Composite Optimization Algorithms for Sigmoid Networks

In this paper, we use composite optimization algorithms to solve sigmoid networks. We equivalently transfer the sigmoid networks to a convex composite optimization and propose the composite optimization algorithms based on the linearized proximal algorithms and the alternating direction method of multipliers. Under the assumptions of the weak sharp minima and the regularity condition, the algorithm is guaranteed to converge to a globally optimal solution of the objective function even in the case of non-convex and non-smooth problems. Furthermore, the convergence results can be directly related to the amount of training data and provide a general guide for setting the size of sigmoid networks. Numerical experiments on Franke's function fitting and handwritten digit recognition show that the proposed algorithms perform satisfactorily and robustly

Back Attention Knowledge Transfer for Low-Resource Named Entity Recognition

In recent years, great success has been achieved in the field of natural language processing (NLP), thanks in part to the considerable amount of annotated resources. For named entity recognition (NER), most languages do not have such an abundance of labeled data as English, so the performances of those languages are relatively lower. To improve the performance, we propose a general approach called Back Attention Network (BAN). BAN uses a translation system to translate other language sentences into English and then applies a new mechanism named back attention knowledge transfer to obtain task-specific information from pre-trained high-resource languages NER model. This strategy can transfer high-layer features of well-trained model and enrich the semantic representations of the original language. Experiments on three different language datasets indicate that the proposed approach outperforms other state-of-the-art methods

Structure-based design, synthesis and characterization of the first irreversible inhibitor of Focal Adhesion Kinase

Focal Adhesion Kinase signaling pathway and its functions have been involved in the development and aggressiveness of tumor malignancy, it then presents a promising cancer therapeutic target. Several reversible FAK inhibitors have been developed and are being conducted in clinical trials. On the other hand, irreversible covalent inhibitors would bring many desirable pharmacological features including high potency and increased duration of action. Herein we report the structure-guided development of the first highly potent and irreversible inhibitor of the FAK kinase. This inhibitor showed a very potent decrease of autophosphorylation of FAK in squamous cell carcinoma. A cocrystal structure of the FAK kinase domain in complex with this compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor

Transforming growth factor-β1 protects mechanically injured cortical murine neurons by reducing trauma-induced autophagy and apoptosis

Transforming growth factor β1 (TGF-β1) has a neuroprotective function in traumatic brain injury (TBI) through its anti-inflammatory and immunomodulatory properties. However, the precise mechanisms underlying the neuroprotective actions of TGF-β1 on the cortex require further investigation. In this study, we were aimed to investigate the regulatory function of TGF-β1 on neuronal autophagy and apoptosis using an in vitro primary cortical neuron trauma-injury model. LDH activity was assayed to measure cell viability, and intracellular [Ca2+] was measured using Fluo-4-AM in an in vitro primary cortical neuron trauma-injury model. RNA-sequencing (RNAseq), immunofluorescent staining, transmission electron microscopy (TEM), western blot and CTSD activity detection were employed. We observed significant enrichment of DEGs related to autophagy, apoptosis, and the lysosome pathway in trauma-injured cortical neurons. TEM confirmed the presence of autophagosomes as well as autophagolysosomes. Western blot revealed upregulation of autophagy-related protein light chain 3 (LC3-II/LC3-I), sequestosome 1 (SQSTM1/p62), along with apoptosis-related protein cleaved-caspase 3 in trauma-injured primary cortical neurons. Furthermore, trauma-injured cortical neurons showed an upregulation of lysosomal marker protein (LAMP1) and lysosomal enzyme mature cathepsin D (mCTSD), but a decrease in the activity of CTSD enzyme. These results indicated that apoptosis was up-regulated in trauma- injured cortical neurons at 24 h, accompanied by lysosomal dysfunction and impaired autophagic flux. Notably, TGF-β1 significantly reversed these changes. Our results suggested that TGF-β1 exerted neuroprotective effects on trauma- injured cortical neurons by reducing lysosomal dysfunction, decreasing the accumulation of autophagosomes and autophagolysosomes, and enhancing autophagic flux

Synthèse d'inhibiteurs mixtes des enzymes impliquées dans la dégradation des enképhalines

PARIS-BIUP (751062107) / SudocSudocFranceF

Synthesis of 2(S)-benzyl-3-[hydroxy(1?(R)-amino ethyl)phosphinyl]propanoyl-L-3-[125I]-iodotyrosine: a radiolabelled inhibitor of aminopeptidase N

International audience2(S)‐benzyl‐3‐[hydroxy(1′(R)‐aminoethyl)phosphinyl]propanoyl‐L‐3‐[125I]‐iodo tyrosine was prepared from 1(R)‐(N‐benzyloxycarbonylamino)ethylphosphinic acid in a six step synthesis. This new iodinated compound, which is a highly efficient aminopeptidase N inhibitor (Ki=0·95 nM), can be used for complete characterization of the biochemical and pharmacological properties of aminopeptidase N and its in vivo inhibition. A high radiochemical purity was obtained with a specific activity of 217 Ci/mmol at the end of the synthesis. Copyright © 2000 John Wiley & Sons, Ltd

Ultrasound-Mediated Cavitation Enhances EGFR-Targeting PLGA-PEG Nano-Micelle Delivery for Triple-Negative Breast Cancer Treatment

Triple-negative breast cancer (TNBC) is highly recurring and metastatic breast cancer with overexpressing epidermal growth factor receptor (EGFR). Herein, a series of in vitro and in vivo analyses were used to explore the therapeutic effect of EGFR-targeting nano-micelles (PLGA-PEG/DOX@anti-EGFR) combined with ultrasound-mediated cavitation (UMC). The prepared nano-micelle drug carriers have good biocompatibility and can greatly increase the drug accumulation in tumor regions, thereby reducing off-target toxicity while enhancing anti-tumor efficacy. Moreover, an in vivo analysis of the practical utility of this treatment modality was conducted by using SonoVueTM microbubbles to achieve cavitation under different power intensity levels, with an ultrasonic power intensity of 0.5 W/cm2 maximizing the intra-tumoral blood perfusion. Relative to PLGA-PEG@DOX/anti-EGFR nano-micelles treatment alone, the combination with UMC was better able to suppress tumor growth even at low concentrations. As such, combining actively targeted drug-carrier molecules with UMC represents an effective approach to enhancing therapeutic efficacy while reducing the adverse, systemic effects associated with DOX and other chemotherapeutic drugs, and it can be considered as a promising clinical prospect in the treatment of TNBC

Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11

International audienceTumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zinc metallopeptidases involved in the inactivation of the opioid peptides enkephalins, produces potent physiological analgesic responses, without major side-effects, in all animal models of pain in which morphine is active. Dual inhibitors of both enzymes could fill the gap between opioid analgesics and antalgics. Until now, attempts to find a compound with high affinity both for neutral endopeptidase and aminopeptidase N have failed. We report here the design of dual competitive inhibitors of both enzymes with K(I) values in the nanomolar range. These have been obtained by selecting R(1), R(2,) and R(3) determinants in aminophosphinic-containing inhibitors: NH(2)—CH(R(1))P(O)—(OH)CH(2)—CH(R(2))CONH—CH(R(3))COOH, for optimal recognition of the two enkephalin inactivating enzymes, whose active site peculiarities, determined by site-directed mutagenesis, have been taken into account. The best inhibitors were 10× more potent than described dual inhibitors in alleviating acute and inflammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effects