High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different ...studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L - lard; HF-O - olive oil; HF-C - coconut fat; HF-F - fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma omega-3 polyunsaturated fatty acid (omega-3-PUFA) and saturated fatty acid (C(12)-C(14), SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPARalpha-dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA- or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.
The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double‐blind, randomized, placebo‐controlled, two‐way crossover study, 161 primary insomnia patients received either ...the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1‐week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose‐dependent almorexant effects were observed on SE, LPS, and WASO. SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (–18 min (P = 0.02)) and WASO (–54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse‐event incidence was dose‐related. Almorexant consistently and dose‐dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.
Clinical Pharmacology & Therapeutics (2012); 91 6, 975–985. doi:10.1038/clpt.2011.370
We report on the MIT Epoch of Reionization (MITEoR) experiment, a pathfinder low-frequency radio interferometer whose goal is to test technologies that improve the calibration precision and reduce ...the cost of the high-sensitivity 3D mapping required for 21 cm cosmology. MITEoR accomplishes this by using massive baseline redundancy, which enables both automated precision calibration and correlator cost reduction. We demonstrate and quantify the power and robustness of redundancy for scalability and precision. We find that the calibration parameters precisely describe the effect of the instrument upon our measurements, allowing us to form a model that is consistent with X2 per degree of freedom <1.2 for as much as 80 per cent of the observations. We use these results to develop an optimal estimator of calibration parameters using Wiener filtering, and explore the question of how often and how finely in frequency visibilities must be reliably measured to solve for calibration coefficients. The success of MITEoR with its 64 dual-polarization elements bodes well for the more ambitious Hydrogen Epoch of Reionization Array project and other next-generation instruments, which would incorporate many identical or similar technologies.
Studies of genetic diversity in natural populations are important for the definition of conservation strategies, especially in populations reduced by processes of fragmentation and continuous forest ...extraction. Molecular markers stand out as interesting tools for these studies. The objective of this research was to characterize the diversity and genetic structure of Plathymenia reticulata (Fabaceae), occurring in two fragments of the Montana Semideciduous Forest in the southern of Espírito Santo State, Brazil, using inter-simple sequence repeat (ISSR) molecular markers. DNA samples from 149 individuals were analyzed using 10 ISSR primers, generating 156 fragments, of which 101 were polymorphic (64.74%). The individuals sampled were classified into three units: adult trees (A), a mixture of progenies (B), and young regenerating individuals (C). The number of loci used (N = 101) was greater than that established as optimal number (N = 88), indicating precision in analyses. The genetic diversity index of Nei (H' = 0.407) and the Shannon index (I = 0.594) were found to have high genetic diversity. Besides, through the diversity parameters evaluated, it was possible to confirm that in the areas of natural regeneration and progeny mix there is genetic diversity equivalent to that found in adults. The analysis of molecular variance indicated that most of the genetic variation is found within the groups (96.53%). Genetic differentiation among adult trees was low (Φ
= 0.03) indicating that high gene flow rates (N
= 12.70) are counteracting the effects of genetic drift. The data obtained allowed to evaluate the potential of adult trees as matrices for seed collection and to obtain seedlings with confirmed genetic variability.
Assessment of contaminant impacts to federally identified endangered, threatened and candidate, and state-identified endangered species (collectively referred to as "listed" species) requires ...understanding of a species' sensitivities to particular chemicals. The most direct approach would be to determine the sensitivity of a listed species to a particular contaminant or perturbation. An indirect approach for aquatic species would be application of toxicity data obtained from standard test procedures and species commonly used in laboratory toxicity tests. Common test species (fathead minnow, Pimephales promelas; sheepshead minnow, Cyprinodon variegatus; and rainbow trout, Oncorhynchus mykiss) and 17 listed or closely related species were tested in acute 96-hour water exposures with five chemicals (carbaryl, copper, 4-nonylphenol, pentachlorophenol, and permethrin) representing a broad range of toxic modes of action. No single species was the most sensitive to all chemicals. For the three standard test species evaluated, the rainbow trout was more sensitive than either the fathead minnow or sheepshead minnow and was equal to or more sensitive than listed and related species 81% of the time. To estimate an LC50 for a listed species, a factor of 0.63 can be applied to the geometric mean LC50 of rainbow trout toxicity data, and more conservative factors can be determined using variance estimates (0.46 based on 1 SD of the mean and 0.33 based on 2 SD of the mean). Additionally, a low- or no-acute effect concentration can be estimated by multiplying the respective LC50 by a factor of approximately 0.56, which supports the United States Environmental Protection Agency approach of multiplying the final acute value by 0.5 (division by 2). When captive or locally abundant populations of listed fish are available, consideration should be given to direct testing. When direct toxicity testing cannot be performed, approaches for developing protective measures using common test species toxicity data are available.
A sprained ankle is a common musculoskeletal sports injury and it is often treated by immobilization of the joint. Despite the beneficial effects of this therapeutic measure, the high prevalence of ...residual symptoms affects the quality of life, and remobilization of the joint can reverse this situation. The aim of this study was to analyze the effects of immobilization and remobilization on the ankle joint of Wistar rats. Eighteen male rats had their right hindlimb immobilized for 15 days, and were divided into the following groups: G1, immobilized; G2, remobilized freely for 14 days; and G3, remobilized by swimming and jumping in water for 14 days, performed on alternate days, with progression of time and a series of exercises. The contralateral limb was the control. After the experimental period, the ankle joints were processed for microscopic analysis. Histomorphometry did not show any significant differences between the control and immobilized/remobilized groups and members, in terms of number of chondrocytes and thickness of the articular cartilage of the tibia and talus. Morphological analysis of animals from G1 showed significant degenerative lesions in the talus, such as exposure of the subchondral bone, flocculation, and cracks between the anterior and mid-regions of the articular cartilage and the synovial membrane. Remobilization by therapeutic exercise in water led to recovery in the articular cartilage and synovial membrane of the ankle joint when compared with free remobilization, and it was shown to be an effective therapeutic measure in the recovery of the ankle joint.
As the human population continues to expand, increased encroachment on natural landscapes and wildlife habitats is expected. Organisms able to acclimate to human-altered environments should have a ...selective advantage over those unable to do so. Over the past two decades, bats have increasingly begun to roost and raise offspring in spaces beneath pre-cast concrete bridges. Few studies have examined the health or fitness of individuals living in these anthropogenic sites. In the present study, we examined birth size and postnatal growth, as surrogates of reproductive success, in Brazilian free-tailed bat pups born at a natural and a human-made roost. Based on putative stress-related conditions (noise from vehicular traffic, chemical pollutants and a modified social environment) present at bridges, we predicted that bats at these sites would have reduced reproductive success. Contrary to our prediction, pups born at a bridge site were on average heavier and larger at birth and grew faster than those born at a cave site. Also, both birth size and growth rates of pups differ between years. We attribute observed differences to a combination of roost-related conditions (i.e. roost temperature and proximity to foraging areas), climate and maternal effects with larger mothers raising larger pups. Thus, some bridge roosts, at least in the short term, are suitable, and in some cases may provide better conditions, for raising young bat pups than cave roosts.
Objective
This study evaluated the association of four histopathological grading systems (WHO grading system, malignancy grading of the deep invasive margins (MG), histological risk (HR) model, and ...tumor budding and depth of invasion (BD) model) with clinicopathological parameters and outcome of 113 oral squamous cell carcinomas to identify their roles in prognosis.
Methods
Demographic and clinical features were obtained from patients' records. Sections from all paraffin‐embedded blocks were evaluated according to the four grading systems. Demographic and clinical associations were analyzed using chi‐square test, and correlations between the grading systems were established with the Spearman's rank correlation test. Survival curves were performed with Kaplan–Meier method, and multivariate analysis based on Cox proportional hazard model was calculated.
Results
Significant associations with survival were observed for WHO grading system and BD model in the univariate analysis, but only the BD model was significantly associated with disease outcome as an independent prognostic marker. Age, tumor size, and presence of regional metastasis were also independent markers of reduced survival.
Conclusion
A significant association between the BD model and outcome of OSCC patients was observed, indicating this new histopathological grading system as a possible prognostic tool.
A time-marching computational fluid dynamics method is developed and applied to the computation of multiphase mixture flows. The model accounts for finite acoustic speeds in the constituent phases, ...which typically lead to transonic/supersonic flow and associated compressibility phenomena such as shock formation in the mixture region. Preconditioning or artificial compressibility methods are devised using perturbation theory to insure that the method retains efficiency and accuracy in both the incompressible and compressible flow regimes. The resulting algorithm is incorporated within an existing multiphase code, and several representative applications are used to demonstrate the capabilities of the method. In particular, our results suggest that the present compressible formulation provides an improved description of cavitation dynamics compared with previous incompressible computations.
HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ...ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
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