The tyrosine kinase inhibitor Gefitinib reduces stress-induced sleep, but not likely via LET-23/EGFR inhibition.

The anticancer drug Gefitinib is a tyrosine kinase inhibitor with selectivity for the Epidermal Growth Factor Receptor (EGFR/ErbB1). As the EGF receptor LET-23 shares notable structural homology over its kinase domain with human EGFR, we wished to examine whether Gefitinib treatment can interfere with LET-23-dependent processes. We show that Gefitinib disrupts stress-induced sleep (SIS) but does not impact EGF overexpression-induced sleep nor vulva induction.

Elucidating the Temporal Patterns of Gene Expression in the Inferred Regulatory Interactions of in .

The ( ) gene in has a central role in photoperiodic regulation of flowering. However, the roles of genes in mediating flowering in soybeans ( ) remain uncertain. We previously inferred regulatory interactions of a soybean homolog, , using in-house RNA-seq data and the network inference algorithm package CausNet.

Clarifying the Temporal Dynamics of the Circadian Clock and Flowering Gene Network Using Overexpression and Targeted Mutagenesis of Soybean ( ).

With progressing climate fluctuations, an understanding of the molecular mechanisms of crop plants that regulate their flowering responses to environments is crucial. To achieve this goal, we aimed at clarifying the gene regulatory networks among the circadian clock and flowering genes in soybean ( ). Based on our network inference approach we hypothesize that , one of the Evening Complex (EC) gene homologs in soybean's circadian clock, may have an integrative role in transcriptional regulation of the circadian clock and flowering gene network.

Clinical validation of automated hippocampal segmentation in temporal lobe epilepsy.

Objective: To provide a multi-atlas framework for automated hippocampus segmentation in temporal lobe epilepsy (TLE) and clinically validate the results with respect to surgical lateralization and post-surgical outcome.

Methods: We retrospectively identified 47 TLE patients who underwent surgical resection and 12 healthy controls. T1-weighted 3 T MRI scans were acquired for all subjects, and patients were identified by a neuroradiologist with regards to lateralization and degree of hippocampal sclerosis (HS).

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy.

Objective: Temporal lobe epilepsy (TLE) is a chronic epilepsy syndrome defined by seizures and progressive neurological disabilities, including cognitive impairments, anxiety, and depression. Here, human TLE specimens were investigated focusing on the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and complex 2 (mTORC2) activities in the brain, given that both pathways may represent unique targets for treatment.

Methods: Surgically resected hippocampal and temporal lobe samples from therapy-resistant TLE patients were analyzed by western blotting to quantify the expression of established mTORC1 and mTORC2 activity markers and upstream or downstream signaling pathways involving the two complexes.

Advanced structural multimodal imaging of a patient with subcortical band heterotopia.

Subcortical band heterotopia (SBH) is a disorder of neuronal migration most commonly due to mutations of the gene. A range of phenotypes is seen, with most patients having some degree of epilepsy and intellectual disability. Advanced diffusion and structural magnetic resonance imaging (MRI) sequences may be useful in identifying heterotopias and dysplasias of different sizes in drug-resistant epilepsy.

Animal Models of Psychosis: Current State and Future Directions.

Psychosis is an abnormal mental state characterized by disorganization, delusions and hallucinations. Animal models have become an increasingly important research tool in the effort to understand both the underlying pathophysiology and treatment of psychosis. There are multiple animal models for psychosis, with each formed by the coupling of a manipulation and a measurement.

Interactions between phytase and xylanase enzymes in male broiler chicks fed phosphorus-deficient diets from 1 to 18 days of age.

A total of 735 one-day-old male broiler chicks were used to evaluate the interactions between different levels of phytase and xylanase enzymes on performance and bone mineralization. Basal nonphytate P (nPP)-deficient diets (0.15%) were supplemented with different levels of phytase [0X, 1X, 2X, 3X, and 4X of recommended level (X = 500 phytase units per kg of feed)] alone or in combination with 3 levels of a xylanase preparation [0X, 1X, and 2X of recommended level (X = 0.

Effect of the potent antiviral 1-cinnamoyl-3,11-dihydroxymeliacarpin on cytokine production by murine macrophages stimulated with HSV-2.

The limonoid 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM) isolated from leaf extracts of Melia azedarach L, has potent antiherpetic effect in epithelial cells. Since Meliacine, the partially purified extract source of CDM, has therapeutic effect on murine genital herpes, the potential use of CDM as microbicide against herpetic infections was studied here. To determine the cytotoxic effect of CDM, the MTT assay and acridine orange staining of living cells were performed.

Assessment of potential enhancing effects of a carbohydrase mixture on phytase efficacy in male broiler chicks fed phosphorus-deficient diets from 1 to 18 days of age.

A total of 540 one-day-old male broiler chicks were used to evaluate the potential enhancing effects of a mixture of 2 commercial carbohydrase preparations on phytase efficacy. A nonphytate phosphorus (nPP) deficient diet (0.15%) was supplemented with different levels of phytase (0X, 1X, 2X, and 3X of recommended level of 500 phytase units per kg of feed), individually or in combination with different levels of a mixture of 2 commercial carbohydrase enzymes [0X, 1X, and 2X of recommended level (X = 0.

Plant and animal steroids a new hope to search for antiviral agents.

Scientific literature provides evidence about the use of steroids as an adjunct treatment to antiviral therapies. Immunomodulatory activity of some steroids would account for the recovery in patients with herpetic and other viral infections. However, in vitro studies have demonstrated a direct antiviral effect of this kind of molecules.

High-frequency oscillation and surfactant treatment in an acid aspiration model.

Both exogenous surfactant therapy and high-frequency oscillation (HFO) have been proposed as clinical interventions in acute respiratory distress syndrome (ARDS). The combination of these 2 interventions has not been studied in a relevant model of ARDS. It was hypothesized that surfactant treatment combined with HFO is superior to either surfactant treatment or HFO alone in a model of ARDS.

Therapeutic effect of meliacine, an antiviral derived from Melia azedarach L., in mice genital herpetic infection.

Since natural products are considered powerful sources of novel drug discovery, a partially purified extract (meliacine) from the leaves of Melia azedarach L., a plant used in traditional medicine in India for the treatment of several diseases, has been studied. Meliacine exhibits a potent antiviral effect against several viruses without displaying cytotoxicity.

Antiviral effect of a synthetic brassinosteroid on the replication of vesicular stomatitis virus in Vero cells.

The antiviral mode of action of the synthetic brassinosteroid (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one (6b) against replication of vesicular stomatitis virus (VSV) in Vero cells was investigated. Time-related experiments showed that 6b mainly affects a late event of the virus growth cycle. Virus adsorption, internalisation and early RNA synthesis are not the target of the inhibitory action.

The synergistic effect of IFN-alpha and IFN-gamma against HSV-2 replication in Vero cells is not interfered by the plant antiviral 1-cinnamoyl-3, 11-dihydroxymeliacarpin.

Background: Recent studies have shown that gamma interferon (IFN-gamma) synergizes with IFN-alpha/beta to inhibit herpes simplex virus type 1 (HSV-1) replication in vitro. Since IFN response represents an early host defense event against viral infection and the fact that treatment with meliacine, a plant antiviral, ameliorate the severity of the herpetic infection in female mice infected intravaginally with HSV-2, we wanted to investigate whether the administration of meliacine to HSV-2 infected mice could altered the homoestasis of IFNs host response. For this purpose we studied the effect of the compound 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), which is the responsible for meliacine antiviral action, on the HSV-2 inhibition exerted by IFN alpha, IFN-gamma or their combination.

Antiviral mode of action of a synthetic brassinosteroid against Junin virus replication.

The antiviral mode of action of the synthetic brassinosteroid (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one (6b) against Junin virus replication in Vero cells was investigated. Time-related experiments showed that 6b mainly affects an early event of virus growth cycle. Neither adsorption nor internalization of viral particles was the target of the inhibitory action.

The Pediatric Rheumatology International Trials Organization criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: prospective validation of the disease activity core set.

Objective: To validate and promulgate a core set of outcome measures for the evaluation of response to treatment in patients with juvenile systemic lupus erythematosus (SLE).

Methods: In 2001, a preliminary consensus-derived core set of measures for evaluating the response to therapy in juvenile SLE was established. In the present study, the core set was validated through an evidence-based, large-scale data collection process that led to the enrollment of 557 patients from 39 different countries.

Antiherpetic mode of action of (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one in vitro.

The replication of herpes simplex virus (HSV) type 1 in Vero cells is inhibited in the presence of (22S,23S)-3beta-bromo-5alpha,22,23-trihydroxystigmastan-6-one (6b), a synthetic brassinosteroid derivative. Attempts to disclose the mode of action of 6b indicate that a late step of virus multiplication is affected. In the presence of 6b, HSV late protein synthesis was severely diminished and this inhibitory effect of 6b on HSV antigen expression was confirmed by immunofluorescence assays.

Block of vesicular stomatitis virus endocytic and exocytic pathways by 1-cinnamoyl-3,11-dihydroxymeliacarpin, a tetranortriterpenoid of natural origin.

Previously, it has been shown that 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM), a natural compound isolated from leaf extracts of Melia azedarach L., inhibits the vesicular stomatitis virus (VSV) multiplication cycle when added before or after infection. Here, we have established that the lack of VSV protein synthesis in CDM pre-treated Vero cells is ascribed to the inhibition of an initial step during virus multiplication, although indirect immunofluorescence (IFI) studies confirmed that the binding and uptake of [(35)S]methionine-labelled VSV was not affected by CDM pre-treatment.

Antiherpes virus activities of new 6-19 carbon-bridged steroids and some synthetic precursors.

Three synthetic 6,19-carbon bridged steroids: 3beta,20beta-diacetyloxy-5alpha-chloro-19a(R)-hydroxy-6,19-methanopregnane, 3beta,20beta-diacetyloxy-5alpha-chloro-6,19-methanopregnane, 6,19-methanopregn-4-ene-3,20-dione and four synthetic precursors: 3beta,20beta-diacetyloxy-19-hydroxypregn-5-ene, 3beta,20beta-diacetyloxy-pregn-5-en-19-al, 3beta,20beta-diacetyloxy-19(E)-(methoxymethylidene)-pregn-5-ene and 20beta-acetyloxy-3beta-hydroxy-19(E)-(methoxymethylidene)-pregn-5-ene were tested against herpes virus replication in cell cultures. Several compounds were cytotoxic for stationary cells. Antiviral studies performed with all compounds against HSV-1 indicated a dose-dependent virus susceptibility with selectivity indexes (SI) values in the range 1.

Enterocin CRL35 inhibits late stages of HSV-1 and HSV-2 replication in vitro.

The replication of herpes simplex virus (HSV) type 1 and 2 in Vero cells is inhibited in the presence of enterocin CRL35 (ECRL), a bacteriocin produced by Enterococcus faecium CRL35. Attempts to resolve the mode of action of ECRL indicate that virus adsorption and penetration are not affected. Instead, a late step of virus multiplication is hindered since the addition of 100 microg/ml of ECRL at 8h post infection still causes a 90% inhibition of virus release.

An antiviral meliacarpin from leaves of Melia azedarach L.

Bioassay guided purification of the ethyl acetate extract of leaves of Melia azedarach led to the isolation of the limonoid 1-cinnamoyl-3,11-dihydroxymeliacarpin, which showed IC50 values of 6 microM and 20 microM for vesicular stomatitis (VSV) and herpes simplex (HSV-1) viruses, respectively. Its structure was established by spectroscopic methods.

Effect of meliacine, a plant derived antiviral, on tumor necrosis factor alpha.

The effect of meliacine (MAS) and two fractions MAB 1 and MAB 2 obtained from it on the in vitro production of TNF-alpha of murine macrophages induced by bacterial lipopolysaccharide (LPS) (from Escherichia coli) was tested. Simultaneous administration of the above fractions (ranging from 14 to 56 microg/ml) and LPS (10 microg/ml) to a macrophage culture significantly increased the amount of TNF-alpha released at 24 h of induction in a dose-dependent manner. Meliacine alone, at a concentration of 56 microg/ml, is a weak inducer of TNF-alpha production.

Therapeutic action of meliacine, a plant-derived antiviral, on HSV-induced ocular disease in mice.

Ocular herpes simplex virus type-1 (HSV-1) infections remain an important cause of corneal disease which may result in a loss of vision. Meliacine (MA), an antiviral activity present in crude leaf extracts of Melia azedarach L. that inhibits HSV-1 multiplication in vitro, was studied in a murine herpetic stromal keratitis experimental model.