Phosphorylation of LCRMP-1 by GSK3β Promotes Filopoda Formation, Migration and Invasion Abilities in Lung Cancer Cells

LCRMP-1, a novel isoform of CRMP-1, can promote cancer cell migration, invasion and associate with poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). However, the underlying regulatory mechanisms of LCRMP-1 in cancer cell invasiveness still remain obscure. Here, we report that GSK3β can phosphorylate LCRMP-1 at Thr-628 in consensus sequences and this phosphorylation is crucial for function of LCRMP-1 to promote filopodia formation, migration and invasion in cancer cells. Impediment of Thr-628 phosphorylation attenuates the stimulatory effects of LCRMP-1 on filopodia forming, migration and invasion abilities in cancer cells; simultaneously, kinase-dead GSK3β diminishes regulation of LCRMP-1 on cancer cell invasion. Furthermore, we also found that patients with low-level Ser-9-phosphorylated GSK3β expression and high-level LCRMP-1 expression have worse overall survival than those with high-level inactive GSK3β expressions and low-level LCRMP-1 expressions (P<0.0001). Collectively, these results demonstrate that GSK3β-dependent phosphorylation of LCRMP-1 provides an important mechanism for regulation of LCRMP-1 on cancer cell invasiveness and clinical outcome

SLC37A1 and SLC37A2 Are Phosphate-Linked, Glucose-6-Phosphate Antiporters

Blood glucose homeostasis between meals depends upon production of glucose within the endoplasmic reticulum (ER) of the liver and kidney by hydrolysis of glucose-6-phosphate (G6P) into glucose and phosphate (Pi). This reaction depends on coupling the G6P transporter (G6PT) with glucose-6-phosphatase-α (G6Pase-α). Only one G6PT, also known as SLC37A4, has been characterized, and it acts as a Pi-linked G6P antiporter. The other three SLC37 family members, predicted to be sugar-phosphate:Pi exchangers, have not been characterized functionally. Using reconstituted proteoliposomes, we examine the antiporter activity of the other SLC37 members along with their ability to couple with G6Pase-α. G6PT- and mock-proteoliposomes are used as positive and negative controls, respectively. We show that SLC37A1 and SLC37A2 are ER-associated, Pi-linked antiporters, that can transport G6P. Unlike G6PT, neither is sensitive to chlorogenic acid, a competitive inhibitor of physiological ER G6P transport, and neither couples to G6Pase-α. We conclude that three of the four SLC37 family members are functional sugar-phosphate antiporters. However, only G6PT/SLC37A4 matches the characteristics of the physiological ER G6P transporter, suggesting the other SLC37 proteins have roles independent of blood glucose homeostasis

Strontium potently inhibits mineralisation in bone-forming primary rat osteoblast cultures and reduces numbers of osteoclasts in mouse marrow cultures

The basic mechanisms by which strontium ranelate acts on bone are still unclear. We show that an important action of strontium salts is to block calcification in cultures of osteoblasts, the bone-forming cells. These results suggest that strontium treatment could have previously overlooked effects on bone

Signal Transduction Pathways in the Pentameric Ligand-Gated Ion Channels

The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the β1-β2 loop or through pre-TM1. The β1-β2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs. © 2013 Mowrey et al

Different atmospheric moisture divergence responses to extreme and moderate El Niños

On seasonal and inter-annual time scales, vertically integrated moisture divergence provides a useful measure of the tropical atmospheric hydrological cycle. It reflects the combined dynamical and thermodynamical effects, and is not subject to the limitations that afflict observations of evaporation minus precipitation. An empirical orthogonal function (EOF) analysis of the tropical Pacific moisture divergence fields calculated from the ERA-Interim reanalysis reveals the dominant effects of the El Niño-Southern Oscillation (ENSO) on inter-annual time scales. Two EOFs are necessary to capture the ENSO signature, and regression relationships between their Principal Components and indices of equatorial Pacific sea surface temperature (SST) demonstrate that the transition from strong La Niña through to extreme El Niño events is not a linear one. The largest deviation from linearity is for the strongest El Niños, and we interpret that this arises at least partly because the EOF analysis cannot easily separate different patterns of responses that are not orthogonal to each other. To overcome the orthogonality constraints, a self-organizing map (SOM) analysis of the same moisture divergence fields was performed. The SOM analysis captures the range of responses to ENSO, including the distinction between the moderate and strong El Niños identified by the EOF analysis. The work demonstrates the potential for the application of SOM to large scale climatic analysis, by virtue of its easier interpretation, relaxation of orthogonality constraints and its versatility for serving as an alternative classification method. Both the EOF and SOM analyses suggest a classification of “moderate” and “extreme” El Niños by their differences in the magnitudes of the hydrological cycle responses, spatial patterns and evolutionary paths. Classification from the moisture divergence point of view shows consistency with results based on other physical variables such as SST

Ipl1/aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis

Cells coordinate spindle formation with DNA repair and morphological modifications to chromosomes prior to their segregation to prevent cell division with damaged chromosomes. Here we uncover a novel and unexpected role for Aurora kinase in preventing the formation of spindles by Clb5-CDK (S-CDK) during meiotic prophase I and when the DDR is active in budding yeast. This is critical since S-CDK is essential for replication during premeiotic S-phase as well as double-strand break induction that facilitates meiotic recombination and, ultimately, chromosome segregation. Furthermore, we find that depletion of Cdc5 polo kinase activity delays spindle formation in DDR-arrested cells and that ectopic expression of Cdc5 in prophase I enhances spindle formation, when Ipl1 is depleted. Our findings establish a new paradigm for Aurora kinase function in both negative and positive regulation of spindle dynamics

Prevalence and risk factors for esophageal squamous cell cancer and precursor lesions in Anyang, China: a population-based endoscopic survey

BACKGROUND: The etiology of esophageal squamous cell cancer (ESCC) in high prevalence regions of China remains unclear. METHODS: Endoscopic biopsies were conducted among 7381 inhabitants aged from 25 to 65 of Anyang, China. RESULTS: In this study, 2.57, 0.20 and 0.16% of the participants had mild, moderate and severe squamous dysplasia, respectively; 0.19 and 0.08% showed squamous carcinoma in situ and invasive ESCC. Using deep well (depth &gt;100 meters) as water source (odds ratio = 0.72, 95% confidence interval: 0.54-0.96) was negatively associated with ESCC and its precursors, whereas tobacco and alcohol use were not significantly associated with ESCC. CONCLUSIONS: Water source and other factors in this region need further evaluation by longitudinal studies. British Journal of Cancer (2010) 103, 1085-1088. doi:10.1038/sj.bjc.6605843 www.bjcancer.com Published online 10 August 2010 (C) 2010 Cancer Research UKOncologySCI(E)PubMed19ARTICLE71085-108810

The Physical Drivers and Observational Tracers of CO-to-H2 Conversion Factor Variations in Nearby Barred Galaxy Centers

The CO-to-H-2 conversion factor (alpha CO) is central to measuring the amount and properties of molecular gas. It is known to vary with environmental conditions, and previous studies have revealed lower alpha CO in the centers of some barred galaxies on kiloparsec scales. To unveil the physical drivers of such variations, we obtained Atacama Large Millimeter/submillimeter Array bands (3), (6), and (7) observations toward the inner similar to 2 kpc of NGC 3627 and NGC 4321 tracing (CO)-C-12, (CO)-C-13, and (CO)-O-18 lines on similar to 100 pc scales. Our multiline modeling and Bayesian likelihood analysis of these data sets reveal variations of molecular gas density, temperature, optical depth, and velocity dispersion, which are among the key drivers of aCO. The central 300 pc nuclei in both galaxies show strong enhancement of temperature Tk greater than or similar to 100 K and density n(H2) &gt; 10(3) cm(-3). Assuming a CO-to-H-2 abundance of 3 x 10(-4), we derive 4-15 times lower alpha(CO) than the Galactic value across our maps, which agrees well with previous kiloparsec-scale measurements. Combining the results with our previous work on NGC 3351, we find a strong correlation of alpha(CO) with low-J (CO)-C-12 optical depths (tau(CO)), as well as an anticorrelation with Tk. The tCO correlation explains most of the aCO variation in the three galaxy centers, whereas changes in T-k influence alpha(CO) to second order. Overall, the observed line width and (CO)-C-12/(CO)-C-13 2-1 line ratio correlate with tCO variation in these centers, and thus they are useful observational indicators for alpha(CO) variation. We also test current simulation-based alpha(CO) prescriptions and find a systematic overprediction, which likely originates from the mismatch of gas conditions between our data and the simulations

SV-IV Peptide1–16 reduces coagulant power in normal Factor V and Factor V Leiden

Native Factor V is an anticoagulant, but when activated by thrombin, Factor X or platelet proteases, it becomes a procoagulant. Due to these double properties, Factor V plays a crucial role in the regulation of coagulation/anticoagulation balance

ANMM4CBR: a case-based reasoning method for gene expression data classification

<p>Abstract</p> <p>Background</p> <p>Accurate classification of microarray data is critical for successful clinical diagnosis and treatment. The "curse of dimensionality" problem and noise in the data, however, undermines the performance of many algorithms.</p> <p>Method</p> <p>In order to obtain a robust classifier, a novel Additive Nonparametric Margin Maximum for Case-Based Reasoning (ANMM4CBR) method is proposed in this article. ANMM4CBR employs a case-based reasoning (CBR) method for classification. CBR is a suitable paradigm for microarray analysis, where the rules that define the domain knowledge are difficult to obtain because usually only a small number of training samples are available. Moreover, in order to select the most informative genes, we propose to perform feature selection via additively optimizing a nonparametric margin maximum criterion, which is defined based on gene pre-selection and sample clustering. Our feature selection method is very robust to noise in the data.</p> <p>Results</p> <p>The effectiveness of our method is demonstrated on both simulated and real data sets. We show that the ANMM4CBR method performs better than some state-of-the-art methods such as support vector machine (SVM) and <it>k </it>nearest neighbor (<it>k</it>NN), especially when the data contains a high level of noise.</p> <p>Availability</p> <p>The source code is attached as an additional file of this paper.</p