Actions of Agonists, Fipronil and Ivermectin on the Predominant In Vivo Splice and Edit Variant (RDLbd, I/V) of the Drosophila GABA Receptor Expressed in Xenopus laevis Oocytes

Ionotropic GABA receptors are the targets for several classes of insecticides. One of the most widely-studied insect GABA receptors is RDL (resistance to dieldrin), originally isolated from Drosophila melanogaster. RDL undergoes alternative splicing and RNA editing, which influence the potency of GABA. Most work has focussed on minority isoforms. Here, we report the first characterisation of the predominant native splice variant and RNA edit, combining functional characterisation with molecular modelling of the agonist-binding region. The relative order of agonist potency is GABA> muscimol> TACA> β-alanine. The I/V edit does not alter the potency of GABA compared to RDLbd. Docking calculations suggest that these agonists bind and activate RDLbdI/V through a similar binding mode. TACA and β-alanine are predicted to bind with lower affinity than GABA, potentially explaining their lower potency, whereas the lower potency of muscimol and isoguvacine cannot be explained structurally from the docking calculations. The A301S (resistance to dieldrin) mutation reduced the potency of antagonists picrotoxin, fipronil and pyrafluprole but the I/V edit had no measurable effect. Ivermectin suppressed responses to GABA of RDLbdI/V, RDLbd and RDLbdI/VA301S. The dieldrin resistant variant also showed reduced sensitivity to Ivermectin. This study of a highly abundant insect GABA receptor isoform will help the design of new insecticides

Are Potency and Actuality Compatible in Aristotle?

The belief that Aristotle opposes potency (dunamis) to actuality (energeia or entelecheia) has gone untested. This essay defines and distinguishes forms of the Opposition Hypothesis—the Actualization, Privation, and Modal—examining the texts and arguments adduced to support them. Using Aristotle’s own account of opposition, the texts appear instead to show that potency and actuality are compatible, while arguments for their opposition produce intractable problems. Notably, Aristotle’s refutation of the Megarian Identity Hypothesis applies with equal or greater force to the Opposition Hypothesis. For Aristotle, then, potency and actuality are compatible

Frequency and Severity of Neutropenia Associated with Food and Drug Administration Approved and Compounded Formulations of Lomustine in Dogs with Cancer.

BackgroundCompounded lomustine is used commonly in veterinary patients. However, the potential variability in these formulations is unknown and concern exists that compounded formulations of drugs may differ in potency from Food and Drug Administration (FDA)-approved products.Hypothesis/objectivesThe initial objective of this study was to evaluate the frequency and severity of neutropenia in dogs treated with compounded or FDA-approved formulations of lomustine. Subsequent analyses aimed to determine the potency of lomustine obtained from several compounding pharmacies.AnimalsThirty-seven dogs treated with FDA-approved or compounded lomustine.MethodsDogs that received compounded or FDA-approved lomustine and had pretreatment and nadir CBCs performed were eligible for inclusion. Variables assessed included lomustine dose, neutrophil counts, and severity of neutropenia. Lomustine 5 mg capsules from 5 compounding sources were tested for potency using high-pressure liquid chromatography (HPLC) with ultraviolet (UV) detection.ResultsTwenty-one dogs received FDA-approved lomustine and 16 dogs were treated with lomustine prescribed from a single compounding pharmacy. All dogs treated with FDA-approved lomustine were neutropenic after treatment; 15 dogs (71%) developed grade 3 or higher neutropenia. Four dogs (25%) given compounded lomustine became neutropenic, with 2 dogs (12.5%) developing grade 3 neutropenia. The potency of lomustine from 5 compounding pharmacies ranged from 50 to 115% of the labeled concentration, with 1 sample within ±10% of the labeled concentration.Conclusions and clinical importanceThese data support broader investigation into the potency and consistency of compounded chemotherapy drugs and highlight the potential need for greater oversight of these products

STUDI POTENSI TOLERANSI ISOLAT FUNGI LIMBAH COMBERAN \ud TERHADAP DETERGEN, SABUN MANDI DAN SABUN COLEK KAWASAN \ud PADAT HUNI DI KOTA MALANG

Detergent and Soap is cleanser of sintetic having negative impact to health either through is direct (physical contact) and also indirectly (residing in nature or environment in the form of waste). This research aim to to know chosen fungi isolate which most have lenient potency to detergent, toilet soap and soap of colek. This process is started with insulation of fungi of waste nature, namely waste of comberan by using selective media CZAPEK.DOX.AGAR fungi. found Isolate [is] later;then given letter code and number, namely B1, B2, B3,.....etc, where (B=Fungi, \ud 1,2,3...=jenis to). [Gift/ giving] of code pursuant to difference of characteristic of makroskopis and [is] microscopic the than fungi isolate. From 21 type of isolate found by isolate of rank pursuant to amount of colony many, chosen so that 7 isolate which later; then referred with \ud chosen isolate. ideally functioning soap and detergent as cleaner and also antiseptic and disinfectant to microorganisme specially fungi, but result of insulation indicate that there are fungi which not die, so that assumed by the fungi isolate lenient and can elaborate third the materials in nature. Research type the used is descriptive with approach of laboratory, where this \ud research aim to for description concerning lenient potency of chosen fungi isolate to detergent, toilet soap and soap of colek, later; then to know the tolerance potency test by using detergent, toilet soap and soap clean concentration 25%, 50%, 75% and 95%. Smaller assess zona diameter \ud pursue {progressively come near zero ( 0)}, hence is ever greater of its tolerance potency Result of research indicate that: (1) Pursuant to range assess zona diameter pursue smallestly, hence most isolate have potency to be lenient to detergent is B8 isolate, isolate having potency \ud most lenient to toilet soap is B4 isolate, while most isolate have lenient potency to soap of colek is B19 isolate. ( 2) Storey;Level resilience of isolate fungi, to detergent: B8, B21, B2, B4, B16, B19 and of B13, for the toilet soap of: B4, B19, B16, B13, B21, B2, and B8, while soap of colek:\ud B19, B13, B8, B2, B21, B4, and B16. found of lenient fungi isolate to detergentt, toilet soap and soap of colek, can give information in area of microbiological science in the effort yielding product of inokulum microbe capable to pregnant waste degredate third disinfectant type and \ud antiseptic

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Afterthoughts | Complexities of Potency

Afterthoughts to themed perspectives on Complexities of Potency

Yield Performance of Locally Selected Cocoa Clones in North Luwu

Participatory selection in North Luwu District selected some locally cocoa clones, of which MCC 01 and MCC 02 the most promising to be developed as clonal material. This research has objectives to observe the stability performance of yield of these clones that enable be characterized of the potency as the basis for recommendation. Observation were carried out in 35 selected-farms be differentiated according to clone\u27s type, namely MCC 01, MCC 02 and Sulawesi 01 (control) and the year of planting (age). These farms were establised at the main area of cocoa in North Luwu. The assessed variables were the number of pod, yield components, the resistance to cocoa pod borer (CPB), vascular-streak dieback (VSD) and phytophthora pod rot (PPR). Data were recorded through 20 sampled-trees per farm in the period of April 2013 to April 2014 with monthly basis assessment. Data were analyzed refer to Eberhart & Russel method to perform stability parameters of the yield. The results indicate that these clones stable performing yield potency among plant age. MCC 01 and MCC 02 performed yield potency in amount of 3,682 kg/ha and 3,132 kg/ha respectively higher than Sulawesi 01 of 2,772 kg/ha. Evaluation of the resistance, MCC 01 having moderate resistance to CPB and VSD and resistance to PPR, however MCC 02 having resistance to CPB, VSD and PPR. Referring to the potency thus MCC 01 and MCC 02 were legally recommended as clonal material for farmers, restricted at the agroclimatic area similar to the condition in North Luwu

Mind the gap: Can we explain declining male reproductive health with known antiandrogens?

This article has been made available through the Brunel Open Access Publishing Fund.Several countries have experienced rises in cryptorchidisms, hypospadias and testicular germ cell cancer. The reasons for these trends are largely unknown, but Skakkebaek has proposed that these disorders form a testicular dysgenesis syndrome and can be traced to androgen insufficiency in foetal life. This suggests that antiandrogenic chemicals might contribute to risks, but few chemicals have been linked to these diseases in epidemiological studies. In animal studies with p,p0-dichlorodiphenyldichloroethylene, effects typical of disruptions of male sexual differentiation became apparent when the foetal levels of this androgen receptor (AR) antagonist approached values associated with responses in in vitro assays. This prompted us to analyse whether the 22 chemicals with AR antagonistic properties would produce mixture effects in an in vitro AR antagonism assay when combined at concentrations found in human serum. Other antiandrogenic modalities could not be considered. Two scenarios were investigated, one representative of average serum levels reported in European countries, the other in line with levels towards the high exposures. In both situations, the in vitro potency of the 22 selected AR antagonists was too low to produce combined AR antagonistic effects at the concentrations found in human serum, although the high exposure scenario came quite close to measurable effects. Nevertheless, our analysis exposes an explanation gap which can only be bridged by conjuring up as yet undiscovered high potency AR antagonists or, alternatively, high exposures to unknown agents of average potency