Regarding “Co-expression of SNAIL and TWIST determines prognosis in estrogen receptor-positive early breast cancer patients”

We read the interesting research article published by van Nes et al. [1], which described the use of Snail and TWIST together in the prognosis of breast cancer, and in particular in estrogen receptor (ER)-positive breast cancer patients.

Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology.

Aims/hypothesis
Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy.
Methods
Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24 weeks of hyperglycaemia. N e-(Carboxyethyl)lysine (CEL), N e-(carboxymethyl)lysine (CML) and MG-derived-hydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS). Müller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts.
Results
GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p?<?0.01). Diabetes-related increases in Müller glial GFAP levels and loss of Kir4.1 at the vascular end-feet were significantly prevented by GLO1 overexpression (p?<?0.05) at both 12- and 24-week time points. GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p?<?0.001) at 24 weeks’ diabetes.
Conclusions/interpretation
Detoxification of MG reduces AGE adduct accumulation, which, in turn, can prevent formation of key retinal neuroglial and vascular lesions as diabetes progresses. MG-derived AGEs play an important role in diabetic retinopathy.

Structural changes in the hippocampus and amygdala at first episode of psychosis

Hippocampus and amygdala changes have been implicated in the pathophysiology and symptomatology of both schizophrenia (SCZ) and bipolar disorder (BD). However relationships between illness course, neuropathological changes and variations in symptomatology remain unclear. This investigation examined the associations between hippocampus and amygdala volumes and symptom dimensions in schizophrenia and bipolar disorder patients after their first episode of psychosis. Symptom severity was associated with decreases in hippocampus/amygdala complex volume across groups. In keeping with previous work bilateral hippocampus and amygdala volume reductions were also identified in the SCZ patients while in BD patients only evidence of amygdala inflation reached significance. The study concludes that there appear to be important relationships between volume changes in the hippocampus and amygdala and dimensions and severity of symptomatology in psychosis. Structural alterations are apparent in both SCZ and BD after first episode of psychosis but present differently in each illness and are more severe in SCZ.

Fasciola hepatica: time-dependent disruption of spermatogenesis following in vivo treatment with triclabendazole

Sheep infected with the Cullompton isolate of Fasciola hepatica were treated with triclabendazole at a concentration of 10 mg/kg at 12 weeks post-infection. Adult flukes were recovered from the liver and, where present, from the gall bladder at 48, 72 and 96 h post-treatment (pt). Gross changes to the spermatogenic cells of the testis were examined by histology and ultrastructural alterations were visualised via transmission electron microscopy. Disruption was progressive in nature, with the testis tubules becoming shrunken, vacuolated and gradually more denuded of cellular content over the 96-h time period. From 48 h pt, the number of primary and secondary spermatogonia decreased and multinucleate spermatogonial cells were frequent. Later, developmental stages were uncommon, giving rise to much empty space within the tubules. By 72 h pt, the tubules contained many apoptotic and degraded cells and had an extremely disorganised appearance. At 96 h pt, the tubules were almost completely empty, with the exception of the remains of degraded spermatogenic cells. These results indicate that triclabendazole severely disrupts spermatogenesis in the liver fluke from 48 h pt in vivo.

Evidential Holism and Indispensability Arguments

The indispensability argument is a method for showing that abstract mathematical objects exist (call this mathematical Platonism). Various versions of this argument have been proposed (§1). Lately, commentators seem to have agreed that a holistic indispensability argument (§2) will not work, and that an explanatory indispensability argument is the best candidate. In this paper I argue that the dominant reasons for rejecting the holistic indispensability argument are mistaken. This is largely due to an overestimation of the consequences that follow from evidential holism. Nevertheless, the holistic indispensability argument should be rejected, but for a different reason (§3)—in order that an indispensability argument relying on holism can work, it must invoke an unmotivated version of evidential holism. Such an argument will be unsound. Correcting the argument with a proper construal of evidential holism means that it can no longer deliver mathematical Platonism as a conclusion: such an argument for Platonism will be invalid. I then show how the reasons for rejecting the holistic indispensability argument importantly constrain what kind of account of explanation will be permissible in explanatory versions (§4).

Determining the parametric effectiveness of a CAD model

The motivation for this paper is to present an approach for rating the quality of the parameters in a computer-aided design model for use as optimization variables. Parametric Effectiveness is computed as the ratio of change in performance achieved by perturbing the parameters in the optimum way, to the change in performance that would be achieved by allowing the boundary of the model to move without the constraint on shape change enforced by the CAD parameterization. The approach is applied in this paper to optimization based on adjoint shape sensitivity analyses. The derivation of parametric effectiveness is presented for optimization both with and without the constraint of constant volume. In both cases, the movement of the boundary is normalized with respect to a small root mean squared movement of the boundary. The approach can be used to select an initial search direction in parameter space, or to select sets of model parameters which have the greatest ability to improve model performance. The approach is applied to a number of example 2D and 3D FEA and CFD problems.

Diabetes-related adduct formation and retinopathy

The pathogenesis of diabetic retinopathy is complex, reflecting the array of systemic and tissue-specific metabolic abnormalities. A range of pathogenic pathways are directly linked to hyperglycaemia and dyslipidaemia, and the retina appears to be exquisitely sensitive to damage. Establishing the biochemical and molecular basis for this pathology remains an important research focus. This review concentrates on the formation of a range of protein adducts that form after exposure to modifying intermediates known to be elevated during diabetes. These so-called advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs) are thought to play an important role in the initiation and progression of diabetic retinopathy, and mechanisms leading to dysfunction and death of various retinal cells are becoming understood. Perspective is provided on AGE/ALE formation in the retina and the impact that such adducts have on retinal cell function. There will be emphasis placed on the role of the receptor for AGEs and how this may modulate retinal pathology, especially in relation to oxidative stress and inflammation. The review will conclude by discussion of strategies to inhibit AGE/ALE formation or harmful receptor interactions in order to prevent disease progression from the point of diabetes diagnosis to sight-threatening proliferative diabetic retinopathy and diabetic macular oedema.

A New Model for Automated Examination Timetabling

Automated examination timetabling has been addressed by a wide variety of methodologies and techniques over the last ten years or so. Many of the methods in this broad range of approaches have been evaluated on a collection of benchmark instances provided at the University of Toronto in 1996. Whilst the existence of these datasets has provided an invaluable resource for research into examination timetabling, the instances have significant limitations in terms of their relevance to real-world examination timetabling in modern universities. This paper presents a detailed model which draws upon experiences of implementing examination timetabling systems in universities in Europe, Australasia and America. This model represents the problem that was presented in the 2nd International Timetabling Competition (ITC2007). In presenting this detailed new model, this paper describes the examination timetabling track introduced as part of the competition. In addition to the model, the datasets used in the competition are also based on current real-world instances introduced by EventMAP Limited. It is hoped that the interest generated as part of the competition will lead to the development, investigation and application of a host of novel and exciting techniques to address this important real-world search domain. Moreover, the motivating goal of this paper is to close the currently existing gap between theory and practice in examination timetabling by presenting the research community with a rigorous model which represents the complexity of the real-world situation. In this paper we describe the model and its motivations, followed by a full formal definition.

Motor Skills in Children Aged 7–10 Years, Diagnosed with Autism Spectrum Disorder

This study used the Movement Assessment Battery for Children (M-ABC2) to assess the level of motor skill in children aged 7-10 years with autism (n=18) and compared their performance to two groups of age-matched typically developing children; a receptive vocabulary matched group (n=19) and a nonverbal IQ matched group (n=22). Although the results support previous work, as indicated by a significant general motor impairment in the group with autism, a sub-analysis of the M-ABC2 revealed that there were only 2 out of 8 subcomponent skills which showed universally significant specific deficits for the autism group; namely catching a ball and static balance. These results suggest that motor skill deficits associated with autism may not be pervasive but more apparent in activities demanding complex, interceptive actions or core balance ability.

Olfactory discrimination in the western lowland gorilla, Gorilla gorilla gorilla

The olfactory abilities of great apes have been subject to little empirical investigation, save for a few observational reports. This study, using an habituation/dishabituation task, provides experimental evidence for a core olfactory ability, namely, olfactory discrimination, in the gorilla. In Experiment 1, six zoo-housed western lowland gorillas were individually presented with the same odour on four trials, and with a novel odour on the fifth trial. Odours (almond and vanilla) were presented on plastic balls, and behavioural responses of sniffing and chewing/licking the balls were recorded. A second experiment presented the same odour on four trials and no odour on the fifth to examine whether any dishabituation was due to the presence of a new odour or the absence of the familiar odour. Gorillas habituated their behaviour with repeated presentation of the same odour, but dishabituated, i. e. increased sniffing and chewing/licking, when presented with the novel odour. No dishabituation was noted when using water as the stimulus across all trials or when used as the novel odour. Overall, results show that gorillas are able to discriminate between odours. © 2012 Japan Monkey Centre and Springer.

High-precision transit observations of the exoplanet WASP-13b with the RISE instrument

WASP-13b is a sub-Jupiter mass exoplanet orbiting a G1V type star with a period of 4.35 d.The current uncertainty in its impact parameter (0 < b < 0.46) results in poorly definedstellar and planetary radii. To better constrain the impact parameter, we have obtained highprecisiontransit observations with the rapid imager to search for exoplanets (RISE) instrumentmounted on 2.0-m Liverpool Telescope. We present four new transits which are fitted witha Markov chain Monte Carlo routine to derive accurate system parameters. We found anorbital inclination of 85. ◦ 2 ± 0. ◦ 3 resulting in stellar and planetary radii of 1.56 ± 0.04 Rand 1.39 ± 0.05RJup, respectively. This suggests that the host star has evolved off the mainsequence and is in the hydrogen-shell-burning phase.We also discuss how the limb darkeningaffects the derived system parameters.With a density of 0.17ρJ,WASP-13b joins the group oflow-density planets whose radii are too large to be explained by standard irradiation models.We derive a new ephemeris for the system, T0 = 245 5575.5136 ± 0.0016 (HJD) and P =4.353 011 ± 0.000 013 d. The planet equilibrium temperature (Tequ = 1500 K) and the brighthost star (V = 10.4mag) make it a good candidate for follow-up atmospheric studies.

Cache-Integrated Network Interfaces: Flexible On-Chip Communication and Synchronization for Large-Scale CMPs

Per-core scratchpad memories (or local stores) allow direct inter-core communication, with latency and energy advantages over coherent cache-based communication, especially as CMP architectures become more distributed. We have designed cache-integrated network interfaces, appropriate for scalable multicores, that combine the best of two worlds – the flexibility of caches and the efficiency of scratchpad memories: on-chip SRAM is configurably shared among caching, scratchpad, and virtualized network interface (NI) functions. This paper presents our architecture, which provides local and remote scratchpad access, to either individual words or multiword blocks through RDMA copy. Furthermore, we introduce event responses, as a technique that enables software configurable communication and synchronization primitives. We present three event response mechanisms that expose NI functionality to software, for multiword transfer initiation, completion notifications for software selected sets of arbitrary size transfers, and multi-party synchronization queues. We implemented these mechanisms in a four-core FPGA prototype, and measure the logic overhead over a cache-only design for basic NI functionality to be less than 20%. We also evaluate the on-chip communication performance on the prototype, as well as the performance of synchronization functions with simulation of CMPs with up to 128 cores. We demonstrate efficient synchronization, low-overhead communication, and amortized-overhead bulk transfers, which allow parallelization gains for fine-grain tasks, and efficient exploitation of the hardware bandwidth.