Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα + γ Agonists

Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds

Altercentric bias in preverbal infants memory

Human infants would seem to face a daunting challenge in selecting what they should attend, encode and remember. We investigated whether early in life, infants might use others’ attention as an exploitable source of information filtering, by prioritizing the encoding of events that are co-witnessed with someone else over events witnessed alone. In a series of studies (n=255), we show that infants who can otherwise remember an object’s location, misremembered the object where another agent had seen it, even if infants themselves had subsequently seen the object move somewhere else. With further exploratory analyses, we also found that infants’ attention to the agent rather than the object seems to drive their memory for the object’s location. This series points to an initial encoding bias that likely facilitates information selection but which can, under some circumstances, lead to predictable memory errors

Kentucky Research: A Flexible Pavement Design and Management System

Various strategies for designing pavement structures are discussed. Initial full-life design, stage designs and planned extensions of service life, final design, surface renewals for deslicking, no-defect designs for high-type high-volume facilities, and allowable-defect designs are considered. Economics enter in terms of salvage value of existing pavements and alternate designs using different proportions of materials within the structure. The elastic model represented in Chevron\u27s n-layered computer program is the basis for theoretical relationships. Ranges of values are given for input variables such as Young\u27s moduli, Poisson\u27s ratio, thicknesses for layers, tire pressure, and load. The Kentucky CBR is related to modulus by E = 1500 x CBR and is correlated with the AASHO Soil Support value and other strength relationships. The modulus of crushed stone base is shown to be a function of the moduli of the asphaltic concrete and sub grade. Appropriate relationships are given

Detection of epithelial cancer cells in peripheral blood by reverse transcriptase-polymerase chain reaction.

Circulating cancer cells in the blood play a central role in the metastatic process. Their number can be very small and techniques for their detection need to be both sensitive and specific. Polymerase chain reaction (PCR) has been successfully used to detect small numbers of tumour cells in haematological cancer in which abnormalities in DNA are sufficiently consistent to make this possible. For most solid tumours this not yet feasible. However, we have found that reverse transcriptase (RT)-PRC for tissue-specific gene expression is a useful technique for identifying small numbers of circulating cells in melanoma and neuroblastoma patients. In this report we describe detection of colon carcinoma cells by RT-PCR using CK 20 mRNA as a marker. Unlike other cytokeratin genes examined (CK 8 and CK 19), CK 20 was not transcribed in normal haematopoietic cells. This suggests a role for RT-PCR in the detection of colon carcinoma metastasis in blood and bone marrow, using CK 20 as the target gene. Future analysis of clinical material will determine the clinical significance of this technique

Influenza classification from short reads with VAPOR facilitates robust mapping pipelines and zoonotic strain detection for routine surveillance applications

Motivation: Influenza viruses represent a global public health burden due to annual epidemics and pandemic potential. Due to a rapidly evolving RNA genome, inter-species transmission, intra-host variation, and noise in short-read data, reads can be lost during mapping, and de novo assembly can be time consuming and result in misassembly. We assessed read loss during mapping, and designed a graph-based classifier, VAPOR, for selecting mapping references, assembly validation, and detection of strains of non-human origin. Results: Standard human reference viruses were insufficient for mapping diverse influenza samples in simulation. VAPOR retrieved references for 257 real whole genome sequencing (WGS) samples with a mean of >99.8% identity to assemblies, and increased the proportion of mapped reads by up to 13.3% compared to standard references. VAPOR has the potential to improve the robustness of bioinformatics pipelines for surveillance and could be adapted to other RNA viruses

Characterization of an hrp-aox-polyaniline-graphite composite biosensor

Nowadays there is an increasing demand to develop new and robust biosensors in order to detect low concentrations of different chemicals, in practical and small devices, giving fast and confident responses. The electrode material was a polyaniline-graphite-epoxy composite (PANI/GEC). Alcohol oxidase (AOX) and horseradish peroxidase (HRP) enzymes were immobilized and the responses were tested by cyclic voltammetry. The conductivities for the composites of graphite/polyaniline were determined. The cyclic voltammograms allowed detecting ethanol in pure diluted samples in a range from 0.036 to 2.62 M. Differential scanning calorimetry (DSC) and thermal gravimetry analysis (TGA) were used to verify the thermal characteristics of the composites (0, 10, 20, 30 and 100 % of graphite). The Imax value was determined for the dual enzyme biosensor (0.0724 mA), and the Kapp m as 1.41 M (with R2 =0.9912)

DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies

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Fully automated image-based estimation of postural point-features in children with cerebral palsy using deep learning

The aim of this study was to provide automated identification of postural point-features required to estimate the location and orientation of the head, multi-segmented trunk and arms from videos of the clinical test ‘Segmental Assessment of Trunk Control’ (SATCo). Three expert operators manually annotated 13 point-features in every fourth image of 177 short (5–10 s) videos (25 Hz) of 12 children with cerebral palsy (aged: 4.52 ± 2.4 years), participating in SATCo testing. Linear interpolation for the remaining images resulted in 30 825 annotated images. Convolutional neural networks were trained with cross-validation, giving held-out test results for all children. The point-features were estimated with error 4.4 ± 3.8 pixels at approximately 100 images per second. Truncal segment angles (head, neck and six thoraco-lumbar–pelvic segments) were estimated with error 6.4 ± 2.8°, allowing accurate classification (F1 > 80%) of deviation from a reference posture at thresholds up to 3°, 3° and 2°, respectively. Contact between arm point-features (elbow and wrist) and supporting surface was classified at F1 = 80.5%. This study demonstrates, for the first time, technical feasibility to automate the identification of (i) a sitting segmental posture including individual trunk segments, (ii) changes away from that posture, and (iii) support from the upper limb, required for the clinical SATCo