Many tasks require humans to manipulate dynamically complex objects and maintain appropriate safety margins, such as placing a cup of coffee on a coaster without spilling. This study examined how humans learn such safety margins, and how they are shaped by task constraints and changing variability with improved skill. Eighteen subjects used a manipulandum to transport a shallow virtual cup containing a ball to a target without losing the ball. Half were to complete the cup transit in a comfortable target-time of two seconds (a redundant task with infinitely many equivalent solutions); the other half in minimum-time (a non-redundant task with one explicit cost to optimize). The safety margin was defined as the ball energy relative to escape, i.e. as an energy margin. The first hypothesis - subjects converge to a single strategy in the minimum-time task, but choose different strategies in the less-constrained target-time task - was not supported. Both groups developed individualized strategies with practice. The second hypothesis - subjects decrease safety margins in the minimum-time task but increase them in the target-time task - was supported. The third hypothesis - in both tasks subjects modulate energy margins according to their execution variability - was partially supported. In the target-time group changes in energy margins correlated positively with changes in execution variability; in the minimum-time group such a relation was observed only at the end of practice, not across practice. These results show that when learning a redundant object manipulation task, most subjects increase their safety margins and shape their movement strategies in accordance with their changing variability.

A novel Mn-promoted aerobic oxidative C-C bond cleavage of aldehydes with dioxygen activation has been developed. The usage of molecular oxygen (1 atm) as oxidant, reactant, and an initiator to trigger this transformation makes this transformation very green and practical. A plausible radical process is proposed on the basis of mechanistic studies. Furthermore, this method provides a practical, neutral, and mild synthetic approach to formamides, which are important units in biologically active molecules.

Particle Replication in Non-Wetting Templates (PRINT(®)) is a platform particle drug delivery technology that coopts the precision and nanoscale spatial resolution inherently afforded by lithographic techniques derived from the microelectronics industry to produce precisely engineered particles. We describe the utility of PRINT technology as a strategy for formulation and delivery of small molecule and biologic therapeutics, highlighting previous studies where particle size, shape, and chemistry have been used to enhance systemic particle distribution properties. In addition, we introduce the application of PRINT technology towards respiratory drug delivery, a particular interest due to the pharmaceutical need for increased control over dry powder characteristics to improve drug delivery and therapeutic indices. To this end, we have produced dry powder particles with micro- and nanoscale geometric features and composed of small molecule and protein therapeutics. Aerosols generated from these particles show attractive properties for efficient pulmonary delivery and differential respiratory deposition characteristics based on particle geometry. This work highlights the advantages of adopting proven microfabrication techniques in achieving unprecedented control over particle geometric design for drug delivery.

ABSTRACT: BACKGROUND: N-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA; 22:6n-3), has clinical significance in the prevention and reversal of nonalcoholic steatohepatitis (NASH). However, the precious mechanism underlying remains unclear. The inflammasome, a multiprotein complex formed by NOD-like receptor (NLR) family members, has been recently shown to be activated in NASH and promote the cleavage of the pro-inflammatory cytokines to their maturation forms. METHODS: HepG2 cells were exposed to different dose of PA for 24 h with or without the preincubation of 50 muM DHA for another 24 h and then lipid deposition was assessed with Oil red O staining and intracellular triglyceride (TG) determination. Secretory levels of inflammatory cytokines and Caspase-1 activity were determined by ELISA assays. Gene expression and protein levels were determined by quantitative RCR and western blotting, respectively. RESULTS: Palmitate (PA) dose-dependently increased lipid accumulation, TG content and induced the secretion of interleukin-1beta (IL-1beta), IL-18, TNF-alpha and MCP-1 from HepG2 cells. Preincubation with DHA significantly alleviated PA-induced lipid accumulation and inflammatory agents. DHA was also found to attenuate PA-induced NOD-like receptor protein 4 (NLRC4) mRNA expression. Furthermore, PA induced caspase-1 activation in a dose-dependent manner, resulting in exacerbating of procaspase-1 and pro-IL-1beta processing. Knockdown of NLRC4 partially abrogated PA-induced caspase-1 activation and IL-1beta maturation and completely abolished these events in the presence of DHA. CONCLUSIONS: Our findings indicate DHA attenuates PA-induced lipid accumulation and inflammation through suppressing NLRC4 inflammasome activation, caspase-1 activation and IL-1beta cleavage.

The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) regulates expression of genes for metabolism and muscle fiber type. Recently, a novel splice variant of PGC-1α (NT-PGC-1α, amino acids 1-270) was cloned and found to be expressed in muscle. Here we use Flag-tagged NT-PGC-1α to examine the subcellular localization and regulation of NT-PGC-1α in skeletal muscle fibers. Flag-NT-PGC-1α is located predominantly in the myoplasm. Nuclear NT-PGC-1α can be increased by activation of protein kinase A. Activation of p38 MAPK by muscle activity or of AMPK had no effect on the subcellular distribution of NT-PGC-1α. Inhibition of CRM1-mediated export only caused relatively slow nuclear accumulation of NT-PGC-1α, indicating that nuclear export of NT-PGC-1α may be mediated by both CRM1-dependent and -independent pathways. Together these results suggest that the regulation of NT-PGC-1α in muscle fibers may be very different from that of the full-length PGC-1α, which is exclusively nuclear.

Mammalian target of rapamycin (mTOR) controls lymphangiogenesis. However, the underlying mechanism is not clear. Here we show that rapamycin suppressed insulin-like growth factor 1 (IGF-1)- or fetal bovine serum (FBS)-stimulated lymphatic endothelial cell (LEC) tube formation, an in vitro model of lymphangiogenesis. Expression of a rapamycin-resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of LEC tube formation, suggesting that rapamycin inhibition of LEC tube formation is mTOR kinase activity dependent. Also, rapamycin inhibited proliferation and motility in the LECs. Furthermore, we found that rapamycin inhibited protein expression of VEGF receptor 3 (VEGFR-3) by inhibiting protein synthesis and promoting protein degradation of VEGFR-3 in the cells. Down-regulation of VEGFR-3 mimicked the effect of rapamycin, inhibiting IGF-1- or FBS-stimulated tube formation, whereas over-expression of VEGFR-3 conferred high resistance to rapamycin inhibition of LEC tube formation. The results indicate that rapamycin inhibits LEC tube formation at least in part by downregulating VEGFR-3 protein expression.

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, the underlying mechanism is not well understood. Here we show that CPT induced caspase-independent cell death in human tumor cells (Rh30, DU145, and MCF-7). Besides downregulating anti-apoptotic protein expression of survivin and Mcl-1, CPT increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), and inhibited phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Inhibition of p38 with SB202190 or JNK with SP600125 attenuated CPT-induced cell death. Similarly, silencing p38 or c-Jun also in part prevented CPT-induced cell death. In contrast, expression of constitutively active MKK1 conferred resistance to CPT inhibition of Erk1/2 phosphorylation and induction of cell death. Furthermore, we found that all of these were attributed to CPT induction of reactive oxygen species (ROS). This is evidenced by the findings that CPT induced ROS in a concentration- and time-dependent manner; CPT induction of ROS was inhibited by N-acetyl-L-cysteine (NAC), a ROS scavenger; and NAC attenuated CPT activation of p38/JNK, inhibition of Erk1/2, and induction of cell death. The results suggested that CPT induction of ROS activates p38/JNK and inhibits Erk1/2, leading to caspase-independent cell death in tumor cells.

Abstract Deng, Bingjun, Tingguang Luo, Yanfei Huang, Tianhang Shen, Jing Ma. Prevalence and determinants of hyperlipidemia in moderate altitude areas of the Yunnan-Kweichow Plateau in Southwestern China. High Alt. Med. Biol. 13:13-21.-The objective of the current study was to determine the prevalence and determinants of hyperlipidemia among the populations living at moderate altitude on the Yunnan-Kweichow Plateau in Southwestern China. We randomly recruited 1415 people for this study. These subjects underwent a physical examination and a comprehensive questionnaire regarding their daily habits and diets. Furthermore, blood samples from the participants were collected for assessing the lipid profile. We found that 49.3% of participants (95% CI: 46.7-51.9%) suffered from hyperlipidemia. The prevalence in men was significantly higher than that in women (53.6% vs. 44.7%, p<0.01). The prevalence of hypercholesterolemia was 23.3% and of hypertriglyceridemia was 34.1%. Low HDL-C showed a prevalence of 17.5% and high LDL-C of 9.0%. The prevalence of hyperlipidemia also increased with age, as did the prevalence of high TC, TG, and LDL-C. Hyperlipidemic subjects tended to be older and have a higher BMI and WHR than the normolipidemic subjects in the study cohort (p<0.05). The hyperlipidemic subjects, both men and women, tended to dine out often and consume more animal-based foods and alcohol. In addition, the hyperlipidemic men in our cohort consumed more salted food then their normolipidemic counterparts (p<0.01). Normolipidemic subjects of both sexes were also found to prefer a vegetarian diet (p<0.01). Age, alcohol consumption, a preference for meat and animal products, regular dining out, and BMI were found to be the main determinants of hyperlipidemia in women, whereas a prevalence of salted food was observed to be related to hyperlipidemia in men from the Yunnan-Kweichow Plateau subpopulation under study (p<0.05). The average daily energy, and protein and fat intakes of the sampled subjects were also higher than the levels set by the Chinese Recommendation Nutrient Intakes (RNI), while hyperlipidemic subjects had an even higher average daily intake of total fat, cholesterol, and lower dietary fiber compared with the normolipidemic subjects in the study group (p<0.05). In conclusion, this study reveals a higher prevalence of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, increased BMI and WHR values in men, as well as a slightly higher prevalence of low HDL-C and high LDL-C in women from Yunnan-Kweichow Plateau. The incidence of hyperlipidemia also increased with age, as did the prevalence of an abnormal TC, TG, LDL-C, and WHR in our study cohort. A high BMI, and less healthy living habits and dietary preferences thus play significant roles in the onset of hyperlipidemia.

Typical quasistatic compression algorithms for generating jammed packings of purely repulsive, frictionless particles begin with dilute configurations and then apply successive compressions with the relaxation of the elastic energy allowed between each compression step. It is well known that during isotropic compression these systems undergo a first-order-like jamming transition at packing fraction φ_{J} from an unjammed state with zero pressure and no force-bearing contacts to a jammed, rigid state with nonzero pressure, a percolating network of force-bearing contacts, and contact number z=2d, where d is the spatial dimension. Using computer simulations of two-dimensional systems with monodisperse and bidisperse particle size distributions, we investigate the second-order-like contact percolation transition, which precedes the jamming transition with φ_{P}<φ_{J} and signals the formation of a system-spanning cluster of non-force-bearing contacts between particles. By measuring the number of nonfloppy modes of the dynamical matrix, the displacement field between successive compression steps, and the overlap between the adjacency matrix, which represents the network of contacting grains, at φ and φ_{J}, we find that the contact percolation transition also signals the onset of a nontrivial mechanical response to applied stress. Our results show that cooperative particle motion occurs in unjammed systems significantly below the jamming transition for φ_{P}<φ<φ_{J}, not only for jammed systems with φ>φ_{J}.

Artemisinin (QHS) is one of the first-line antimalarials, and autoinduction of CYP-mediated metabolism can result in its reduced exposure. To better understand the autoinduction of QHS, we evaluated the pharmacokinetics of QHS and its phase I metabolites in rats using an liquid chromatography-high resolution mass spectrometry (LC-HRMS) method. The LC separation was improved, allowing the separation of QHS and its metabolites from their diastereomers, and seven metabolites of QHS with relatively high exposure were identified in rat plasma, including deoxyartemisinin (DQHS), three monoyhydroxylated plus deoxyl metabolites (M1-M3) and three monohydroxylated metabolites (M4-M6). For detection, a high-resolution LTQ/Orbitrap mass spectrometer with an electrospray ionization (ESI) inlet in the positive ion mode was used. High-resolution extracted ion chromatograms for each analyte were obtained by processing the full-scan MS dataset with 10 ppm mass tolerance. The plasma samples were pretreated by protein precipitation with acetonitrile. The standard curve was linear (r(2)  > 0.99) over the QHS and DQHS concentration range of 5.0-200.0 ng/ml in 50 µl of plasma, which offered sufficient sensitivity and accuracy for the determination of QHS and its metabolites. A 3-day validation approach was used for absolute quantitation of QHS and DQHS. The other six metabolites of QHS were semiquantified based on the calibration curve of QHS. The present method was applied to the pharmacokinetic study of QHS in rats after a single oral administration. The data shown here also suggest that this type of mass analyzer will be capable of a quantitative-qualitative workflow. Copyright © 2012 John Wiley & Sons, Ltd.