Post-Transcriptional Regulation of Cadherin-11 Expression by GSK-3 and β-Catenin in Prostate and Breast Cancer Cells

The cell-cell adhesion molecule cadherin-11 is important in embryogenesis and bone morphogenesis, invasion of cancer cells, lymphangiogenesis, homing of cancer cells to bone, and rheumatoid arthritis. However, very little is known about the regulation of cadherin-11 expression.Here we show that cell density and GSK-3beta regulate cadherin-11 levels in cancer cells. Inactivation of GSK3beta with lithium chloride or the GSK3 inhibitor BIO and GSK3beta knockdown with siRNA repressed cadherin-11 mRNA and protein levels. RNA Polymerase II chromatin immunoprecipitation experiments showed that inhibition of GSK3 does not affect cadherin-11 gene transcription. Although the cadherin-11 3'UTR contains putative microRNA target sites and is regulated by Dicer, its stability is not regulated by GSK3 inhibition or density. Our data show that GSK3beta regulates cadherin-11 expression in two ways: first a beta-catenin-independent regulation of cadherin-11 steady state mRNA levels, and second a beta-catenin-dependent effect on cadherin-11 3'UTR stability and protein translation.Cadherin-11 mRNA and protein levels are regulated by the activity of GSK3beta and a significant degree of this regulation is exerted by the GSK3 target, beta-catenin, at the level of the cadherin-11 3'UTR

Linking microarray reporters with protein functions

<p>Abstract</p> <p>Background</p> <p>The analysis of microarray experiments requires accurate and up-to-date functional annotation of the microarray reporters to optimize the interpretation of the biological processes involved. Pathway visualization tools are used to connect gene expression data with existing biological pathways by using specific database identifiers that link reporters with elements in the pathways.</p> <p>Results</p> <p>This paper proposes a novel method that aims to improve microarray reporter annotation by BLASTing the original reporter sequences against a species-specific EMBL subset, that was derived from and crosslinked back to the highly curated UniProt database. The resulting alignments were filtered using high quality alignment criteria and further compared with the outcome of a more traditional approach, where reporter sequences were BLASTed against EnsEMBL followed by locating the corresponding protein (UniProt) entry for the high quality hits. Combining the results of both methods resulted in successful annotation of > 58% of all reporter sequences with UniProt IDs on two commercial array platforms, increasing the amount of Incyte reporters that could be coupled to Gene Ontology terms from 32.7% to 58.3% and to a local GenMAPP pathway from 9.6% to 16.7%. For Agilent, 35.3% of the total reporters are now linked towards GO nodes and 7.1% on local pathways.</p> <p>Conclusion</p> <p>Our methods increased the annotation quality of microarray reporter sequences and allowed us to visualize more reporters using pathway visualization tools. Even in cases where the original reporter annotation showed the correct description the new identifiers often allowed improved pathway and Gene Ontology linking. These methods are freely available at http://www.bigcat.unimaas.nl/public/publications/Gaj_Annotation/.</p

Pigment epithelium-derived factor protects retinal ganglion cells

BACKGROUND: Retinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors. RESULTS: Cultured adult rat RGCs exposed to glutamate for 3 days showed signs of cytotoxicity and death. The toxic effect of glutamate was concentration-dependent (EC(50 )= 31 μM). In the presence of 100 μM glutamate, RGC number decreased to 55 ± 4% of control (mean ± SEM, n = 76; P < 0.001). The glutamate effect was completely eliminated by MK801, an NMDA receptor antagonist. Trophic factor withdrawal also caused a similar loss of RGCs (54 ± 4%, n = 60, P < 0.001). PEDF protected against both insults with EC(50 )values of 13.6 ng/mL (glutamate) and 3.4 ng/mL (trophic factor withdrawal), respectively. At 100 ng/mL, PEDF completely protected the cells from both insults. Inhibitors of the nuclear factor κB (NFκB) and extracellular signal-regulated kinases 1/2 (ERK1/2) significantly reduced the protective effects of PEDF. CONCLUSION: We demonstrated that PEDF potently and efficaciously protected adult rat RGCs from glutamate- and trophic factor withdrawal-mediated cytotoxicity, via the activation of the NFκB and ERK1/2 pathways. The neuroprotective effect of PEDF represents a novel approach for potential treatment of retinopathies, such as glaucoma

Unconstrained three-dimensional reaching in Rhesus monkeys

To better understand normative behavior for quantitative evaluation of motor recovery after injury, we studied arm movements by non-injured Rhesus monkeys during a food-retrieval task. While seated, monkeys reached, grasped, and retrieved food items. We recorded three-dimensional kinematics and muscle activity, and used inverse dynamics to calculate joint moments due to gravity, segmental interactions, and to the muscles and tissues of the arm. Endpoint paths showed curvature in three dimensions, suggesting that maintaining straight paths was not an important constraint. Joint moments were dominated by gravity. Generalized muscle and interaction moments were less than half of the gravitational moments. The relationships between shoulder and elbow resultant moments were linear during both reach and retrieval. Although both reach and retrieval required elbow flexor moments, an elbow extensor (triceps brachii) was active during both phases. Antagonistic muscles of both the elbow and hand were co-activated during reach and retrieval. Joint behavior could be described by lumped-parameter models analogous to torsional springs at the joints. Minor alterations to joint quasi-stiffness properties, aided by interaction moments, result in reciprocal movements that evolve under the influence of gravity. The strategies identified in monkeys to reach, grasp, and retrieve items will allow the quantification of prehension during recovery after a spinal cord injury and the effectiveness of therapeutic interventions

Effect of garlic on cardiovascular disorders: a review

Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficary of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Overview of the medium and high frequency telescopes of the LiteBIRD space mission

LiteBIRD is a JAXA-led Strategic Large-Class mission designed to search for the existence of the primordial gravitational waves produced during the inflationary phase of the Universe, through the measurements of their imprint onto the polarization of the cosmic microwave background (CMB). These measurements, requiring unprecedented sensitivity, will be performed over the full sky, at large angular scales, and over 15 frequency bands from 34 GHz to 448 GHz. The LiteBIRD instruments consist of three telescopes, namely the Low-, Medium-and High-Frequency Telescope (respectively LFT, MFT and HFT). We present in this paper an overview of the design of the Medium-Frequency Telescope (89{224 GHz) and the High-Frequency Telescope (166{448 GHz), the so-called MHFT, under European responsibility, which are two cryogenic refractive telescopes cooled down to 5 K. They include a continuous rotating half-wave plate as the first optical element, two high-density polyethylene (HDPE) lenses and more than three thousand transition-edge sensor (TES) detectors cooled to 100 mK. We provide an overview of the concept design and the remaining specific challenges that we have to face in order to achieve the scientific goals of LiteBIRD

GWAS and drug targets

Genome wide association studies (GWAS) have revealed a large number of links between genome variation and complex disease. Among other benefits, it is expected that these insights will lead to new therapeutic strategies, particularly the identification of new drug targets. In this paper, we evaluate the power of GWAS studies to find drug targets by examining how many existing drug targets have been directly 'rediscovered' by this technique, and the extent to which GWAS results may be leveraged by network information to discover known and new drug targets. We find that only a very small fraction of drug targets are directly detected in the relevant GWAS studies. We investigate two possible explanations for this observation. First, we find evidence of negative selection acting on drug target genes as a consequence of strong coupling with the disease phenotype, so reducing the incidence of SNPs linked to the disease. Second, we find that GWAS genes are substantially longer on average than drug targets and than all genes, suggesting there is a length related bias in GWAS results. In spite of the low direct relationship between drug targets and GWAS reported genes, we found these two sets of genes are closely coupled in the human protein network. As a consequence, machine-learning methods are able to recover known drug targets based on network context and the set of GWAS reported genes for the same disease. We show the approach is potentially useful for identifying drug repurposing opportunities. Although GWA studies do not directly identify most existing drug targets, there are several reasons to expect that new targets will nevertheless be discovered using these data. Initial results on drug repurposing studies using network analysis are encouraging and suggest directions for future development.https://doi.org/10.1186/1471-2164-15-S4-S

LiteBIRD satellite: JAXA's new strategic L-class mission for all-sky surveys of cosmic microwave background polarization

LiteBIRD, the Lite (Light) satellite for the study of B-mode polarization and Inflation from cosmic background Radiation Detection, is a space mission for primordial cosmology and fundamental physics. JAXA selected LiteBIRD in May 2019 as a strategic large-class (L-class) mission, with its expected launch in the late 2020s using JAXA's H3 rocket. LiteBIRD plans to map the cosmic microwave background (CMB) polarization over the full sky with unprecedented precision. Its main scientific objective is to carry out a definitive search for the signal from cosmic inflation, either making a discovery or ruling out well-motivated inflationary models. The measurements of LiteBIRD will also provide us with an insight into the quantum nature of gravity and other new physics beyond the standard models of particle physics and cosmology. To this end, LiteBIRD will perform full-sky surveys for three years at the Sun-Earth Lagrangian point L2 for 15 frequency bands between 34 and 448 GHz with three telescopes, to achieve a total sensitivity of 2.16 μK-arcmin with a typical angular resolution of 0.5° at 100 GHz. We provide an overview of the LiteBIRD project, including scientific objectives, mission requirements, top-level system requirements, operation concept, and expected scientific outcomes