment (0-100 µM) decreased cell survival of Hela cells in a dose-dependent manner. At concentrations ranging from 0.1 to 100 µM, rotenone induced a dose-dependent increase in the expression of microtubule-associated protein 1 light chain 3 (LC3)-II, a protein associated with the autophagosomal membrane. Knockdown of Bax or Omi using shRNA inhibited 1 µM rotenone-induced autophagy. To determine whether melatonin would protect cells against rotenone-induced cell death and autophagy, we pretreated Hela cells with 250 µM melatonin for 24 hr in the presence of rotenone. Melatonin inhibited Bax expression and the release of the omi/HtrA2 into the cytoplasm induced by 1 µM rotenone. Melatonin 250 µM treatment also suppressed cell death induced by 0.1-100 µM rotenone and protected against the formation of LC3-II in cells exposed to 1 µM rotenone. This work demonstrates a novel role for melatonin as a neuroprotective agent against rotenone.

Marine cyclotripeptide X-13 promotes angiogenesis in zebrafish and human endothelial cells via PI3K/Akt/eNOS signaling pathways.

Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508). We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or L-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.

[Protective effects of Lycium barbarum extract against MPP(+) -induced neurotoxicity in Caenorhabditis elegans and PC12 cells].

OBJECTIVE: To investigate the neuroprotective effects of Lycium barbarum extract against MPP(+) -induced neurotoxicity in Caenorhabditis elegans and PC12 cells and its mechanism. METHODS: Pretreated MPP(+) -induced nearotoxicity in C. elegans and PC12 cells with Lycium barbarum at different dosages. The viability and DA neurodegeneration was assessed in C. elegans selectively expressing green fluorescent protein (GFP) in DA neurons. PC12 cell damage was measured using MTT and nuclear morphology. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential and total GSH were assessed. RESULTS: Lycium barbarum extract protected against MPP(+) -induced loss of viability and DA neurodegeneration in C. elegans in a dose-dependent manner. Similar neuroprotection was replicated in MPP + PC12 cell model. Lycium barbarum extract attenuated MPP(+) -induced intracellular ROS accumulation, loss of mitochondrial membrane potential and restored total GSH levels in PCl2 cells. CONCLUSIONS: Lycium barbarum extract protects against MPP(+) -induced neurotoxicity in C. elegans and PC12 cells and its machanism may be related to its antioxidative property and restoration of total GSH level.

Angiogenic and Antiangiogenic mechanisms of high density lipoprotein from healthy subjects and coronary artery diseases patients.

Normal high-density lipoprotein (nHDL) in normal, healthy subjects is able to promote angiogenesis, but the mechanism remains incompletely understood. HDL from patients with coronary artery disease may undergo a variety of oxidative modifications, rendering it dysfunctional; whether the angiogenic effect is mitigated by such dysfunctional HDL (dHDL) is unknown. We hypothesized that dHDL compromises angiogenesis. The angiogenic effects of nHDL and dHDL were assessed using endothelial cell culture, endothelial sprouts from cardiac tissue from C57BL/6 mice, zebrafish model for vascular growth and a model of impaired vascular growth in hypercholesterolemic low-density lipoprotein receptor null(LDLr-/-)mice. MiRNA microarray and proteomic analyses were used to determine the mechanisms. Lipid hydroperoxides were greater in dHDL than in nHDL. While nHDL stimulated angiogenesis, dHDL attenuated these responses. Protein and miRNA profiles in endothelial cells differed between nHDL and dHDL treatments. Moreover, nHDL suppressed miR-24-3p expression to increase vinculin expression resulting in nitric oxide (NO) production, whereas dHDL delivered miR-24-3p to inhibit vinculin expression leading to superoxide anion (O2•-) generation via scavenger receptor class B type 1. Vinculin was required for endothelial nitric oxide synthase (eNOS) expression and activation and modulated the PI3K/AKT/eNOS and ERK1/2 signaling pathways to regulate nHDL- and VEGF-induced angiogenesis. Vinculin overexpression or miR-24-3p inhibition reversed dHDL-impaired angiogenesis. The expressions of vinculin and eNOS and angiogenesis were decreased, but the expression of miR-24-3p and lipid hydroperoxides in HDL were increased in the ischemic lower limbs of hypercholesterolemic LDLr-/- mice. Overexpression of vinculin or miR-24-3p antagomir restored the impaired-angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Collectively, nHDL stimulated vinculin and eNOS expression to increase NO production by suppressing miR-24-3p to induce angiogenesis, whereas dHDL inhibited vinculin and eNOS expression to enhance O2•- generation by delivering miR-24-3p to impair angiogenesis, and that vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.

Baculovirus-transduced mouse amniotic fluid-derived stem cells maintain differentiation potential.

Amniotic fluid-derived stem cells have attracted considerable attention in the field of regenerative medicine. Approach of genetic modification probably enhances their regenerative potential. In this work, we wanted to determine whether baculovirus as a new gene vector could efficiently and safely transduce mouse amniotic fluid-derived stem cells (mAFSs). Cells were isolated from mouse amniotic fluid and cultured in vitro. These cells were analyzed by examining phenotypes and differentiation potential. They were further transduced with baculovirus. Baculovirus-transduced mAFSs were induced to differentiate into adipogenic, osteogenic, myogenic, and neurogenic lineages. Mouse amniotic fluid-derived stem cells were successfully isolated and cultured in vitro. They were positive for CD29 and Sca-1, but negative for CD34, CD45, or CD11b. Furthermore, they could differentiate into adipocytes, osteocytes, myocytes, and neurocytes in vitro. Baculovirus could efficiently transduced mAFSs. More importantly, baculovirus-transduced mAFSs retained differentiation potential. Thus, baculovirus vector effective and safe transduction is an attractive promise for genetic modification of mAFSs. Baculovirus genetically modified mAFSs will probably be more suitable as vehicles for regenerative medicine.

[Transduction of various mammalian bone marrow-derived mesenchymal stem cells by baculovirus].

The use of stem cells will lead to novel treatments for a wide range of diseases due to their properties of self-renewing, pluripotent, and undifferentiated state, and the stem cells are usually genetically modified for cell and gene therapy. If the baculovirus, as a new gene vector, can be effectively transduced into various mammalian bone marrow-derived mesenchymal stem cells (BMSCs) in vitro, it will be a better gene vector to genetically modify the stem cells. The aim of the present study is to investigate the transduction efficiency of recombinant baculovirus (BacV-CMV-EGFP), which expressed a reporter gene encoding enhanced green fluorescent protein (EGFP) under a cytomegalovirus immediate early (CMV-IE) promoter, into various mammalian BMSCs. The BMSCs of mouse, rat, porcine, rhesus, and human were cultured primarily in vitro. After more than three passages, the mammalian BMSCs were seeded into dishes and cultured in a humidified incubator at 37 °C with 5% CO(2). When the cells reached about 80% confluence, the complete medium was removed by aspiration. The cells were transduced with recombinant baculovirus at a multiplicity of infection (MOI) of 200 vector genomes/cell with 500 µL PBS at 25 °C for 4 h. At the end of baculovirus transduction, cells were washed and incubated with 2 mL complete medium, and baculovirus-transduced mammalian BMSCs were cultured in a humidified incubator for 2 d. Then, the inverted fluorescent microscope was used to observe GFP expressions in different mammalian BMSCs, and flow cytometry was used to detect the transduction efficiency of baculovirus in various mammalian BMSCs. After more than three passages, the BMSCs of mouse, rat, porcine, rhesus, and human showed a homogeneous spindle-shaped morphology. Compared with the BMSCs of mouse, rat and porcine, the inverted fluorescent microscope observations showed that there were more BMSCs expressing GFP and greater mean fluorescence intensity in rhesus and human transduced with baculovirus. The baculovirus could efficiently transduce into the BMSCs of mouse, rat, porcine, rhesus and human, and the transduction efficiency was (20.21±3.02)%, (22.51±4.48)%, (39.13±5.79)%, (71.16±5.36)% and (70.67±3.74)%, respectively. In conclusion, baculovirus displays different transduction efficiency into various mammalian BMSCs. Due to the high transduction efficiency for primate and human BMSCs, baculovirus is possibly a more suitable gene vector to genetically modify BMSCs of human and primates.

[Transduction of rhesus bone marrow mesenchymal stem cells by recombinant baculovirus].

OBJECTIVE: To investigate whether the recombinant baculovirus (Bac-CMV-EGFP) can effectively transduce into rhesus Bone-marrow derived Mesenchymal Stem Cells (rBMSCs) in vitro, and whether there are some efficiency to the rBMSCs of viability, proliferational and differentiational capacity after recombinant baculovirus transducing. METHODS: The rBMSCs were cultured in vitro. After passaged more than three times, the rBMSCs were transduced with various dose of baculovirus (Multiplicity Of Infection, MOI, the MOI is 50, 100, 200, 300, and 500 vector genome (vg)/cell, respectively). We used flow cytometry to detect different transductive efficiency of various dose of baculovirus to rBMSCs. Under a suitable dose of baculovirus (300 v.g/cell), we studied cell viability, proliferation and differentiation capacity, and compared results with the control. RESULTS: Baculovirus could be transduced into rBMSCs in vitro. The transductive efficiency reached about 80% when the MOI was 300 v.g/cell, at 25 degrees C, and incubated for 4 h. Furthermore, under a higher transductive efficiency of baculovirus, there were no obvious influence to the rBMSCs of viability, proliferation and differentiation capacity compared with that of the control. CONCLUSION: The baculovirus can be safely and effectively transduced into rBMSCs in vitro, without any negative efficiency to cell viability, proliferation and differentiation capacity.

Injected Amyloid Beta in the Olfactory Bulb Transfers to Other Brain Regions via Neural Connections in Mice.

Alzheimer's disease (AD) is characterized by progressive neuronal degeneration and pathological accumulation of amyloid plaques in the brain. It has been proposed that the prion-like spreading of amyloid beta (Aß) protein could contribute to the progression of the disease. Olfactory bulb (OB) is one of the earliest brain regions affected in AD and olfaction is easily impaired prior to cognitive symptoms. However, it remains unclear whether Aß accumulation in the OB would spread along olfactory projections to other connected brain regions and trigger further neurodegeneration. In the present study, we experimentally injected recombinant human Aß1-42 (monomers and oligomers, respectively) into the mouse OB and tracked the spreading of Aß to connected brain regions over 3 days. The results showed that both Aß monomers and oligomers were rapidly and readily transferred from the injection site to interconnected brain regions in a neural connection manner and triggered neuronal apoptosis in the affected brain regions. Oligomeric Aß1-42 spread more efficiently and induced more neuronal apoptosis in the affected brain regions compared to monomeric Aß1-42. Therefore, the study provides evidence that Aß peptides can transfer via neural connections and the pattern of Aß peptide spreading provides understanding to manage AD.

Correction: Continuous Positive Airway Pressure Treatment Reduces Mortality in Elderly Patients with Moderate to Severe Obstructive Severe Sleep Apnea: A Cohort Study.

[This corrects the article DOI: 10.1371/journal.pone.0127775.].

Modeling the Pathogenesis of Charcot-Marie-Tooth Disease Type 1A Using Patient-Specific iPSCs.

Charcot-Marie-Tooth disease type 1A (CMT1A), one of the most frequent inherited peripheral neuropathies, is associated with PMP22 gene duplication. Previous studies of CMT1A mainly relied on rodent models, and it is not yet clear how PMP22 overexpression leads to the phenotype in patients. Here, we generated the human induced pluripotent stem cell (hiPSC) lines from two CMT1A patients as an in vitro cell model. We found that, unlike the normal control cells, CMT1A hiPSCs rarely generated Schwann cells through neural crest stem cells (NCSCs). Instead, CMT1A NCSCs produced numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system, and similar results were obtained in a PMP22-overexpressing iPSC model. Therefore, despite the demyelination-remyelination and/or dysmyelination theory for CMT1A pathogenesis, developmental disabilities of Schwann cells may be considered as an underlying cause of CMT1A. Our results may have important implications for the uncovering of the underlying mechanism and the development of a promising therapeutic strategy for CMT1A neuropathy.

[Carrier genetic diagnosis of intron and/or exon-deletion Duchenne muscular dystrophy by microsatellite analysis and quantitative polymerase chain reaction].

OBJECTIVE: To detect the female carriers from the intron and/or exon-deletion Duchenne/Becker musclular dystrophy (DMD) familial members for prenatal or preimplantation genetic diagnosis. METHODS: Using method of PCR to five microsatellite markers (located in 5' terminus and intron 44, 45, 49, 50), analysing of the short tandem repeat sequence polymorphism with the genescan and binding with the quantitative polymerase chain reaction, we detected the DMD carriers from 1 intron and exon -deletion family and 1 intron-deletion family. RESULTS: The STR-50 genotype of II 2 in family 5 was 245/245, so II3 is DMD gene carrier. The STR-45 genotype of II6 and II8 were del/172, III19 was del/178, so they were all DMD gene carriers. CONCLUSION: The STR haploid linkage analysis combined with quantitative polymerase chain reaction is accurate and efficient to detect the female carriers from the intron and/or exon-deletion DMD familial members.

[Association between angiotensin-converting enzyme and polymorphisms of N5, N10-methylenetetrahydrofolic acid reductase gene in patients with ischemic stroke].

OBJECTIVE: To explore the association between angiotensin-converting enzyme (ACE) and the polymorphisms of N5, N10-methylenetetrahydrofolic acid reductase (MTHFR) gene in patients with ischemic stroke (IS). METHODS: Totally 454 patients with IS (IS group) and 334 controls (control group) were recruited in our study. Their I/D polymorphisms of ACE gene and C677T polymorphisms of MTHFR gene were detected by PCR and denaturing high performance liquid chromatography. RESULTS: The frequencies of DD, ID, II and CC, CT, TT genotype in IS group were 22.5%, 43.4%, 34.1%, and 51.8%, 40.5%, 7.7%, respectively, and were 17.4%, 45.5%, 37.1% and 56.9%, 38.3%, 4.8% in the control group, respectively. DD genotype was associated with large-artery atherosclerosis (LAA), and TT genotype and T allele were associated with LAA and cardioembolism. Synergistic effects were found between TT and DD/ID DD genotypes in the pathogenesis of ischemic stroke. CONCLUSION: DD, TT genotype and T allele are risk factors of IS, and ACE gene and MTHFR gene have synergistic effects in the pathogenesis of IS.

[Sibling brother and sister both with Duchenne muscular dystrophy].

OBJECTIVE: To investigate the clinical and lab features of sibling brother and sister both with Duchenne muscular dystrophy (DMD). METHODS: We conducted comprehensive clinical and lab investigations including the test of serum enzymes, electromyography (EMG), electrocardiography, color Doppler echocardiography, HE staining of skeletal muscles, immunohistochemical study of dystrophin and utrophin, multiple ligation probe amplification (MLPA) on exon 1-79 of dystrophin gene, and short tandem repeat-poly- merase chain reaction of CA repeats located in dystrophin gene. RESULTS: These two patients were confirmed to suffer from DMD. They were characterized by typical features of DMD including typical clinical manifestations, increased serum enzymes, EMG presenting myogenic impairment, HE staining presentation belonging to DMD, negative dystrophin in brother, and inconstantly positive on the sarcolemma of sister. Furthermore, no deletion or duplication was found in the 1-79 exons of dystrophin gene. The suffering brother and sister carried the same maternal X chromosome. CONCLUSIONS: Carriers of DMD gene show typical clinical and laboratory manifestations of DMD. Comprehensive examinations should be performed for such carriers.

[Relationship between angiotensin converting enzyme gene and ischemic stroke].

OBJECTIVE: To study relationship between angiotensin converting enzyme (ACE) gene and ischemic stroke (IS). METHODS: (1)Four hundred and fifty-four patients and 334 controls were recruited in our study, their I/D polymorphisms of ACE gene were detected by polymerase chain reaction (PCR) and denaturing high performance liquid chromatogram, and their risk factors of IS were recorded at the same time. (2)In addition, 29 stroke-prone spontaneously hypertensive rats (SHR-SP) and 40 Sprague-Dawley (SD) rats were enrolled, and hypoxia- apnoea animal models and simple apnoea animal models were used at the same time. Their plasma angiotensin II (Ang II) levels were determined. RESULTS: The frequencies of DD, ID and II genotype in IS patients were 22.5%, 43.4% and 34.1%, respectively, and 17.4%, 45.5% and 37.1%, respectively in controls. DD genotype was associated with large artery arteriosclerosis (LAA). Plasma Ang II level in SHR-SP group was (164.49+/-34.58) ng/L, and it was higher than that in control group [(150.92+/-24.92)ng/L] with no significant difference (P>0.05). Ang II levels in apnoea and hypoxia-apnoea group were (382.84+/-62.75) ng/L and (295.90+/-55.07) ng/L, respectively, and they were significantly higher than that in control group (all P<0.01). The relative risks of DD genotype and D alleles in IS patients with smoking, alcohol abuse, or with diabetes mellitus were higher than those in controls, but II genotype and I alleles were lower than those in controls. CONCLUSION: DD genotype is a risk factor for IS, Ang II takes part in the course of hypoxia-stress, and it is correlated with smoking, alcohol abuse and diabetes mellitus in the pathogenesis of IS.

Characterization of the constitutive behavior of municipal solid waste considering particle compressibility.

This paper presents a characterization of the mechanical behavior of municipal solid waste (MSW) under consolidated drained and undrained triaxial conditions. The constitutive model was established based on a deviatoric hardening plasticity model. A power form function and incremental hyperbolic form function were proposed to describe the shear strength and the hardening role of MSW. The stress ratio that corresponds to the zero dilatancy was not fixed but depended on mean stress, making the Rowe's rule be able to describe the stress-dilatancy of MSW. A pore water pressure reduction coefficient, which attributed to the compressibility of a particle and the solid matrix, was introduced to the effective stress formulation to modify the Terzaghi's principle. The effects of particle compressibility and solid matrix compressibility on the undrained behavior of MSW were analyzed by parametric analysis, and the changing characteristic of stress-path, stress-strain, and pore-water pressure were obtained. The applicability of the proposed model on MSW under drained and undrained conditions was verified by model predictions of three triaxial tests. The comparison between model simulations and experiments indicated that the proposed model can capture the observed different characteristics of MSW response from normal soil, such as nonlinear shear strength, pressure dependent stress dilatancy, and the reduced value of pore water pressure.

A non-invasive risk score for predicting incident diabetes among rural Chinese people: A village-based cohort study.

OBJECTIVE: To develop a new non-invasive risk score for predicting incident diabetes in a rural Chinese population. METHODS: Data from the Handan Eye Study conducted from 2006-2013 were utilized as part of this analysis. The present study utilized data generated from 4132 participants who were ≥30 years of age. A non-invasive risk model was derived using two-thirds of the sample cohort (selected randomly) using stepwise logistic regression. The model was subsequently validated using data from individuals from the final third of the sample cohort. In addition, a simple point system for incident diabetes was generated according to the procedures described in the Framingham Study. Incident diabetes was defined as follows: (1) fasting plasma glucose (FPG) ≥ 7.0 mmol/L; or (2) hemoglobin A1c (HbA1c) ≥ 6.5%; or (3) self-reported diagnosis of diabetes or use of anti-diabetic medications during the follow-up period. RESULTS: The simple non-invasive risk score included age (8 points), Body mass index (BMI) (3 points), waist circumference (WC) (7 points), and family history of diabetes (9 points). The score ranged from 0 to 27 and the area under the receiver operating curve (AUC) of the score was 0.686 in the validation sample. At the optimal cutoff value (which was 9), the sensitivity and specificity were 74.32% and 58.82%, respectively. CONCLUSIONS: Using information based upon age, BMI, WC, and family history of diabetes, we developed a simple new non-invasive risk score for predicting diabetes onset in a rural Chinese population, using information from individuals aged 30 years of age and older. The new risk score proved to be more optimal in the prediction of incident diabetes than most of the existing risk scores developed in Western and Asian countries. This score system will aid in the identification of individuals who are at risk of developing incident diabetes in rural China.