Modeling Commodity Flow in the Context of Invasive Species Spread: Study of Tuta absoluta in Nepal.

Trade and transport of goods is widely accepted as a primary pathway for the introduction and dispersal of invasive species. However, understanding commodity flows remains a challenge owing to its complex nature, unavailability of quality data, and lack of systematic modeling methods. A robust network-based approach is proposed to model seasonal flow of agricultural produce and examine its role in pest spread. It is applied to study the spread of Tuta absoluta, a devastating pest of tomato in Nepal. Further, the long-term establishment potential of the pest and its economic impact on the country are assessed. Our analysis indicates that regional trade plays an important role in the spread of T. absoluta. The economic impact of this invasion could range from USD 17-25 million. The proposed approach is generic and particularly suited for data-poor scenarios.

Commentary on Ferguson, et al., "Impact of Non-pharmaceutical Interventions (NPIs) to Reduce COVID-19 Mortality and Healthcare Demand".

A recent manuscript (Ferguson et al. in Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand, Imperial College COVID-19 Response Team, London, 2020. https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf) from Imperial College modelers examining ways to mitigate and control the spread of COVID-19 has attracted much attention. In this paper, we will discuss a coarse taxonomy of models and explore the context and significance of the Imperial College and other models in contributing to the analysis of COVID-19.

Primary rat and mouse hepatic stellate cells express the macrophage inhibitor cytokine interleukin-10 during the course of activation In vitro.

Activation of local tissue macrophages (Kupffer cells) and of quiescent hepatic stellate cells (HSCs) to a myofibroblast phenotype are two key events in liver inflammation and fibrosis. It is known that products of activated macrophages may activate stellate cells. We have hypothesized that the products of activated HSCs may also modulate the activity of Kupffer cells. The cytokine interleukin-10 (IL-10), produced by lymphocytes and macrophages, has profound inhibitory actions on macrophages. Normal rat and mouse HSCs that differentiate in vivo and in vitro to activated myofibroblasts were isolated by enzyme perfusion and density centrifugation with or without centrifugal elutriation, confirmed by vitamin A autofluorescence and positive immunostaining for the myofibroblast markers desmin and smooth muscle actin (SMA). Conditioned media and lysates from these cells were found to down-regulate lipopolysaccharide (LPS)-induced tumor necrosis factor- (TNF-) secretion by the mouse macrophage line RAW 267.4. In highly purified preparations of rat HSCs, messenger RNA (mRNA) for IL-10 was detected by reverse-transcription polymerase chain reaction (RT-PCR), from the time of isolation to up to 120 days of culture on plastic. Long-term cultures of unstimulated mouse HSCs secreted IL-10 protein as detected by immunoblotting and specific enzyme-linked immunosorbent assay (ELISA). IL-10 protein was undetectable by immunohistochemistry in mouse HSCs for the first 3 days in culture. After this, the percentage of IL-10-positive cells increased to 45% at day 7 and 100% by day 14, and expression of IL-10 continued in long-term cultures of up to 120 days. The expression of IL-10 by the stromal cells that govern the fibrotic process in the liver may have important implications for the regulation of inflammation and fibrosis in the liver.

Bradykinin antagonists in human systems: correlation between receptor binding, calcium signalling in isolated cells, and functional activity in isolated ileum.

The determination of the relationship between ligand affinity and bioactivity is important for the understanding of receptor function in biological systems and for drug development. Several physiological and pathophysiological functions of bradykinin (BK) are mediated via the B2 receptor. In this study, we have examined the relationship between B2 receptor (soluble and membrane-bound) binding of BK peptidic antagonists, inhibition of calcium signalling at a cellular level, and in vitro inhibition of ileum contraction. Only human systems were employed in the experiments. Good correlations between the studied activities of BK antagonists were observed for a variety of different peptidic structures. The correlation coefficients (r) were in the range of 0.905 to 0.955. In addition, we analyzed the effect of the C-terminal Arg9 removal from BK and its analogs on B2 receptor binding. The ratios of binding constants (Ki(+Arg)/Ki(-Arg)) for the Arg9 containing compounds and the corresponding des-Arg9 analogs varied from about 10 to 250,000. These ratios strongly depend on the chemical structures of the compounds. The highest ratios were observed for two natural agonist pairs, BK/des-Arg9-BK and Lys0-BK/des-Arg9-Lys0-BK.

Bradykinin receptor antagonists containing N-substituted amino acids: in vitro and in vivo B(2) and B(1) receptor antagonist activity.

We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B(2)) receptor for antagonist activity by incorporating N-alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-Tic(7)-N-Chg (8)-Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) B(2) receptor antagonist devoid of in vitro B(1) antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B(2) antagonist activity. Although devoid of activity in a classic B(1) isolated tissue assay, B(1) antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK(1) receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B(2) pA(2) = 9.1). Antagonist 13 (Hyp(2), Nchg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human B(2) receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action.

Pre-clinical toxicity of IDPH-791: a new centrally acting muscle relaxant in rats.

IDPH-791, a novel centrally acting muscle relaxant, in doses up to 500 mg/kg (po) for 14 days did not result in any appreciable adverse effect on body weight gain, food or water consumption including biochemical and haematologica parameters in rats. Variations observed in the biochemistry and haematology were either comparable to controls or were within normal limits.

Effects of pyridoxine on implantation and pregnancy in Wistar rat.

Pyridoxine hydrochloride was gavaged to 2 groups of pregnant Wistar rats from day 0 to 13 and day 6 to 15 of gestation at doses of 100, 200, 400 and 800 mg/kg. A higher number of implantations, live pups and corpora lutea were observed in the treated rats, but a significant reduction in the body weights of the pups was noticed in the groups treated with 400 and 800 mg/kg. No other adverse effects on implantation and pregnancy were noticed. No evidence of dismorphogenic effects was seen.

Embryotoxicity and teratogenicity of lithium carbonate in Wistar rat.

Lithium carbonate was administered orally to pregnant Wistar rats from day 6-15 of gestation at doses of 50 and 100 mg/kg. Evidence of embryotoxic and teratogenic potential of lithium carbonate was noticed at the dose of 100 mg/kg. Reduction in number and weight of the litter, increase in the number of resorptions, wavy ribs, short and deformed bones of the limbs, or an increased incidence of incomplete ossification of sternebrae and wide bone separation in the skull were the important findings suggesting the nature and extent of embryotoxicity and teratogenicity of lithium carbonate in Wistar rats.

Pre-clinical toxicity studies on the new nitroimidazole 1-methylsulphonyl-3-(1-methyl-5-nitroimidazole-2-yl)-2- imidazolidinone.

Administration of 1-methylsulphonyl-3-(1-methyl-5-nitro-2-imidazole-yl)-2-imidazolidinone (Go 10213) at a dose of 5000 mg/kg to rat, mouse, guinea pig and rabbit and 3000 mg/kg to dog did not induce any toxic symptoms or mortality. Repeated daily gavaging with doses ranging from 50-3000 mg/kg/day were tolerated by rats for 2 weeks. No mortality was noticed in treated animals. Reduction in weight gain was observed in male rats on 2000 mg/kg per day and females on 1000 mg/kg per day. No toxic changes were noticed in dogs treated with 200 mg/kg per day for 2 weeks. One monkey treated with 75 mg/kg per day for 4 weeks tolerated the compound without exhibiting any toxic effects. No drug induced alterations were noticed in rats gavaged with 60 and 200 mg/kg per day for 4 weeks. Rats treated with a daily dose of 600 mg/kg showed reduction in body weight gain and atrophy of testes and these changes were reversible after stopping of medication. Dogs medicated with 30 and 100 mg/kg per day tolerated the drug for 4 weeks. Except slight ataxia in a few dogs treated with 100 mg/kg per day, no other drug induced toxic effects were noticed. Neurological symptoms were noticed in all dogs on high dose of 200 mg/kg. Three animals out of six were sacrificed in extremis in this dose. After discontinuation of Go 10213 all dogs on 100 and 200 mg/kg per day recovered normal gait in about a week. No definitive drug induced changes were noticed in laboratory investigations, gross and histopathological examinations.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicological effects of aerial application of monocrotophos.

Aerial application of the insecticide Nuvacron 40% (monocrotophos) had no significant effect on the cholinesterase level of plasma and erythrocytes of cattle, chicken, buffaloes, and human volunteers exposed to the spray. Contamination of canal water with the pesticide was completely eliminated within 24 hr, whereas that in the soil was reduced by 80% in 72 hr. The degradation of insecticide residue in grass was about 90% in seven days and in cotton leaves about 85% for the same period.