Particulate Matter Exposure Exacerbates High Glucose-Induced Cardiomyocyte Dysfunction through ROS Generation

Diabetes mellitus and fine particulate matter from diesel exhaust (DEP) are both important contributors to the development of cardiovascular disease (CVD). Diabetes mellitus is a progressive disease with a high mortality rate in patients suffering from CVD, resulting in diabetic cardiomyopathy. Elevated DEP levels in the air are attributed to the development of various CVDs, presumably since fine DEP (<2.5 µm in diameter) can be inhaled and gain access to the circulatory system. However, mechanisms defining how DEP affects diabetic or control cardiomyocyte function remain poorly understood. The purpose of the present study was to evaluate cardiomyocyte function and reactive oxygen species (ROS) generation in isolated rat ventricular myocytes exposed overnight to fine DEP (0.1 µg/ml), and/or high glucose (HG, 25.5 mM). Our hypothesis was that DEP exposure exacerbates contractile dysfunction via ROS generation in cardiomyocytes exposed to HG. Ventricular myocytes were isolated from male adult Sprague-Dawley rats cultured overnight and sarcomeric contractile properties were evaluated, including: peak shortening normalized to baseline (PS), time-to-90% shortening (TPS90), time-to-90% relengthening (TR90) and maximal velocities of shortening/relengthening (±dL/dt), using an IonOptix field-stimulator system. ROS generation was determined using hydroethidine/ethidium confocal microscopy. We found that DEP exposure significantly increased TR90, decreased PS and ±dL/dt, and enhanced intracellular ROS generation in myocytes exposed to HG. Further studies indicated that co-culture with antioxidants (0.25 mM Tiron and 0.5 mM N-Acetyl-L-cysteine) completely restored contractile function in DEP, HG and HG+DEP-treated myocytes. ROS generation was blocked in HG-treated cells with mitochondrial inhibition, while ROS generation was blocked in DEP-treated cells with NADPH oxidase inhibition. Our results suggest that DEP exacerbates myocardial dysfunction in isolated cardiomyocytes exposed to HG-containing media, which is potentially mediated by various ROS generation pathways

A Two-Stage Random Forest-Based Pathway Analysis Method

Pathway analysis provides a powerful approach for identifying the joint effect of genes grouped into biologically-based pathways on disease. Pathway analysis is also an attractive approach for a secondary analysis of genome-wide association study (GWAS) data that may still yield new results from these valuable datasets. Most of the current pathway analysis methods focused on testing the cumulative main effects of genes in a pathway. However, for complex diseases, gene-gene interactions are expected to play a critical role in disease etiology. We extended a random forest-based method for pathway analysis by incorporating a two-stage design. We used simulations to verify that the proposed method has the correct type I error rates. We also used simulations to show that the method is more powerful than the original random forest-based pathway approach and the set-based test implemented in PLINK in the presence of gene-gene interactions. Finally, we applied the method to a breast cancer GWAS dataset and a lung cancer GWAS dataset and interesting pathways were identified that have implications for breast and lung cancers

Graph Theoretical Analysis of Functional Brain Networks: Test-Retest Evaluation on Short- and Long-Term Resting-State Functional MRI Data

Graph-based computational network analysis has proven a powerful tool to quantitatively characterize functional architectures of the brain. However, the test-retest (TRT) reliability of graph metrics of functional networks has not been systematically examined. Here, we investigated TRT reliability of topological metrics of functional brain networks derived from resting-state functional magnetic resonance imaging data. Specifically, we evaluated both short-term (<1 hour apart) and long-term (>5 months apart) TRT reliability for 12 global and 6 local nodal network metrics. We found that reliability of global network metrics was overall low, threshold-sensitive and dependent on several factors of scanning time interval (TI, long-term>short-term), network membership (NM, networks excluding negative correlations>networks including negative correlations) and network type (NT, binarized networks>weighted networks). The dependence was modulated by another factor of node definition (ND) strategy. The local nodal reliability exhibited large variability across nodal metrics and a spatially heterogeneous distribution. Nodal degree was the most reliable metric and varied the least across the factors above. Hub regions in association and limbic/paralimbic cortices showed moderate TRT reliability. Importantly, nodal reliability was robust to above-mentioned four factors. Simulation analysis revealed that global network metrics were extremely sensitive (but varying degrees) to noise in functional connectivity and weighted networks generated numerically more reliable results in compared with binarized networks. For nodal network metrics, they showed high resistance to noise in functional connectivity and no NT related differences were found in the resistance. These findings provide important implications on how to choose reliable analytical schemes and network metrics of interest

Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome

Glucocorticoids are the primary therapy for nephrotic syndrome (NS), but have serious side effects and are ineffective in ~20-50% of patients. Thiazolidinediones have recently been suggested to be renoprotective, and to modulate podocyte glucocorticoid-mediated nuclear receptor signaling. We hypothesized that thiazolidinediones could enhance glucocorticoid efficacy in NS. We found that puromycin aminonucleoside-induced proteinuria in rats was significantly reduced by both high-dose glucocorticoids (79%) and pioglitazone (61%), but not low-dose glucocorticoids (25%). Remarkably, pioglitazone + low-dose glucocorticoids also reduced proteinuria (63%) comparably to high-dose glucocorticoids, whereas pioglitazone + high-dose glucocorticoids reduced proteinuria to almost control levels (97%). Molecular analysis revealed that both glucocorticoids and pioglitazone enhanced glomerular synaptopodin and nephrin expression, and reduced COX-2 expression, after injury. Furthermore, the glomerular phosphorylation of glucocorticoid receptor and Akt, but not PPARγ, correlated with treatment-induced reductions in proteinuria. Notably, clinical translation of these findings to a child with refractory NS by the addition of pioglitazone to the treatment correlated with marked reductions in both proteinuria (80%) and overall immunosuppression (64%). These findings together suggest that repurposing pioglitazone could potentially enhance the proteinuria-reducing effects of glucocorticoids during NS treatment

Highly Variable Chloroplast Markers for Evaluating Plant Phylogeny at Low Taxonomic Levels and for DNA Barcoding

BACKGROUND: At present, plant molecular systematics and DNA barcoding techniques rely heavily on the use of chloroplast gene sequences. Because of the relatively low evolutionary rates of chloroplast genes, there are very few choices suitable for molecular studies on angiosperms at low taxonomic levels, and for DNA barcoding of species. METHODOLOGY/PRINCIPAL FINDINGS: We scanned the entire chloroplast genomes of 12 genera to search for highly variable regions. The sequence data of 9 genera were from GenBank and 3 genera were of our own. We identified nearly 5% of the most variable loci from all variable loci in the chloroplast genomes of each genus, and then selected 23 loci that were present in at least three genera. The 23 loci included 4 coding regions, 2 introns, and 17 intergenic spacers. Of the 23 loci, the most variable (in order from highest variability to lowest) were intergenic regions ycf1-a, trnK, rpl32-trnL, and trnH-psbA, followed by trnS(UGA)-trnG(UCC), petA-psbJ, rps16-trnQ, ndhC-trnV, ycf1-b, ndhF, rpoB-trnC, psbE-petL, and rbcL-accD. Three loci, trnS(UGA)-trnG(UCC), trnT-psbD, and trnW-psaJ, showed very high nucleotide diversity per site (π values) across three genera. Other loci may have strong potential for resolving phylogenetic and species identification problems at the species level. The loci accD-psaI, rbcL-accD, rpl32-trnL, rps16-trnQ, and ycf1 are absent from some genera. To amplify and sequence the highly variable loci identified in this study, we designed primers from their conserved flanking regions. We tested the applicability of the primers to amplify target sequences in eight species representing basal angiosperms, monocots, eudicots, rosids, and asterids, and confirmed that the primers amplified the desired sequences of these species. SIGNIFICANCE/CONCLUSIONS: Chloroplast genome sequences contain regions that are highly variable. Such regions are the first consideration when screening the suitable loci to resolve closely related species or genera in phylogenetic analyses, and for DNA barcoding

Task-Related Effects on the Temporal and Spatial Dynamics of Resting-State Functional Connectivity in the Default Network

Recent evidence points to two potentially fundamental aspects of the default network (DN), which have been relatively understudied. One is the temporal nature of the functional interactions among nodes of the network in the resting-state, usually assumed to be static. The second is possible influences of previous brain states on the spatial patterns (i.e., the brain regions involved) of functional connectivity (FC) in the DN at rest. The goal of the current study was to investigate modulations in both the spatial and temporal domains. We compared the resting-state FC of the DN in two runs that were separated by a 45 minute interval containing cognitive task execution. We used partial least squares (PLS), which allowed us to identify FC spatiotemporal patterns in the two runs and to determine differences between them. Our results revealed two primary modes of FC, assessed using a posterior cingulate seed – a robust correlation among DN regions that is stable both spatially and temporally, and a second pattern that is reduced in spatial extent and more variable temporally after cognitive tasks, showing switching between connectivity with certain DN regions and connectivity with other areas, including some task-related regions. Therefore, the DN seems to exhibit two simultaneous FC dynamics at rest. The first is spatially invariant and insensitive to previous brain states, suggesting that the DN maintains some temporally stable functional connections. The second dynamic is more variable and is seen more strongly when the resting-state follows a period of task execution, suggesting an after-effect of the cognitive activity engaged during task that carries over into resting-state periods

Risk factors for overweight and obesity, and changes in body mass index of Chinese adults in Shanghai

<p>Abstract</p> <p>Background</p> <p>Over the past two decades, the prevalence of overweight or obesity has increased in China. The aims of this study were to firstly assess the baseline prevelences and the risk factors for overweight and obesity, and secondly to detect the changes of body mass index (BMI) over a follow-up period in Chinese adults in Shanghai.</p> <p>Methods</p> <p>The data set of a population-based longitudinal study was analyzed. Anthropometric and biochemical data were collected for 5364 subjects (aged 25–95 years) during a period of 1998–2001. Among those individuals, 3032 subjects were interviewed and reexamined at the second survey from 2003 to 2004. Then the standardized prevalences for overweight and obesity were calculated using baseline data; the possible contributing factors of overweight and obesity were detected using binary logistic regression analysis; and the changes of BMI were evaluated after an average of 3.6-year follow-up period.</p> <p>Results</p> <p>(1) According to the WHO standard and the Chinese standard, the sex- and age-standardized prevalences were 27.5% and 32.4% for overweight, and 3.7% and 9.1% for obesity, respectively. (2) The risks of overweight and obesity differed among different age groups. Family history of obesity increased the risk of overweight and obesity by about 1.2-fold for both genders. Current male smokers had a lower risk of overweight and obesity (OR = 0.76, <it>p </it>< 0.05) than nonsmokers. In contrast, current male drinkers had a higher risk of overweight and obesity (OR = 1.42, <it>p </it>< 0.05) than nondrinkers. Compared with low-educated women, medium- and high- educated women were at lower risk of overweight and obesity, and the corresponding ORs (95% CIs) were 0.64 (0.52–0.79) and 0.50(0.36–0.68), respectively. (3) The annual changes of BMI means ranged from an increase of 0.1 kg/m²to a decrease of 0.2 kg/m²(by genders and age groups). Meanwhile, the BMI increase was statistically significant in the 35–44 years age group, and the BMI decrease was significant above 65 years for both genders.</p> <p>Conclusion</p> <p>This study showed high prevalence of overweight and obesity in Shanghai metropolis populations. The risk factors of overweight and obesity were multifactorial and gender specific. After 3.6 years, BMI means changed slightly, BMI increased mainly in middle-aged individuals and decreased in old individuals.</p

Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay

The decay channel $\psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p})$ is studied using a sample of $1.06\times 10^8$ $\psi^\prime$ events collected by the BESIII experiment at BEPCII. A strong enhancement at threshold is observed in the $p\bar{p}$ invariant mass spectrum. The enhancement can be fit with an $S$-wave Breit-Wigner resonance function with a resulting peak mass of $M=1861^{+6}_{-13} {\rm (stat)}^{+7}_{-26} {\rm (syst)} {\rm MeV/}c^2$ and a narrow width that is $\Gamma<38 {\rm MeV/}c^2$ at the 90% confidence level. These results are consistent with published BESII results. These mass and width values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics

A Novel Approach to Molecular Recognition Surface of Magnetic Nanoparticles Based on Host–Guest Effect

A novel route has been developed to prepared β-cyclodextrin (β-CD) functionalized magnetic nanoparticles (MNPs). The MNPs were first modified with monotosyl-poly(ethylene glycol) (PEG) silane and then tosyl units were displaced by amino-β-CD through the nucleophilic substitution reaction. The monotosyl-PEG silane was synthesized by modifying a PEG diol to form the corresponding monotosyl-PEG, followed by a reaction with 3-isocyanatopropyltriethoxysilane (IPTS). The success of the synthesis of the monotosyl-PEG silane was confirmed with1H NMR and Fourier transform infrared (FTIR) spectroscopy. The analysis of FTIR spectroscopy and X-ray photoelectron spectroscopy (XPS) confirmed the immobilization of β-CD onto MNPs. Transmission electron microscopy (TEM) indicated that the β-CD functionalized MNPs were mostly present as individual nonclustered units in water. The number of β-CD molecules immobilized on each MNP was about 240 according to the thermogravimetric analysis (TGA) results. The as-prepared β-CD functionalized MNPs were used to detect dopamine with the assistance of a magnet

Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models

Mineralized collagen fibrils have been usually analyzed like a two phase composite material where crystals are considered as platelets that constitute the reinforcement phase. Different models have been used to describe the elastic behavior of the material. In this work, it is shown that, when Halpin-Tsai equations are applied to estimate elastic constants from typical constituent properties, not all crystal dimensions yield a model that satisfy thermodynamic restrictions. We provide the ranges of platelet dimensions that lead to positive definite stiffness matrices. On the other hand, a finite element model of a mineralized collagen fibril unit cell under periodic boundary conditions is analyzed. By applying six canonical load cases, homogenized stiffness matrices are numerically calculated. Results show a monoclinic behavior of the mineralized collagen fibril. In addition, a 5-layer lamellar structure is also considered where crystals rotate in adjacent layers of a lamella. The stiffness matrix of each layer is calculated applying Lekhnitskii transformations and a new finite lement model under periodic boundary conditions is analyzed to calculate the homogenized 3D anisotropic stiffness matrix of a unit cell of lamellar bone. Results are compared with the rule-of-mixtures showing in general good agreement.The authors acknowledge the Ministerio de Economia y Competitividad the financial support given through the project DPI2010-20990 and the Generalitat Valenciana through the Programme Prometeo 2012/023. The authors thank Ms. Carla Gonzalez Carrillo by her help in the development of some of the numerical models.Vercher Martínez, A.; Giner Maravilla, E.; Arango Villegas, C.; Tarancón Caro, JE.; Fuenmayor Fernández, FJ. (2014). Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models. Biomechanics and Modeling in Mechanobiology. 13(2):1-21. https://doi.org/10.1007/s10237-013-0507-yS121132Akiva U, Wagner HD, Weiner S (1998) Modelling the three-dimensional elastic constants of parallel-fibred and lamellar bone. J Mater Sci 33:1497–1509Ascenzi A, Bonucci E (1967) The tensile properties of single osteons. Anat Rec 158:375–386Ascenzi A, Bonucci E (1968) The compressive properties of single osteons. Anat Rec 161:377–392Ashman RB, Cowin SC, van Buskirk WC, Rice JC (1984) A continuous wave technique for the measurement of the elastic properties of cortical bone. J Biomech 17:349–361Bar-On B, Wagner HD (2012) Elastic modulus of hard tissues. J Biomech 45:672–678Bondfield W, Li CH (1967) Anisotropy of nonelastic flow in bone. J Appl Phys 38:2450–2455Cowin SC (2001) Bone mechanics handbook, 2nd edn. CRC Press Boca Raton, FloridaCowin SC, van Buskirk WC (1986) Thermodynamic restrictions on the elastic constant of bone. J Biomech 19:85–86Currey JD (1962) Strength of bone. Nature 195:513Cusack S, Miller A (1979) Determination of the elastic constants of collagen by brillouin light scattering. J Mol Biol 135:39–51Doty S, Robinson RA, Schofield B (1976) Morphology of bone and histochemical staining characteristics of bone cells. In: Aurbach GD (ed) Handbook of physiology. American Physiology Soc, Washington, pp 3–23Erts D, Gathercole LJ, Atkins EDT (1994) Scanning probe microscopy of crystallites in calcified collagen. J Mater Sci Mater Med 5:200–206Faingold A, Sidney RC, Wagner HD (2012) Nanoindentation of osteonal bone lamellae. J Mech Biomech Materials 9:198–206Franzoso G, Zysset PK (2009) Elastic anisotropy of human cortical bone secondary osteons measured by nanoindentation. J Biomech Eng 131:021001Gebhardt W (1906) Über funktionell wichtige Anordnungsweisen der eineren und grösseren Bauelemente des Wirbeltierknochens. II. Spezieller Teil. Der Bau der Haversschen Lamellensysteme und seine funktionelle Bedeutung. Arch Entwickl Mech Org 20:187–322Gibson RF (1994) Principles of composite material mechanics. McGraw-Hill, New YorkGiraud-Guille M (1988) Twisted plywood architecture of collagen fibrils in human compact bone osteons. Calcif Tissue Int 42:167–180Gurtin ME (1972) The linear theory of elasticity. Handbuch der Physik VIa/ 2:1–296Halpin JC (1992) Primer on composite materials: analysis, 2nd edn. CRC Press, Taylor & Francis, Boca Raton, FloridaHassenkam T, Fantner GE, Cutroni JA, Weaver JC, Morse DE, Hanma PK (2004) High-resolution AFM imaging of intact and fractured trabecular bone. Bone 35:4–10Hohe J (2003) A direct homogenization approach for determination of the stiffness matrix for microheterogeneous plates with application to sandwich panels. Composites Part B 34:615–626Hulmes DJS, Wess TJ, Prockop DJ, Fratzl P (1995) Radial packing, order, and disorder in collagen fibrils. Biophys J 68:1661–1670Jäger I, Fratzl P (2000) Mineralized collagen fibrils: a mechanical model with a staggered arrangement of mineral particles. Biophys J 79:1737–1746Ji B, Gao H (2004) Mechanical properties of nanostructure of biological materials. J Mech Phy Sol 52:1963–1990Landis WJ, Hodgens KJ, Aerna J, Song MJ, McEwen BF (1996) Structural relations between collagen and mineral in bone as determined by high voltage electron microscopic tomography. Microsc Res Tech 33:192–202Lekhnitskii SG (1963) Theory of elasticity of an anisotropic elastic body. Holden-Day, San FranciscoLempriere BM (1968) Poisson’s ratio in orthotropic materials. Am Inst Aeronaut Astronaut J J6:2226–2227Lowenstam HA, Weiner S (1989) On biomineralization. Oxford University, New YorkLusis J, Woodhams RT, Xhantos M (1973) The effect of flake aspect ratio on flexural properties of mica reinforced plastics. Polym Eng Sci 13:139–145Martínez-Reina J, Domínguez J, García-Aznar JM (2011) Effect of porosity and mineral content on the elastic constants of cortical bone: a multiscale approach. Biomech Model Mechanobiol 10:309–322Orgel JPRO, Miller A, Irving TC, Fischetti RF, Hammersley AP, Wess TJ (2001) The in situ supermolecular structure of type I collagen. Structure 9:1061–1069Padawer GE, Beecher N (1970) On the strength and stiffness of planar reinforced plastic resins. Polym Eng Sci 10:185–192Pahr DH, Rammerstofer FG (2006) Buckling of honeycomb sandwiches: periodic finite element considerations. Comput Model Eng Sci 12:229–242Reisinger AG, Pahr DH, Zysset PK (2010) Sensitivity analysis and parametric study of elastic properties of an unidirectional mineralized bone fibril-array using mean field methods. Biomech Model Mechanobiol 9:499–510Reisinger AG, Pahr DH, Zysset PK (2011) Elastic anisotropy of bone lamellae as a function of fibril orientation pattern. Biomech Model Mechanobiol 10:67–77Rezkinov N, Almany-Magal R, Shahar R, Weiner S (2013) Three-dimensional imaging of collagen fibril organization in rat circumferential lamellar bone using a dual beam electron microscope reveals ordered and disordered sub-lamellar structures. Bone 52(2):676–683Rho JY, Kuhn-Spearing L, Zioupos P (1998) Mechanical properties and the hierarchical structure of bone. Med Eng Phys 20:92–102Rubin MA, Jasiuk I, Taylor J, Rubin J, Ganey T, Apkarian RP (2003) TEM analysis of the nanostructure of normal and osteoporotic human trabecular bone. Bone 33:270–282Suquet P (1987) Lecture notes in physics-homogenization techniques for composite media. Chapter IV. Springer, BerlinWagermaier W, Gupta HS, Gourrier A, Burghammer M, Roschger P, Fratzl P (2006) Spiral twisting of fiber orientation inside bone lamellae. Biointerphases 1:1–5Wagner HD, Weiner S (1992) On the relationship between the microstructure of bone and its mechanical stiffness. J Biomech 25:1311–1320Weiner S, Wagner HD (1998) The material bone: structure-mechanical function relations. Annu Rev Mater Sci 28:271–298Weiner S, Traub W, Wagner H (1999) Lamellar bone: structure-function relations. J Struct Biol 126:241–255Yao H, Ouyang L, Ching W (2007) Ab initio calculation of elastic constants of ceramic crystals. J Am Ceram 90:3194–3204Yoon YJ, Cowin SC (2008b) The estimated elastic constants for a single bone osteonal lamella. Biomech Model Mechanobiol 7:1–11Yuan F, Stock SR, Haeffner DR, Almer JD, Dunand DC, Brinson LC (2011) A new model to simulate the elastic properties of mineralized collagen fibril. Biomech Model Mechanobiol 10:147–160Zhang Z, Zhang YWF, Gao H (2010) On optimal hierarchy of load-bearing biological materials. Proc R Soc B 278:519–525Zuo S, Wei Y (2007) Effective elastic modulus of bone-like hierarchical materials. Acta Mechanica Solida Sinica 20:198–20