Regulation of cell death and epileptogenesis by the mammalian target of rapamycin (mTOR): A double-edged sword?

Identification of cell signaling mechanisms mediating seizure-related neuronal death and epileptogenesis is important for developing more effective therapies for epilepsy. The mammalian target of rapamycin (mTOR) pathway has recently been implicated in regulating neuronal death and epileptogenesis in rodent models of epilepsy. In particular, kainate-induced status epilepticus causes abnormal activation of the mTOR pathway, and the mTOR inhibitor, rapamycin, can decrease the development of neuronal death and chronic seizures in the kainate model. Here, we discuss the significance of these findings and extend them further by identifying upstream signaling pathways through which kainate status epilepticus activates the mTOR pathway and by demonstrating limited situations where rapamycin may paradoxically increase mTOR activation and worsen neuronal death in the kainate model. Thus, the regulation of seizure-induced neuronal death and epileptogenesis by mTOR is complex and may have dual, opposing effects depending on the physiological and pathological context. Overall, these findings have important implications for designing potential neuroprotective and antiepileptogenic therapies that modulate the mTOR pathway

Poly[[aqua­(μ2-oxalato)(μ2-2-oxido­pyridinium-3-carboxylato)holmium(III)] monohydrate]

In the title complex, {[Ho(C2O4)(C6H4NO3)(H2O)]·(H2O)}n, the HoIII ion is coordinated by three O atoms from two 2-oxidopyridinium-3-carboxylate ligands, four O atoms from two oxalate ligands and one water mol­ecule in a distorted bicapped trigonal-prismatic geometry. The 2-oxidopyridin­ium-3-carboxylate and oxalate ligands link the HoIII ions into a layer in (100). These layers are further connected by inter­molecular O—H⋯O hydrogen bonds involving the coordinated water mol­ecules to assemble a three-dimensional supra­molecular network. The uncoordin­ated water mol­ecule is involved in N—H⋯O and O—H⋯O hydrogen bonds within the layer

Poly[bis­(4,4′-bipyridine)(μ3-4,4′-dicarboxybiphenyl-3,3′-di­carboxyl­ato)iron(II)]

In the polymeric title complex, [Fe(C16H8O8)(C10H8N2)2]n, the iron(II) cation is coordinated by four O atoms from three different 4,4′-dicarboxybiphenyl-3,3′-di­carboxyl­ate ligands and two N atoms from two 4,4′-bipyridine ligands in a distorted octa­hedral geometry. The 4,4′-dicarboxybiphenyl-3,3′-di­carboxyl­ate ligands bridge adjacent cations, forming chains parallel to the c axis. The chains are further connected by inter­molecular O—H⋯N hydrogen bonds, forming two-dimensional supra­molecular layers parallel to (010)

Simultaneous and Direct Determination of Vancomycin and Cephalexin in Human Plasma by Using HPLC-DAD Coupled with Second-Order Calibration Algorithms

A simple, rapid, and sensitive method for the simultaneous determination of vancomycin and cephalexin in human plasma was developed by using HPLC-DAD with second-order calibration algorithms. Instead of a completely chromatographic separation, mathematical separation was performed by using two trilinear decomposition algorithms, that is, PARAFAC-alternative least squares (PARAFAC-ALSs) and self-weight-alternative-trilinear-decomposition- (SWATLD-) coupled high-performance liquid chromatography with DAD detection. The average recoveries attained from PARAFAC-ALS and SWATLD with the factor number of 4 (N = 4) were 101 ± 5% and 102 ± 4% for vancomycin, and 96 ± 3% and 97 ± 3% for cephalexininde in real human samples, respectively. The statistical comparison between PARAFAC-ALS and SWATLD is demonstrated to be similar. The results indicated that the combination of HPLC-DAD detection with second-order calibration algorithms is a powerful tool to quantify the analytes of interest from overlapped chromatographic profiles for complex analysis of drugs in plasma

ENAT-PT: An Enhanced NAT-PT Model

NAT-PT would allow IPv4 nodes to communicate with IPv6 nodes transparently by translating the IPv6 address into a registered V4 address. However, NAT-PT would fall flat when the pool of V4 addresses is exhausted. NAPT-PT multiplexes the registered address’ ports and will allow for a maximum of 63K outbound TCP and 63K UDP sessions per IPv4 address, but it is unidirectional. We present in this paper a novel solution ENAT-PT（an enhanced NAT-PT），which will allow for a great number of inbound sessions by using a single V4 address. By using ENAT-PT, we can visit V6 networks from a V4 network with a small address pool

Trade When Opportunity Comes: Price Movement Forecasting via Locality-Aware Attention and Iterative Refinement Labeling

Price movement forecasting aims at predicting the future trends of financial assets based on the current market conditions and other relevant information. Recently, machine learning(ML) methods have become increasingly popular and achieved promising results for price movement forecasting in both academia and industry. Most existing ML solutions formulate the forecasting problem as a classification(to predict the direction) or a regression(to predict the return) problem over the entire set of training data. However, due to the extremely low signal-to-noise ratio and stochastic nature of financial data, good trading opportunities are extremely scarce. As a result, without careful selection of potentially profitable samples, such ML methods are prone to capture the patterns of noises instead of real signals. To address this issue, we propose a novel price movement forecasting framework, called Locality-Aware Attention and Iterative Refinement Labeling(LARA), which consists of two main components: 1)Locality-aware attention automatically extracts the potentially profitable samples by attending to surrounding class-aware label information. Moreover, equipped with metric learning techniques, locality-aware attention enjoys task-specific distance metrics and distributes attention on potentially profitable samples in a more effective way. 2)Iterative refinement labeling further iteratively refines the labels of noisy samples and then combines the learned predictors to be robust to the unseen and noisy samples. In a number of experiments on three real-world financial markets: ETFs, stocks, and cryptocurrencies, LARA achieves superior performance compared with the traditional time-series analysis methods and a set of machine learning based competitors on the Qlib platform. Extensive ablation studies and experiments also demonstrate that LARA indeed captures more reliable trading opportunities

Lamivudine plus adefovir is a good option for chronic hepatitis B patients with viral relapse after cessation of lamivudine treatment

<p>Abstract</p> <p>Aim</p> <p>Currently, there is no consensus on the retreatment recommendation of chronic hepatitis B (CHB) patients with viral rebound after cessation of treatment. In the search of reasonable treatment, we compared the efficacy and safety of adefovir (ADV) plus lamivudine (LAM) and LAM alone for the retreatment of patients with viral relapse but without genotypic resistance after cessation of LAM.</p> <p>Methods</p> <p>This is a prospective controlled study, and a total of 53 hepatitis B e antigen (HBeAg)-positive patients with viral rebound but without resistance were received either LAM plus ADV or LAM alone treatment.</p> <p>Results</p> <p>After 1-year treatment, more patients who received LAM plus ADV than those who received LAM alone had ALT normalization (84% versus 53.6%, P = 0.018) or HBV DNA levels below 1000 copies/mL (80% versus 42.9%, P < 0.006). Seven patients receiving LAM plus ADV had HBeAg seroconversion, as compared with 0 in patients receiving ALM alone (28% versus 0%, P = 0.003). During 1-year retreatment, five patients receiving LAM alone had virological breakthrough and all of them had LAM resistance strains (rtM204V/I), while no LAM- or ADV- associated resistance strains were detected in patients receiving LAM plus ADV. All patients receiving LAM plus ADV were well tolerated, and no serious side effects were noted.</p> <p>Conclusions</p> <p>Patients treated with LAM plus ADV exhibited significantly greater virological, biochemical and serological responses compared with LAM alone. These data suggested that combination of LAM plus ADV would be a good option for the retreatment of CHB patients with viral relapse after cessation of LAM.</p

Cadherin activity is required for activity-induced spine remodeling

Neural activity induces the remodeling of pre- and postsynaptic membranes, which maintain their apposition through cell adhesion molecules. Among them, N-cadherin is redistributed, undergoes activity-dependent conformational changes, and is required for synaptic plasticity. Here, we show that depolarization induces the enlargement of the width of spine head, and that cadherin activity is essential for this synaptic rearrangement. Dendritic spines visualized with green fluorescent protein in hippocampal neurons showed an expansion by the activation of AMPA receptor, so that the synaptic apposition zone may be expanded. N-cadherin-venus fusion protein laterally dispersed along the expanding spine head. Overexpression of dominant-negative forms of N-cadherin resulted in the abrogation of the spine expansion. Inhibition of actin polymerization with cytochalasin D abolished the spine expansion. Together, our data suggest that cadherin-based adhesion machinery coupled with the actin-cytoskeleton is critical for the remodeling of synaptic apposition zone