Phosphatidylinositol 3-Kinase/AKT pathway regulates the endoplasmic reticulum to Golgi traffic of ceramide in glioma cells : a link between lipid signaling pathways involved in the control of cell survival

Different lines of evidence indicate that both aberrant activation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt survival pathway and down-regulation of the death mediator ceramide play a critical role in the aggressive behavior, apoptosis resistance, and adverse clinical outcome of glioblastoma multiforme. Furthermore, the inhibition of the PI3K/Akt pathway and the up-regulation of ceramide have been found functional to the activity of many cytotoxic treatments against glioma cell lines and glioblastomas as well. A reciprocal control between PI3K/Akt and ceramide signaling in glioma cell survival/death is suggested by data demonstrating a protective role of PI3K/Akt on ceramide-induced cell death in glial cells. In this study we investigated the role of the PI3K/Akt pathway in the regulation of the ceramide metabolism in C6 glioma cells, a cell line in which the PI3K/Akt pathway is constitutively activated. Metabolic experiments performed with different radioactive metabolic precursors of sphingolipids and microscopy studies with fluorescent ceramides demonstrated that the chemical inhibition of PI3K and the transfection with a dominant negative Akt strongly inhibited ceramide utilization for the biosynthesis of complex sphingolipids by controlling the endoplasmic reticulum (ER) to Golgi vesicular transport of ceramide. These findings constitute the first evidence for a PI3K/Akt-dependent regulation of vesicle-mediated movements of ceramide in the ER-Golgi district. Moreover, the findings also suggest the activation of the PI3K/Akt pathway as crucial to coordinate the biosynthesis of membrane complex sphingolipids with cell proliferation and growth and/or to maintain low ceramide levels, especially as concerns those treatments that promote ceramide biosynthesis in the ER

Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines

AR056280 awarded to DAB and AL. AIHC supported by IMS and Elphinstone Scholarship from the University of Aberdeen. GRV supported by Medical Research Scotland (Vac-929-2016).Peer reviewedPublisher PD

Aluminum alloy production for the reinforcement of the CMS conductor

The Compact Muon Solenoid (CMS) is one of the general-purpose detectors to be provided for the Large Hadron Collider (LHC) project at CERN. The design field of the CMS superconducting magnet is 4 T, the magnetic length is 12.5 m and the free bore is 6 m. To reinforce the high-purity (99.998%) Al-stabilized conductor of the magnet against the magnetic loadings experienced during operation at 4.2 K, two continuous sections of Al-alloy (AA) reinforcement are Electron Beam (EB) welded to it. The reinforcements have a section of 24*18 mm and are produced in continuous 2.55 km lengths. The alloy EN AW-6082 has been selected for the reinforcement due to its excellent extrudability, high strength in the precipitation hardened states, high toughness and strength at cryogenic temperature and good EB weldability. Each of the continuous lengths of the reinforcement is extruded billet on billet and press quenched on-line from the extrusion temperature in an industrial extrusion plant. In order to insure the ready EB weldability of the reinforcement onto the pure aluminum of the insert, tight dimensional tolerances and proper surface finish of the reinforcement are required in the as-extruded state. As well, in order to facilitate the winding operation of the conductor, the uniformity of the mechanical properties of the extruded reinforcement, especially at the billet on billet joints, is critical. To achieve these requirements in an industrial environment, substantial effort was made to refine existing production techniques and to monitor critical extrusion parameters during production. This paper summarizes the main results obtained during the establishment of the extrusion line and of the production phase of the reinforcement. (10 refs)

Sphingolipids : key regulators of apoptosis and pivotal players in cancer drug resistance

Drug resistance elicited by cancer cells still constitutes a huge problem that frequently impairs the efficacy of both conventional and novel molecular therapies. Chemotherapy usually acts to induce apoptosis in cancer cells; therefore, the investigation of apoptosis control and of the mechanisms used by cancer cells to evade apoptosis could be translated in an improvement of therapies. Among many tools acquired by cancer cells to this end, the de-regulated synthesis and metabolism of sphingolipids have been well documented. Sphingolipids are known to play many structural and signalling roles in cells, as they are involved in the control of growth, survival, adhesion, and motility. In particular, in order to increase survival, cancer cells: (a) counteract the accumulation of ceramide that is endowed with pro-apoptotic potential and is induced by many drugs; (b) increase the synthesis of sphingosine-1-phosphate and glucosylceramide that are pro-survivals signals; (c) modify the synthesis and the metabolism of complex glycosphingolipids, particularly increasing the levels of modified species of gangliosides such as 9-O acetylated GD3 (\u3b1Neu5Ac(2-8)\u3b1Neu5Ac(2-3)\u3b2Gal(1-4)\u3b2Glc(1-1)Cer) or N-glycolyl GM3 (\u3b1Neu5Ac (2-3)\u3b2Gal(1-4)\u3b2Glc(1-1)Cer) and de-N-acetyl GM3 (NeuNH(2)\u3b2Gal(1-4)\u3b2Glc(1-1)Cer) endowed with anti-apoptotic roles and of globoside Gb3 related to a higher expression of the multidrug resistance gene MDR1. In light of this evidence, the employment of chemical or genetic approaches specifically targeting sphingolipid dysregulations appears a promising tool for the improvement of current chemotherapy efficacy

Pessimistic Rescaling and Distribution Shift of Boosting Models for Impression-Aware Online Advertising Recommendation

In this paper, we provide an overview of the approach we used as team Gabibboost for the ACM RecSys Challenge 2023, organized by ShareChat and Moj. The challenge focused on predicting user activity in the online advertising setting based on impression data, in particular, predicting whether a user would install an advertised application using a high-dimensional anonymized feature vector. Our proposed solution is based on an ensemble model that combines the strengths of several machine learning sub-models, including CatBoost, LightGBM, HistGradientBoosting, and two hybrid models. Our proposal is able to harness the strengths of our models through a distribution shift postprocessing and fine-Tune the final prediction via a custom build pessimistic rescaling function. The final ensemble model allowed us to rank 1st on the academic leaderboard and 9th overall

Photoprotection in intact cells of photosynthetic bacteria: quenching of bacteriochlorophyll fluorescence by carotenoid triplets.

Upon high light excitation in photosynthetic bacteria, various triplet states of pigments can accumulate leading to harmful effects. Here, the generation and lifetime of flash-induced carotenoid triplets (3Car) have been studied by observation of the quenching of bacteriochlorophyll (BChl) fluorescence in different strains of photosynthetic bacteria including Rvx. gelatinosus (anaerobic and semianaerobic), Rsp. rubrum, Thio. roseopersicina, Rba. sphaeroides 2.4.1 and carotenoid- and cytochrome-deficient mutants Rba. sphaeroides Ga, R-26, and cycA, respectively. The following results were obtained: (1) 3Car quenching is observed during and not exclusively after the photochemical rise of the fluorescence yield of BChl indicating that the charge separation in the reaction center (RC) and the carotenoid triplet formation are not consecutive but parallel processes. (2) The photoprotective function of 3Car is not limited to the RC only and can be described by a model in which the carotenoids are distributed in the lake of the BChl pigments. (3) The observed lifetime of 3Car in intact cells is the weighted average of the lifetimes of the carotenoids with various numbers of conjugated double bonds in the bacterial strain. (4) The lifetime of 3Car measured in the light is significantly shorter (1-2 mus) than that measured in the dark (2-10 mus). The difference reveals the importance of the dynamics of 3Car before relaxation. The results will be discussed not only in terms of energy levels of the 3Car but also in terms of the kinetics of transitions among different sublevels in the excited triplet state of the carotenoid

Continuous EB welding of the reinforcement of the CMS conductor

The Compact Muon Solenoid (CMS) is one of the general-purpose detectors to be provided for the LHC project at CERN. The design field of the CMS superconducting magnet is 4 T, the magnetic length is 12.5 m and the free bore is 6 m. In order to withstand the electro-mechanical forces during the operation of the CMS magnet, the superconducting cable embedded in a 99.998% pure aluminum matrix is reinforced with two sections of aluminum alloy EN AW-6082 assembled by continuous Electron Beam Welding (EBW). A dedicated production line has been designed by Techmeta, a leading company in the field of EBW. The production line has a total length of 70 m. Non-stop welding of each of the 20 lengths of 2.5 km, required to build the coil, will last 22 hours. EBW is the most critical process involved in the production line. The main advantage of the EBW process is to minimize the Heat Affected Zone; this is particularly important for avoiding damage to the superconducting cable located only 4.7 mm from the welded joints. Two welding guns of 20 kW each operate in parallel in a vacuum chamber fitted with dynamic airlocks. After welding, the conductor is continuously machined on the four faces and on each corner to obtain the required dimensions and surface finish. Special emphasis has been put on quality monitoring. All significant production parameters are recorded during operation and relevant samples are taken from each produced length for destructive testing purposes. In addition, a continuous phased array ultrasonic checking device is located immediately after the welding unit for the continuous welding quality control, along with a dimension laser measurement unit following the machining. (8 refs)

The CMS conductor

The Compact Muon Solenoid (CMS) is one of the experiments, which are being designed in the framework of the Large Hadron Collider (LHC) project at CERN, the design field of the CMS magnet is 4 T, the magnetic length is 13 m and the aperture is 6 m. This high magnetic field is achieved by means of a 4 layer, 5 modules superconducting coil. The coil is wound from an Al-stabilized Rutherford type conductor. The nominal current of the magnet is 20 kA at 4.5 K. In the CMS coil the structural function is ensured, unlike in other existing Al-stabilized thin solenoids, both by the Al-alloy reinforced conductor and the external former. In this paper the retained manufacturing process of the 50-km long reinforced conductor is described. In general the Rutherford type cable is surrounded by high purity aluminium in a continuous co-extrusion process to produce the Insert. Thereafter the reinforcement is joined by Electron Beam Welding to the pure Al of the insert, before being machined to the final dimensions. During the manufacture the bond quality between the Rutherford cable and the high purity aluminium as well as the quality of the EB welding are continuously controlled by a novel ultrasonic phased array system. The dimensions of the insert and the final conductor are measured by laser micrometer. (8 refs)

Chemometric-assisted cocrystallization: Supervised pattern recognition for predicting the formation of new functional cocrystals

Owing to the antimicrobial and insecticide properties, the use of natural compounds like essential oils and their active components has proven to be an effective alternative to synthetic chemicals in different fields ranging from drug delivery to agriculture and from nutrition to food preservation. Their limited application due to the high volatility and scarce water solubility can be expanded by using crystal engineering approaches to tune some properties of the active molecule by combining it with a suitable partner molecule (coformer). However, the selection of coformers and the experimental effort required for discovering cocrystals are the bottleneck of cocrystal engineering. This study explores the use of chemometrics to aid the discovery of cocrystals of active ingredients suitable for various applications. Partial Least Squares–Discriminant Analysis is used to discern cocrystals from binary mixtures based on the molecular features of the coformers. For the first time, by including failed cocrystallization data and considering a variety of chemically diverse compounds, the proposed method resulted in a successful prediction rate of 85% for the test set in the model validation phase and of 74% for the external test set