Endosomes: a legitimate platform for the signaling train

Although long regarded as a conduit for the degradation or recycling of cell surface receptors, the endosomal system is also an essential site of signal transduction. Activated receptors accumulate in endosomes, and certain signaling components are exclusively localized to endosomes. Receptors can continue to transmit signals from endosomes that are different from those that arise from the plasma membrane, resulting in distinct physiological responses. Endosomal signaling is widespread in metazoans and plants, where it transmits signals for diverse receptor families that regulate essential processes including growth, differentiation and survival. Receptor signaling at endosomal membranes is tightly regulated by mechanisms that control agonist availability, receptor coupling to signaling machinery, and the subcellular localization of signaling components. Drugs that target mechanisms that initiate and terminate receptor signaling at the plasma membrane are widespread and effective treatments for disease. Selective disruption of receptor signaling in endosomes, which can be accomplished by targeting endosomal-specific signaling pathways or by selective delivery of drugs to the endosomal network, may provide novel therapies for disease.

Establishing a reliable Jini infrastructure for parallel applications

Java is becoming an increasingly popular language for developing distributed and parallel scientific and engineering applications. Jini is a Java-based infrastructure developed by Sun that can allegedly provide all the services necessary to support distributed applications. It is the aim of this paper to explore and investigate the services and properties that Jini actually provides and match these against the needs of high performance distributed and parallel applications written in Java. The motivation for this work is the need to develop a distributed infrastructure to support an MPI-like interface to Java known as MPJ. In the first part of the paper we discuss the needs of MPJ, the parallel environment that we wish to support. In particular we look at aspects such as reliability and ease of use. We then move on to sketch out the Jini architecture and review the components and services that Jini provides. In the third part of the paper we critically explore a Jini infrastructure that could be used to support MPJ. Here we are particularly concerned with Jini's ability to support reliably a cocoon of MPJ processes executing in a heterogeneous envirnoment. In the final part of the paper we summarise our findings and report on future work being undertaken on Jini and MPJ.

Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs

Flavonoids are low-molecular weight, aromatic compounds derived from fruits, vegetables, and other plant components. The consumption of these phytochemicals has been reported to be associated with reduced cardiovascular disease (CVD) risk, attributed to their anti-inflammatory, anti-proliferative, and anti-thrombotic actions. Flavonoids exert these effects by a number of mechanisms which include attenuation of kinase activity mediated at the cell-receptor level and/or within cells, and are characterized as broad-spectrum kinase inhibitors. Therefore, flavonoid therapy for CVD is potentially complex; the use of these compounds as molecular templates for the design of selective and potent small-molecule inhibitors may be a simpler approach to treat this condition. Flavonoids as templates for drug design are, however, poorly exploited despite the development of analogues based on the flavonol, isoflavonone, and isoflavanone subgroups. Further exploitation of this family of compounds is warranted due to a structural diversity that presents great scope for creating novel kinase inhibitors. The use of computational methodologies to define the flavonoid pharmacophore together with biological investigations of their effects on kinase activity, in appropriate cellular systems, is the current approach to characterize key structural features that will inform drug design. This focussed review highlights the potential of flavonoids to guide the design of clinically safer, more selective, and potent small-molecule inhibitors of cell signalling, applicable to anti-platelet therapy.

The national food safety control system of China: a systematic review

In recent years, there have been increasing concerns over the safety of the Chinese food supply. Although many of these have only raised concern internally within China, several major food safety issues have had international repercussions. In response, China has implemented new food safety laws and management systems to improve its national food safety control system and reduce public and international concerns. This paper has describes and discusses the components of the Chinese system using the five key elements of a national food control system identified by the World Health Organization (WHO) and the Food and Agriculture Organization (FAO) as essential for an effective system. The latest Chinese national food safety control has made significantly improvement on its regulation framework, however, more work need to be done on standards, law enforcement, and information exchange.

Fine-grained multi-phase array designs

Hybrid multiprocessor architectures which combine re-configurable computing and multiprocessors on a chip are being proposed to transcend the performance of standard multi-core parallel systems. Both fine-grained and coarse-grained parallel algorithm implementations are feasible in such hybrid frameworks. A compositional strategy for designing fine-grained multi-phase regular processor arrays to target hybrid architectures is presented in this paper. The method is based on deriving component designs using classical regular array techniques and composing the components into a unified global design. Effective designs with phase-changes and data routing at run-time are characteristics of these designs. In order to describe the data transfer between phases, the concept of communication domain is introduced so that the producer–consumer relationship arising from multi-phase computation can be treated in a unified way as a data routing phase. This technique is applied to derive new designs of multi-phase regular arrays with different dataflow between phases of computation.

Social approach in preschool children with Williams syndrome: the role of the face

Background Indiscriminate social approach behaviour is a salient aspect of the Williams syndrome (WS) behavioural phenotype. The present study examines approach behaviour in preschoolers with WS and evaluates the role of the face in WS social approach behaviour. Method Ten preschoolers with WS (aged 3-6 years) and two groups of typically developing children, matched to the WS group on chronological or mental age, participated in an observed play session. The play session incorporated social and non-social components including two components that assessed approach behaviour towards strangers, one in which the stranger’s face could be seen and one in which the stranger’s face was covered. Results In response to the non-social aspects of the play session, the WS group behaved similarly to both control groups. In contrast, the preschoolers with WS were significantly more willing than either control group to engage with a stranger, even when the stranger’s face could not be seen. Conclusion The findings challenge the hypothesis that an unusual attraction to the face directly motivates social approach behaviour in individuals with WS.

Crystal design approaches for the synthesis of paracetamol co-crystals

Crystal engineering principles were used to design three new co-crystals of paracetamol. A variety of potential cocrystal formers were initially identified from a search of the Cambridge Structural Database for molecules with complementary hydrogen-bond forming functionalities. Subsequent screening by powder X-ray diffraction of the products of the reaction of this library of molecules with paracetamol led to the discovery of new binary crystalline phases of paracetamol with trans-1,4- diaminocyclohexane (1); trans-1,4-di(4-pyridyl)ethylene (2); and 1,2-bis(4-pyridyl)ethane (3). The co-crystals were characterized by IR spectroscopy, differential scanning calorimetry, and 1H NMR spectroscopy. Single crystal X-ray structure analysis reveals that in all three co-crystals the co-crystal formers (CCF) are hydrogen bonded to the paracetamol molecules through O−H···N interactions. In co-crystals (1) and (2) the CCFs are interleaved between the chains of paracetamol molecules, while in co-crystal (3) there is an additional N−H···N hydrogen bond between the two components. A hierarchy of hydrogen bond formation is observed in which the best donor in the system, the phenolic O−H group of paracetamol, is preferentially hydrogen bonded to the best acceptor, the basic nitrogen atom of the co-crystal former. The geometric aspects of the hydrogen bonds in co-crystals 1−3 are discussed in terms of their electrostatic and charge-transfer components.

Periodic auroral events at the high-latitude convection reversal in the 16 MLT region

Combined optical and radar observations of two breakup-like auroral events near the polar cap boundary, within 74–76° MLAT and 1210 – 1240 UT (roughly 1540 – 1610 MLT) on 9 Jan. 1989 are reported. A two-component structure of the auroral phenomenon is indicated, with a local intensification of the pre-existing arc as well as a separate, tailward moving discrete auroral event on the poleward side of the background aurora, close to the reversal between well-defined zones of sunward and tailward ion flows. The all-sky TV observations do not indicate a connection between the two components, which also show different optical spectral composition. The 16 MLT background arc is located on sunward convecting field lines, as opposed to the 12–14 MLT auroral emission observed on this day. Although the magnetospheric plasma source (s) of the 16 MLT events are not easily identified from these ground-based data alone, it is suggested that the lower and higher latitude components, may map to the plasma sheet boundary layer and along open field lines to the magnetopause boundary, respectively. The events occur at the time of enhancements of westward ionospheric ion flow and corresponding eastward electrojet current south of 74° MLAT. Thus, they seem to be very significant events, involving periodic (10 min period), tailward moving filaments of field-aligned current/discrete auroral emission at the 16 MLT polar cap boundary.

The emergence of integrated private reporting

Purpose: Private social and environmental reporting (SER) has grown considerably in recent years, consistent with a rise in institutional investor engagement and dialogue with investee companies. We interpret the emergence of integrated private reporting through the lens of institutional logics. We frame the emergence of integrated private reporting as a merging of two hitherto separate and possibly rival institutional logics. Methodology/Approach: We interviewed 19 companies listed on the FTSE100 and 20 UK institutional investors. The interviews were semi-structured and analysed in an interpretive fashion. Findings and Implications: We provide evidence to suggest that private SER is beginning to merge with private financial reporting and that, as a result integrated private reporting is emerging. This trend is mirroring the international trend in public reporting toward an integrated approach. Specifically, we find that specialist social responsible investment managers are starting to attend private financial reporting meetings whilst mainstream fund managers are starting to attend private meetings on environmental, social and governance (ESG) issues. Further, senior company directors are becoming increasingly conversant with ESG issues. We interpret our findings as two possible scenarios: (i) there is a genuine hybridisation occurring in UK institutional investment such that integrated private reporting is emerging, or; (ii) the financial logic is absorbing and effectively neutralising the responsible investment logic. Originality: This is the first research investigating the evolution of private integrated reporting.

The effects of explicit versus parameterized convection on the MJO in a large-domain high-resolution tropical case study. Part II: Processes leading to differences in MJO development

High-resolution simulations over a large tropical domain (∼20◦S–20◦N and 42◦E–180◦E) using both explicit and parameterized convection are analyzed and compared during a 10-day case study of an active Madden-Julian Oscillation (MJO) event. In Part II, the moisture budgets and moist entropy budgets are analyzed. Vertical subgrid diabatic heating profiles and vertical velocity profiles are also compared; these are related to the horizontal and vertical advective components of the moist entropy budget which contribute to gross moist stability, GMS, and normalized GMS (NGMS). The 4-km model with explicit convection and good MJO performance has a vertical heating structure that increases with height in the lower troposphere in regions of strong convection (like observations), whereas the 12-km model with parameterized convection and a poor MJO does not show this relationship. The 4-km explicit convection model also has a more top-heavy heating profile for the troposphere as a whole near and to the west of the active MJO-related convection, unlike the 12-km parameterized convection model. The dependence of entropy advection components on moisture convergence is fairly weak in all models, and differences between models are not always related to MJO performance, making comparisons to previous work somewhat inconclusive. However, models with relatively good MJO strength and propagation have a slightly larger increase of the vertical advective component with increasing moisture convergence, and their NGMS vertical terms have more variability in time and longitude, with total NGMS that is comparatively larger to the west and smaller to the east.

Should healthy eating programmes incorporate interaction with foods in different sensory modalities? A review of the evidence

Commercial interventions seeking to promote fruit and vegetable consumption by encouraging preschool- and school-aged children to engage with foods with ‘all their senses’ are increasing in number. We review the efficacy of such sensory interaction programmes and consider the components of these that are likely to encourage food acceptance. Repeated exposure to a food's flavour has robust empirical support in terms of its potential to increase food intake. However, children are naturally reluctant to taste new or disliked foods, and parents often struggle to provide sufficient taste opportunities for these foods to be adopted into the child's diet. We therefore explore whether prior exposure to a new food's non-taste sensory properties, such as its smell, sound, appearance or texture, might facilitate the food's introduction into the child's diet, by providing the child with an opportunity to become partially familiar with the food without invoking the distress associated with tasting it. We review the literature pertaining to the benefits associated with exposure to foods through each of the five sensory modalities in turn. We conclude by calling for further research into the potential for familiarisation with the visual, olfactory, somaesthetic and auditory properties of foods to enhance children's willingness to consume a variety of fruits and vegetables.

Multivariate analysis of the energy cycle of the South American rainy season

The South American (SA) rainy season is studied in this paper through the application of a multivariate Empirical Orthogonal Function (EOF) analysis to a SA gridded precipitation analysis and to the components of Lorenz Energy Cycle (LEC) derived from the National Centers for Environmental Prediction (NCEP) reanalysis. The EOF analysis leads to the identification of patterns of the rainy season and the associated mechanisms in terms of their energetics. The first combined EOF represents the northwest-southeast dipole of the precipitation between South and Central America, the South American Monsoon System (SAMS). The second combined EOF represents a synoptic pattern associated with the SACZ (South Atlantic convergence zone) and the third EOF is in spatial quadrature to the second EOF. The phase relationship of the EOFs, as computed from the principal components (PCs), suggests a nonlinear transition from the SACZ to the fully developed SAMS mode by November and between both components describing the SACZ by September-October (the rainy season onset). According to the LEC, the first mode is dominated by the eddy generation term at its maximum, the second by both baroclinic and eddy generation terms and the third by barotropic instability previous to the connection to the second mode by September-October. The predominance of the different LEC components at each phase of the SAMS can be used as an indicator of the onset of the rainy season in terms of physical processes, while the existence of the outstanding spectral peaks in the time dependence of the EOFs at the intraseasonal time scale could be used for monitoring purposes. Copyright (C) 2009 Royal Meteorological Society

Islet neogenesis-associated protein signaling in neonatal pancreatic rat islets: involvement of the cholinergic pathway

Islet neogenesis associated protein (INGAP) increases islet mass and insulin secretion in neonatal and adult rat islets. lit the Present Study, we measured the short- and long-term effects of INGAP-PP (a pentadecapeptide having the 104-118 amino acid sequence of INGAP) upon islet protein expression and phosphorylation of components of the PI3K, MAPK and cholinergic pathways, and on insulin secretion. Short-term exposure of neonatal islets to INGAP-PP (90 s, 5, 15, and 30 min) significantly increased Akt1(-Ser473) and MAPK3/1(-Thr202/Tyr204) phosphorylation and INGAP-PP also acutely increased insulin secretion from islets perifused with 2 and 20 mM glucose. Islets cultured for 4 days in the presence of INGAP-PP showed an increased expression of Akt1, Frap1, and Mapk1 mRNAs as well as of the muscarinic M3 receptor subtype, and phospholipase C (PLC)-beta 2 proteins. These islets also showed increased Akt1 and MAPK3/1 protein phosphorylation. Brief exposure of INGAP-P-treated islets to carbachol (Cch) significantly increased P70S6K(-Thr389) and MAPK3/1 phosphorylation and these islets released more insulin when challenged with Cch that was prevented by the M3 receptor antagonist 4-DAMP in a concentration-dependent manner. In conclusion, these data indicate that short- and long-term exposure to INGAP-PP significantly affects the expression and the phosphorylation of proteins involved in islet PI3K and MAPK signaling pathways. The observations of INGAPP-PP-stimulated up-regulation of cholinergic M3 receptors and PLC-beta 2 proteins, enhanced P70S6K and MAIIK3/1 phosphorylation and Cch-induced insulin secretion suggest a participation of the cholinergic pathway in INGAP-PP-mediated effects.

X-ray spectroscopy applied to radiation shielding calculation in mammography

The protective shielding design of a mammography facility requires the knowledge of the scattered radiation by the patient and image receptor components. The shape and intensity of secondary x-ray beams depend on the kVp applied to the x-ray tube, target/filter combination, primary x-ray field size, and scattering angle. Currently, shielding calculations for mammography facilities are performed based on scatter fraction data for Mo/Mo target/filter, even though modern mammography equipment is designed with different anode/filter combinations. In this work we present scatter fraction data evaluated based on the x-ray spectra produced by a Mo/Mo, Mo/Rh and W/Rh target/filter, for 25, 30 and 35 kV tube voltages and scattering angles between 30 and 165 degrees. Three mammography phantoms were irradiated and the scattered radiation was measured with a CdZnTe detector. The primary x-ray spectra were computed with a semiempirical model based on the air kerma and HVL measured with an ionization chamber. The results point out that the scatter fraction values are higher for W/Rh than for Mo/Mo and Mo/Rh, although the primary and scattered air kerma are lower for W/Rh than for Mo/Mo and Mo/Rh target/filter combinations. The scatter fractions computed in this work were applied in a shielding design calculation in order to evaluate shielding requirements for each of these target/filter combinations. Besides, shielding requirements have been evaluated converting the scattered air kerma from mGy/week to mSv/week adopting initially a conversion coefficient from air kerma to effective dose as 1 Sv/Gy and then a mean conversion coefficient specific for the x-ray beam considered. Results show that the thickest barrier should be provided for Mo/Mo target/filter combination. They also point out that the use of the conversion coefficient from air kerma to effective dose as 1 Sv/Gy is conservatively high in the mammography energy range and overestimate the barrier thickness. (c) 2008 American Association of Physicists in Medicine.

A neural networks study of quinone compounds with trypanocidal activity

This work investigates neural network models for predicting the trypanocidal activity of 28 quinone compounds. Artificial neural networks (ANN), such as multilayer perceptrons (MLP) and Kohonen models, were employed with the aim of modeling the nonlinear relationship between quantum and molecular descriptors and trypanocidal activity. The calculated descriptors and the principal components were used as input to train neural network models to verify the behavior of the nets. The best model for both network models (MLP and Kohonen) was obtained with four descriptors as input. The descriptors were T(5) (torsion angle), QTS1 (sum of absolute values of the atomic charges), VOLS2 (volume of the substituent at region B) and HOMO-1 (energy of the molecular orbital below HOMO). These descriptors provide information on the kind of interaction that occurs between the compounds and the biological receptor. Both neural network models used here can predict the trypanocidal activity of the quinone compounds with good agreement, with low errors in the testing set and a high correctness rate. Thanks to the nonlinear model obtained from the neural network models, we can conclude that electronic and structural properties are important factors in the interaction between quinone compounds that exhibit trypanocidal activity and their biological receptors. The final ANN models should be useful in the design of novel trypanocidal quinones having improved potency.