Pyrrole and furan oligoglycosides from the starfish Asterina batheri and their inhibitory effect on the production of pro-inflammatory cytokines in lipopolysaccharide-stimulated bone marrow-derived dendritic cells

Three new pyrrole oligoglycosides, astebatheriosides A–C (1–3), and a new furan oligoglycoside, astebatherioside D (4), were isolated from the starfish Asterina batheri by various chromatographic methods. Their structures were elucidated by spectroscopic and chemical methods. Compounds 2, 3, and 4 moderately inhibited IL-12 p40 production in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) with IC₅₀ values of 36.4, 31.6, and 22.8 μM, respectively.     

Peptidomimetic modification improves cell permeation of bivalent farnesyltransferase inhibitors

Bivalent enzyme inhibitors, in which a surface binding module is linked to an active site binding module through a spacer, are a robust approach for site-selectively delivering a minimally-sized agent to a protein surface to regulate its functions, such as protein–protein interactions (PPIs). Previous research revealed that these agents effectively disrupt the interaction between farnesyltransferase (FTase) and the C-terminal region of K-Ras4B protein. However, the whole cell activity of these peptide-based agents is limited due to their low membrane permeability. In this study, we tested a peptidomimetic modification of these bivalent agents using a previously developed inhibitor, FTI-249, and evaluated their cell permeability and biological activity in cells. Confocal cell imaging using fluorescently-labeled agents showed that the peptidomimetic 3-BODIPY penetrated cells, while the peptide-based 1-BODIPY did not. Cell-based evaluation demonstrated that peptidomimetic 3 at a concentration of 100 μM inhibited HDJ-2 processing in cells, indicating that this peptidomimetic modification improves cell permeability, thus leading to enhanced whole cell activity of the bivalent compounds.     

Consequential LCA of switching from maize silage-based to grass-based dairy systems

Purpose

This study aimed to investigate the environmental consequences (on climate change and land use) of an increase in preference for grass-based milk in France using a consequential life cycle assessment (CLCA) approach. This increase in preference was assumed to be satisfied domestically, by converting maize silage-based dairy farms (MS farm) to grass-based dairy farms (G farm) while keeping on-farm usable agricultural area and total milk production of farm constant.

Methods

The possible consequences of an increase in preference for grass-based milk were identified based on cause and effect relationships. The conversion from MS to G farm reduced the use of soybean meal, changed the on-farm cropping pattern and produced more animals but less wheat and no rapeseed. Effects on on-farm soil C were predicted with the RothC model and on global land use change (LUC) with models of global agricultural markets (Global Trade Analysis Project (GTAP) and Landbouw Economisch Instituut Trade Analysis Project (LEITAP)). System expansion using animals from a suckler beef production system was applied to estimate the impacts of milk and animal co-products from the dairy system. Land occupation and climate change impacts were estimated. The consequences of farm conversion were attributed only to the milk, as preference for grass-based milk drove the conversion process.

Results and discussion

The conversion from the MS to G farm increases land occupation and climate change impacts for the G farm, respectively, by 9 and 7 % according to GTAP and 14 and 51 % according to LEITAP. Land occupation and climate change impacts of milk produced by the G farm after conversion increased, respectively, by 82 and 13 % with GTAP and 123 and 97 % with LEITAP relative to those for the MS farm (before conversion). The production of additional wheat and rapeseed outside the G farm increased impacts of the G farm (by 29–69 % depending on impacts and model used). Results indicate that the farm conversion would probably have consequences on global LUC and that it is important to account for this in a LCA approach.

Conclusions

Land use and land use change (LULUC) contributed to the impacts of grass-based milk, and results were highly sensitive to the LULUC model used. The many possible chain-of-event pathways that follow a change in preference for a given product yield high uncertainty in CLCA results. This study only assessed one possible way to meet the increase in preference for grass-based milk; it is necessary to perform a sensitivity analysis to investigate other possible scenarios resulting from this increase in preference.     

Why and how to objectively evaluate medical gestures?

Junior physicians mainly learn during their observation in the operative room. The senior physicians evaluate them based on the same kind of observation. Knowledge transfer evaluation is thus done without quantitative methods and it mainly lies on a subjective assessment. In this paper, we present some recent techniques used to objectively evaluate medical gestures. The classical techniques used are Hidden Markov Models (HMM) or Dynamic Time Warping (DTW). Both techniques lies on the temporal analysis of the gestures. We proposed here a technique based on the arc length parametrization in order to analyze the gestures in space which is more appropriate because it gives information about the shape of the gestures independently of the chosen coordinate system.     

Reduced CTGF Expression Promotes Cell Growth,Migration, and Invasion in Nasopharyngeal Carcinoma

Background

The role of CTGF varies in different types of cancer. The purpose of this study is to investigate the involvement of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC).

Experimental design

CTGF expression levels were examined in NPC tissues and cells, nasopharynx (NP) tissues, and NP69 cells. The effects and molecular mechanisms of CTGF expression on cell proliferation, migration, invasion, and cell cycle were also explored.

Results

NPC cells exhibited decreased mRNA expression of CTGF compared to immortalized human nasopharyngeal epithelial cell line NP69. Similarly, CTGF was observed to be downregulated in NPC compared to normal tissues at mRNA and protein levels. Furthermore, reduced CTGF was negatively associated with the progression of NPC. Knocking down CTGF expression enhanced the colony formation, cell migration, invasion, and G1/S cell cycle transition. Mechanistic analysis revealed that CTGF suppression activated FAK/PI3K/AKT and its downstream signals regulating the cell cycle, epithelial-mesenchymal transition (EMT) and MMPs. Finally, DNA methylation microarray revealed a lack of hypermethylation at the CTGF promoter, suggesting other mechanisms are associated with suppression of CTGF in NPC.

Conclusion

Our study demonstrates that reduced expression of CTGF promoted cell proliferation, migration, invasion and cell cycle progression through FAK/PI3K/AKT, EMT and MMP pathways in NPC.     

The Wobbler Mouse Model of Amyotrophic Lateral Sclerosis (ALS) Displays Hippocampal Hyperexcitability,and Reduced Number of Interneurons,but No Presynaptic Vesicle Release Impairments

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is a fatal degenerative disease, best recognized for its debilitating neuromuscular effects. ALS however also induces cognitive impairments in as many as 50% of affected individuals. Moreover, many ALS patients demonstrate cortical hyperexcitability, which has been shown to precede the onset of clinical symptoms. The wobbler mouse is a model of ALS, and like ALS patients the wobbler mouse displays cortical hyperexcitability. Here we investigated if the neocortical aberrations of the wobbler mouse also occur in the hippocampus. Consequently, we performed extracellular field excitatory postsynaptic potential recordings in the CA1 region of the hippocampus on acute brain slices from symptomatic (P45-P60) and presymptomatic (P17-P21) wobbler mice. Significant increased excitation of hippocampal synapses was revealed by leftward shifted input/output-curves in both symptomatic and presymptomatic wobbler mice, and substantiated by population spike occurrence analyses, demonstrating that the increased synaptic excitation precedes the onset of visible phenotypic symptoms in the mouse. Synaptic facilitation tested by paired-pulse facilitation and trains in wobbler and control mice showed no differences, suggesting the absence of presynaptic defects. Immunohistochemical staining revealed that symptomatic wobbler mice have a lower number of parvalbumin positive interneurons when compared to controls and presymptomatic mice. This study reveals that the wobbler mouse model of ALS exhibits hippocampal hyperexcitability. We suggest that the hyperexcitability could be caused by increased excitatory synaptic transmission and a concomitant reduced inhibition due to a decreased number of parvalbumin positive interneurons. Thus we substantiate that wobbler brain impairments are not confined to the motor cortex, but extend to the hippocampus. Importantly, we have revealed more details of the early pathophysiology in asymptomatic animals, and studies like the present may facilitate the development of novel treatment strategies for earlier intervention in ALS patients in the future.     

New derivatives from the aerial parts of Boerhaavia diffusa L. (Nyctaginaceae)

Boerhaavia diffusa L. is used in the traditional medicine of several Asian countries. The isolation and identification of five new compounds, together with 11 known compounds, from the ethyl acetate extract of the aerial part of B. diffusa grown Vietnam is reported. The structure of the new compounds was established by 1D and 2D NMR spectroscopy, and high resolution ESI-MS analysis. New compounds are two rotenoids: 9,11-dihydroxy-6,10-dimethoxy[1]benzopyrano[3,4-b][1]benzopyran-12(6H)-one (boeravinone P, 3) and 3-[2-(β-d-glucopyranosyloxy)-3-hydroxyphenyl]-5-hydroxy-2-hydroxymethyl-7-methoxy-6-methyl-4H-1-benzopyran-4-one (boeravinone Q, 9), an atropisomeric mixture of two rotenoid glycosides (3′,5-dihydroxy-2-hydroxymethyl-7-methoxy-6-methylisoflavone 2′-O-β-d-glucopyranoside, 11), a sesquiterpene lactone (4,10-dihydroxy-8-methoxyguai-7(11)-en-8,12-olide, 5) and a new phenylpropanoid glycoside (boerhaavic acid, 15).     

The association between acanthosis nigricans and dysglycemia in an ethnically diverse group of eighth grade students

Objective:

The purpose of this study was to describe the prevalence of acanthosis nigricans (AN) and to quantify its association with dysglycemia in an ethnically diverse group of eighth‐grade students.

Design and Methods:

Data were collected in 2003 from a cross‐sectional study of students from 12 middle schools in three US states. Sex, race/ethnicity, and pubertal status were self‐reported. Anthropometric measures were recorded. Trained staff identified the presence and severity of AN by inspection of the back of the neck. Fasting and 2 h blood samples were analyzed for impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and high‐risk glycated hemoglobin (A1C), respectively, defined as ≥100 mg/dl, ≥140 mg/dl, and ≥ 5.7‐6.4%.

Results:

Overall, 25.0%, 58.2%, and 16.8% were Black, Hispanic, and White, respectively. AN was present among 406/1,438 (28.2%) of students: 39% among Black, 30% among Hispanic, and 5.4% among White. IGT and high‐risk A1C were present among 2.1%, and 12.4%, respectively. In multivariate logistic modeling after adjusting for gender, family history of diabetes, BMI percentile, and pubertal staging, the presence (vs. absence) of AN was associated with a 59% increased likelihood of high‐risk A1C: (P = 0.04), twice the likelihood of IGT (P = 0.06), and 47% greater likelihood of IGT/IFG combined (P < 0.0001). Adjustment for insulin attenuated the ORs by 25‐70%.

Conclusion:

In a racially/ethnically diverse sample of US adolescents, AN was common, occurring in 28% of the sample. AN was associated with a 50‐100% increased likelihood of dysglycemia even after consideration of established diabetes risk factors.