Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans

Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2(zf35gf) mutants display increased cholinergic-and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in unc-2(zf35gf) mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.Fil: Huang, Yung Chi. University of Massachussets; Estados UnidosFil: Pirri, Jennifer K.. University of Massachussets; Estados UnidosFil: Rayes, Diego Hernán. University of Massachussets; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Gao, Shangbang. Mount Sinai Hospital; Estados UnidosFil: Mulcahy, Ben. Mount Sinai Hospital; Estados UnidosFil: Grant, Jeff. University of Massachussets; Estados UnidosFil: Saheki, Yasunori. The Rockefeller University; Estados UnidosFil: Francis, Michael M.. University of Massachussets; Estados UnidosFil: Zhen, Mei. University of Toronto; Canadá. Mount Sinai Hospital; Estados UnidosFil: Alkema, Mark J.. University of Massachussets; Estados Unido

Influence of short- and long-term administration of Melengestrol acetate on estrus activity and reproductive performance of nulliparous Barki ewes

In Egypt, research focusing on estrous synchronization in small ruminants based on Melengestrol acetate (MGA) supplementation, particularly in nulliparous ewes, is still lacking. The present work aimed to evaluate effect of long-term and short-term administration of melengestrol acetate (MGA) treatments on estrus synchronization and reproductive performance of nulliparous Barki Ewes. This study was performed in Siwa Oasis Research Station (Tegzerty Experimental Farm for animal production), belonged to Desert Research Center, Egypt. Forty five nulliparous Barki ewes with age ranging from 15.5 to 16.5 months, and 38 ± 0.23 kg average live body weight were assigned to one of three groups: (1) control (C, n = 15); (2) long-term treatment with MGA (n = 15, 0.22 mg/ewe/d for 14 days) and (3) short-term treatment with MGA (n = 15, 0.22 mg/ewe/d for 7 days). At the end of MGA treatment (14 or 7 d) all treated ewes were injected by 600 IU PMSG intramuscularly. The results showed that, ewes treated with MGA exhibited highest (

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Moral Analysis in Jeff Kinney's Diary of a Wimpy Kid: Evaluating Action and Consequences in the Context of Middle School Life

This research is research that analyzes the moral values of the protagonist in the novel entitled Diary of a Wimpy Kid by Jeff Kinney. This research uses the theory of consequentialism ethics to measure whether the protagonist's actions are moral or immoral, and what consequences arise from his actions, as well as how the consequences change for the protagonist in the future. This novel tells the life of the middle school protagonist as someone who is geeky but has a strong ambition to become famous during his middle school days. This research includes the protagonist's moral actions which are considered through the protagonist's intentions, actions, and consequences based on the ethical principles of consequentialism, specifically Mill's utilitarian theory. The protagonist's moral reasoning is grouped into 3 morally damaging traits, namely: Egocentrism, Manipulative, and Lack of Empathy. This research further examines the moral values that can be learned from the protagonist character with the aim of providing learning for young readers. The results of the moral analysis above show that the protagonist has an unwise moral nature and is a bad example for young readers. However, the protagonist's character development balances to the protagonist's unwise action

Synthesis, crystal structures, Hirshfeld surface analysis and physico-chemical characterization of two new ZnII and CdII halidometallates

Two new organic–inorganic hybrid materials, based on 1, 3-CycloHexaneBis-(Methyl Amine), abbreviated CHBMA, namely (H2CHBMA)ZnCl4·2H2O (CP1) and (H2CHBMA)CdI4·2H2O (CP2), have been synthesized under mild conditions in acidic media and characterized by single-crystal X-ray diffraction, spectroscopic techniques (13C NMR, FTIR, RAMAN) and thermal analysis. The crystal structures of the two compounds were solved by single-crystal X-ray diffraction methods. Both compounds show a 3-dimensional supramolecular structure directed by various interactions between tetrahalidometallate anions (ZnCl42-, CdI42-), water molecule and organic cations (H2CHBMA)2+. For both compounds, the cyclohexane ring of the template cation is in a chair conformation with the methylammonium substituent in the equatorial positions and the two terminal ammonium groups in a cis conformation but with two different orientations (upward for CP1 and downward for CP2) which influences the supramolecular architecture of the two structures. Hirshfeld surface analysis and the associated two-dimensional finger print plots were used to explore and quantify the intermolecular interactions in the crystals

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Simple Spectrophotometric Method for Determination of Paroxetine in Tablets Using 1,2-Naphthoquinone-4-Sulphonate as a Chromogenic Reagent

Simple and rapid spectrophotometric method has been developed and validated for the determination of paroxetine (PRX) in tablets. The proposed method was based on nucleophilic substitution reaction of PRX with 1,2-naphthoquinone-4-sulphonate (NQS) in an alkaline medium to form an orange-colored product of maximum absorption peak (λmax) at 488 nm. The stoichiometry and kinetics of the reaction were studied, and the reaction mechanism was postulated. Under the optimized reaction conditions, Beer's law correlating the absorbance (A) with PRX concentration (C) was obeyed in the range of 1–8 μg mL−1. The regression equation for the calibration data was: A = 0.0031 + 0.1609 C, with good correlation coefficients (0.9992). The molar absorptivity (ε) was 5.9 × 105 L mol−1 1 cm−1. The limits of detection and quantitation were 0.3 and 0.8 μg mL−1, respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 2%. The proposed method was successfully applied to the determination of PRX in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 97.17 ± 1.06 %. The results obtained by the proposed method were comparable with those obtained by the official method