The YfkO Nitroreductase from Bacillus Licheniformis on Gold-Coated Superparamagnetic Nanoparticles: Towards a Novel Directed Enzyme Prodrug Therapy Approach

The bacterial nitroreductase NfnB has been the focus of a great deal of research for its use in directed enzyme prodrug therapy in combination with the nitroreductase prodrug CB1954 with this combination of enzyme and prodrug even entering clinical trials. Despite some promising results, there are major limitations to this research, such as the fact that the lowest reported Km for this enzyme far exceeds the maximum dosage of CB1954. Due to these limitations, new enzymes are now being investigated for their potential use in directed enzyme prodrug therapy. One such enzyme that has proved promising is the YfkO nitroreductase from Bacillus Licheniformis. Upon investigation, the YfkO nitroreductase was shown to have a much lower Km (below the maximum dosage) than that of NfnB as well as the fact that when reacting with the prodrug it produces a much more favourable ratio of enzymatic products than NfnB, forming more of the desired 4-hydroxylamine derivative of CB1954.

Target Activity of Isaria tenuipes (Hypocreales: Clavicipitaceae) Fungal Strains against Dengue Vector Aedes aegypti (Linn.) and Its Non-Target Activity Against Aquatic Predators

The present investigation aimed to determine the fungal toxicity of Isaria tenuipes (My-It) against the dengue mosquito vector Aedes aegypti L. and its non-target impact against the aquatic predator Toxorhynchitessplendens. Lethal concentrations (LC50 and LC90) of My-It were observed in 2.27 and 2.93 log ppm dosages, respectively. The sub-lethal dosage (My-It-1 × 104 conidia/mL) displayed a significant oviposition deterrence index and also blocked the fecundity rate of dengue mosquitos in a dose-dependent manner. The level of major detoxifying enzymes, such as carboxylesterase (α-and β-) and SOD, significantly declined in both third and fourth instar larvae at the maximum dosage of My-It 1 × 105 conidia/mL. However, the level of glutathione S-transferase (GST) and cytochrome P-450 (CYP450) declined steadily when the sub-lethal dosage was increased and attained maximum reduction in the enzyme level at the dosage of My-It (1 × 105 conidia/mL). Correspondingly, the gut-histology and photomicrography results made evident that My-It (1 × 105 conidia/mL) heavily damaged the internal gut cells and external physiology of the dengue larvae compared to the control. Moreover, the non-target toxicity against the beneficial predator revealed that My-It at the maximum dosage (1 × 1020 conidia/mL) was found to be less toxic with <45% larval toxicity against Tx.splendens. Thus, the present toxicological research on Isaria tenuipes showed that it is target-specific and a potential agent for managing medically threatening arthropods.

Liraglutide and the management of overweight and obesity in people with schizophrenia, schizoaffective disorder and first-episode psychosis: protocol for a pilot trial

Background People with severe mental illness (SMI) are two to three times more likely to be overweight and obese than the general population and this is associated with significant morbidity and premature mortality. Although lifestyle interventions can support people with SMI to lose weight, some are unable to make the necessary lifestyle changes or, despite making the changes, continue to gain weight. Objective To assess the feasibility and acceptability of delivering a full-scale trial evaluating whether liraglutide 3.0 mg, a once-daily injectable therapy, may be an effective treatment of overweight and obesity in people with schizophrenia, schizoaffective disorder and first-episode psychosis. Methods Design: a single-centre, double-blind, randomised, placebo-controlled trial. Setting: mental health facilities within Southern Health NHS Trust. Participants: 60 adults with schizophrenia, schizoaffective or first-episode psychosis prescribed antipsychotic medication will be recruited. Participants will be overweight or obese, defined by their baseline BMI which will be: • BMI ≥ 30 kg/m2 or • BMI ≥ 27 kg/m2 to < 30 kg/m2 in the presence of at least one weight-related consequence. This is in concordance with the current EU licence for liraglutide (maximum dosage 3.0 mg). Intervention: participants will be allocated in a 1:1 ratio using a computer-based randomisation programme to either once-daily subcutaneously administered liraglutide or placebo, titrated to 3.0 mg daily, for 6 months. All participants will receive standardised written information about healthy eating and exercise at their randomisation visit. Outcomes: the main aim of the study is to gather data on recruitment, consent, retention and adherence. Qualitative interviews with a purposive sub-sample of participants and healthcare workers will provide data on intervention feasibility and acceptability. Secondary clinical outcome measurements will be assessed at 3 and 6 months and will include: weight, fasting plasma glucose, lipid profile, HbA1c level; and the Brief Psychiatric Rating Scale. Discussion This study should provide evidence of the potential benefits of liraglutide (maximum dosage 3.0 mg daily) on body weight and metabolic variables in people with schizophrenia, schizoaffective disorder and first-episode psychosis. It will also address the feasibility and acceptability of the use of liraglutide in mental health settings. This will inform the design of a longer outcome study that will be needed to determine whether any weight loss can be maintained in the long term. Trial registration Universal Trial Number (UTN), ID: U1111-1203-0068. Registered on on 2/10/2017. European Clinical Trials Database (EudraCT), ID: 2017-004064-35. Registered on 3/10/2017.

Persistence of insecticides used in peach orchards to larvae and adults of the predator Chrysoperla externa (Neuroptera: Chrysopidae)

ABSTRACT This work aimed to evaluate the persistence (duration of harmful activity) of five insecticides used for pest control in peach orchards, on larvae and adults of the predator Chrysoperla externa. The insecticides were sprayed on cv. Bordô vine plants using the maximum dosage recommended for peach orchards. Weekly, at 3, 10, 17, 24 and 31 days after spraying, larvae and adults of the predator were exposed to treated leaves in order to assess the residual effect of insecticides on mortality and possible effects on reproduction. Given the toxicity observed along the weekly bioassays, the insecticides were classified into persistence categories established by the International Organization for Biological and Integrated Control of Noxious Animals and Plants (IOBC). High persistence was obtained for the organophosphorus insecticides (% of active ingredient) phosmet (0.100) and malathion (0.200), and both were considered persistent (> 30 days of harmful activity) to larvae and adults of C. externa. Similarly, the benzoylurea insecticide lufenuron (0.005), which acts exclusively on immature stages of insects, was persistent to larvae. Differences concerning the persistence for both development stages evaluated were observed for the pyrethroid insecticide deltamethrin (0.001), that was persistent to larvae but moderately persistent (16 – 30 days of harmful activity) to adults; and for the organophosphate fenthion (0.050) which was considered moderately persistent to larvae and short-lived (< 5 days of harmful activity) to adults of C. externa.

Intravitreal and Subconjunctival Melphalan for Retinoblastoma in Transgenic Mice

Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine retinoblastoma model.Methods.LHBETATAG transgenic mice were treated with a single 1 mcg intravitreal injection of melphalan, 100 mcg subconjunctival injection, or semiweekly 10 mcg subconjunctival injections for 3 weeks. At 1 or 3 weeks, eyes were enucleated, serially sectioned, and processed with haematoxylin and eosin (H&E) for tumor burden measurements and probed with immunofluorescence to analyze tumor hypoxia and vasculature.Results. Focal melphalan significantly reduced retinal tumor size (P< 0.02) when given intravitreally or subconjunctivally. Eyes treated with a one-time intravitreal injection of 1 mcg melphalan had significantly smaller tumors at both 1 week (P= 0.017) and at 3 weeks after injection (P= 0.005). Intratumoral hypoxia showed a significant decline in hypoxia at 1 week following intravitreal injection and after maximum dosage of subconjunctival melphalan. Total vasculature was not significantly affected following intravitreal administration.Conclusion. Focal delivery of melphalan via intravitreal or subconjunctival injection has a significant effect on reducing tumor burden, hypoxia, and vasculature, in the treatment of murine retinoblastoma tumors.

OPTIMASI PRODUKSI EMPAT VARIETAS JAGUNG HIBRIDA DI KERTOSONO, KABUPATEN NGANJUK

Maize hybridization system would help Indonesia to become a maize exporter. But the development of maize hybrids in Indonesia is seemed too slow, this impacting in national maize production, which was only 13 million ton per year in 2003. In 2009, the maize hybrid has been planted in about 54% of maize yields. Fertilizing maize is on the most essential and critical parts about growing maize. The objective of the study was to obtain the maximum dosage of composed fertilizer for the highest productivity among four hybrids maize variety in dependingsoil type. The result showed that the prospecting hybrid variety of BI-1 has a maximum production yield of 7.7 ton/ha at the level of fertilizer 1,200 kg/ha and it was only 6.3 ton per ha at zero level fertilizer. Amount of 7.4 ton/ha was achieved by BI-3 maize hybrid at the level of 1,200 kg/ha fertilizer, where those only 5.8 ton/ha at the zero level of fertilizer. The highest productivity was archived by BI-4 where it was 7.1 ton/ha at zero level fertilizer and the highest production yield of 9.2 ton/ha at 900kg/ha of fertilizer, but it was decrease at the level of 1,200 kg/ha fertilizer. Maize variety of DK979 achieved highest productivity of 8.6 ton/ha at 1,200 kg/ha fertilizer and 5.8 ton/ha at zero level fertilizer.

Maximum Recommended Dosage of Lithium for Pregnant Women Based on a PBPK Model for Lithium Absorption

Treatment of bipolar disorder with lithium therapy during pregnancy is a medical challenge. Bipolar disorder is more prevalent in women and its onset is often concurrent with peak reproductive age. Treatment typically involves administration of the element lithium, which has been classified as a class D drug (legal to use during pregnancy, but may cause birth defects) and is one of only thirty known teratogenic drugs. There is no clear recommendation in the literature on the maximum acceptable dosage regimen for pregnant, bipolar women. We recommend a maximum dosage regimen based on a physiologically based pharmacokinetic (PBPK) model. The model simulates the concentration of lithium in the organs and tissues of a pregnant woman and her fetus. First, we modeled time-dependent lithium concentration profiles resulting from lithium therapy known to have caused birth defects. Next, we identified maximum and average fetal lithium concentrations during treatment. Then, we developed a lithium therapy regimen to maximize the concentration of lithium in the mother’s brain, while maintaining the fetal concentration low enough to reduce the risk of birth defects. This maximum dosage regimen suggested by the model was 400 mg lithium three times per day.

Experimental Study on Drying Shrinkage and Water Absorption Rate of Recycled Concrete Hollow Block

On the premise of using the five dosage levels of recycled coarse aggregate, the paper primary study on the drying shrinkage and water absorption rate of recycled concrete hollow block in order to determine the maximum dosage of recycled coarse aggregate, then find out the relationship between the drying shrinkage and the water absorption rate of recycled concrete hollow block. The results showed that: the maximum dosage of recycled coarse aggregate can reach 100%; there is a quadratic relationship between the drying shrinkage and the water absorption rate of the block.