Miracle-dz/UniFAR-FTUs huggingface dataset:
Importance of mechanistic drug metabolism studies in support of drug discovery: A case study with an N -sulfonylated dipeptide VLA-4 antagonist in rats

N-(1-(3,5-dichlorobenzenesulfonyl)-2S-methyl-azetidine-2-carbonyl)-L-4-(2′,6′-dimethoxyphenyl)phenylalanine (1) is a potent antagonist of the very late activating (VLA) antigen-4. During initial screening, 1 exhibited an apparent plasma clearance (CL) of 227 ml min−1 kg−1 in Sprague–Dawley rats following an intravenous bolus dose formulated in an aqueous solution containing 40% polyethylene glycol. Such a high CL value led to speculation that the elimination of compound 1 involved extra-hepatic tissues. However, the apparent plasma CL was reduced to 97 ml in−1 kg−1 when a 2-min time point was added to sample collections, and further decreased to 48 ml min−1 kg−1 after the dose was formulated in rat plasma. The lung extraction of 1 in rats was negligible whereas the hepatic extraction was ≥90%, based on comparison of area under the curve (AUC) values derived from intra-artery, intravenous, and portal vein administration. In rats dosed intravenously with [14C]-1, approximately 91% of the radioactivity was recovered in bile over 48 h, with 85% accounted for in the first 4-h samples. The biliary radioactivity profile consisted of approximately 30% intact parent compound, 20% 1-glucuronide, and 50% oxidation products resulting from O-demethylation or hydroxylation reactions. When incubated with rat liver microsomes, oxidative metabolism of 1 was inhibited completely by 1-aminobenzotriazole (ABT), whereas the oxidation and glucuronidation reactions were little affected in the presence of cyclosporin A (CsA). In contrast, the hepatic extraction of 1 in rats was unperturbed in animals pre-dosed with ABT, but was reduced approximately 60% following treatment with CsA. In vitro, 1 was a substrate of the rat organic anion transporter Oatp1b2, and its cellular uptake was inhibited by CsA. In addition, the hepatic extraction of 1 was approximately 30% lower in Eisai hyperbilirubinaemic rats which lack functional multidrug resistant protein-2 (MRP2). Collectively, these data suggest that the clearance of 1 in rats likely is a result of the combined processes of hepatic oxidation, glucuronidation and biliary excretion, all of which are facilitated by active hepatic uptake of parent compound and subsequent active efflux of both unchanged parent and its metabolites into bile. It was concluded, therefore, that multiple mechanisms contribute to the clearance of 1 in rats, and suggest that appropriate pharmacokinetic properties might be difficult to achieve for this class of compounds. This case study demonstrates that an integrated strategy, incorporating both rapid screening and mechanistic investigations, is of particular value in supporting drug discovery efforts and decision-making processes.
Purification and properties of an aspartic protease from potato tuber that is inhibited by a basic chitinase

A protease was isolated from potato (Solanum tuberosum L. cv. Huinkul) tuber disks after 24 h of aeration when proteolysis is markedly increased. Purification was performed by ammonium sulfate precipitation, ion exchange chromatography, and affinity chromatography. A size of 40 kDa was estimated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and gel filtration, it is monomeric and its properties are consistent with those of aspartic proteinases (EC 3.4.23): it had a pH optimum between 4 and 5 and it was inhibited by pepstatin. Partial homology with other plant aspartic proteinases was observed in two sequenced tryptic fragments. It binds to Sepharose-concanavalin A and can be eluted with α-methyl mannoside, indicating that it is possibly glycosylated. Unlike other aspartic proteinases from Solanaceae that degrade pathogenesis-related proteins, it is unable to cleave a basic chitinase from potato. Moreover, this aspartic protease is strongly inhibited by the basic chitinase; the 50% inhibition is obtained when the molar ratio approaches 1, the same as with pepstatin. The interaction between this aspartic protease and a new type of endogenous inhibitor may be an interesting starting point to study the regulation of these aspartic proteases during stress.
Composition of bacterial communities in deep-sea sediments from the South China Sea, the Andaman Sea and the Indian Ocean

The bacterial diversity of deep-sea sediments collected from the South China Sea (B111), the Andaman Sea (ADM), and the Indian Ocean (P10) was investigated through the construction of 16S recombinant deoxyribonucleic acid (DNA) clone libraries for sequencing. The structure of the bacterial community and their phylogenetic relationships were analyzed using the Mothur software. The nutrient and heavy metal content of the sediments were also analyzed. In total, 263 valid sequences were obtained from 300 sequenced clones. There were 151 operational taxonomic units (OTUs) that belong to Actinobacteria, Proteobacteria, Planctomycetes, Bacteroidetes, Gemmatimonadetes, Nitrospira, Chloroflexi, Acidobacteria, WS3, BRC1, OD1, and numerous unclassified bacteria. The Chao1 and Shannon indices showed that B111 had the highest diversity, but P10 had the richest OTUs. The P < 0.05 value of the parsimony index, LIBSHUFF, and weighted UniFrac analyses indicated important distinctions in the structure and diversity of the bacterial communities. These differences are related to the nutrient and heavy metal content of the sediments. The present study clearly demonstrates the wide bacterial diversity in deep-sea sediments from the South China Sea, the ADM, and the P10, including a large number of unknown bacteria. Due to the different geographical locations of the sediments, the structures of their bacterial communities are also remarkably distinct.
Innovations favouring environmental sustainability in avocado orchards: an analysis of the Spanish Mediterranean coastlands

Avocado cultivation started to take hold on the southern Spanish Mediterranean coast in the early 1970s. Today, avocado is the most widespread tropical crop in the area, occupying some 8,350 ha; average annual production is around 70,000 Mg. In recent years, several technological innovations have been adopted by avocado growers, some of which favour the environmental sustainability of the crop. Among the practices adopted are several non-tillage or conservation tillage techniques (which use no —or very little— herbicide), flower pruning, the use of weed clearing machines, mulching, and organic and integrated farming systems. This paper reports the results of a survey of avocado growers from the southeastern coast of Spain, and analyses their adoption of environmentally friendly technologies. To identify the grower and orchard characteristics that encourage such adoption, an aggregate innovation index was created and a multinomial ordered probit model constructed. The findings might help in the design of strategies for increasing the adoption of environmentally safe technologies. Additional key words: adoption of technological innovations, Persea americana, sustainable agriculture.
Tax Policy and Economic Growth In Nigeria

The Nigerian economy depends on the revenue generated through oil production. However, in recent years the decline in oil prices across the world forced the government to lower domestic oil prices. Consequently, the revenue generation capacity of Nigeria decreased significantly. In view of the prevailing situation, it is important for the government to identify other sources of revenue generation. Thus, we examine the sensitivity of the Nigerian economy on existing tax policies. The study is based on secondary data from 1998 to 2017. The results suggest that the Nigerian government has to focus on revenue generation through direct taxes which are positively associated with economic growth. The results suggest that the government should avoid indirect taxes as it adversely affects economic growth. Moreover, the government must focus on addressing corruption and implement tax reforms. The government may also enhance economic growth by channelizing private savings in productive sectors of Nigeria. Keywords: Economic growth, direct taxes, indirect taxes, taxation policy.
Estimates of density and sustainable harvest of the lowland tapir Tapirus terrestris in the Amazon of French Guiana using a Bayesian spatially explicit capture–recapture model

Abstract The Amazonian moist forest, which covers most of French Guiana, is one of the core habitats for the lowland tapir Tapirus terrestris. Tapirs are hunted in French Guiana, although a law introduced in 2011 restricts hunting to one animal per person per hunting trip. We carried out camera-trap surveys in the Nouragues Nature Reserve for 4 years, with the goal of estimating tapir densities in undisturbed conditions and determining sustainable harvest levels for tapirs in French Guiana. We analysed our data with a Bayesian spatially explicit capture–recapture model, with parameter sharing across surveys to improve estimates, and used the model to calculate derived parameters such as maximum sustainable harvest levels. Density estimates for all four surveys were similar and the model indicated a difference in encounter rates for the two camera models used but no difference in encounter rates or home range sizes for males and females or between years. Based on the calculated density of 0.32 tapir km−2 we estimated sustainable harvest levels at 0.009 tapir km−2. Comparing this value to hunting surveys from 11 sites between 1999 and 2006, we found that hunting levels were unsustainable in at least seven villages. We conclude that even the new restrictive hunting law will not prevent overhunting of tapirs in certain areas and thus stronger regulations are needed. However, because of the remoteness of tapir habitat in many parts of French Guiana tapirs are not immediately threatened in the country as a whole.
Nitrogen inputs and losses from clover/grass pastures grazed by dairy cows, as affected by nitrogen fertilizer application

Nitrogen (N) inputs and outputs were measured over 3 years in a trial with four farmlets (each with 16 randomly-allocated 0·4 ha paddocks) on permanent white clover/ryegrass pastures which were grazed throughout the year by dairy cows near Hamilton, New Zealand. Three farmlets were stocked at 3·3 cows/ha and received nominal rates of N fertilizer (urea in 8–10 split applications) of 0, 200 or 400 kg N/ha per year. A fourth farmlet with 4·4 cows/ha received 400 kg N/ha per year and was supplemented with maize grain during the first two years. Nitrogen balances were calculated, with [sum ]N inputs[ape ][sum ]N outputs. Annual inputs from N2 fixation were 99–231 kg N/ha in the 0 N farmlet, but declined to 15–44 kg N/ha in the 400 N farmlets. The main N outputs (in kg N/ha per year) were in milk (72–126), nitrate leaching (20–204), and transfer of N via cow excreta from pastures to lanes and milking shed (54–92). Gaseous losses by denitrification (3–34) and volatilization (15–78) were smaller than the other N outputs but increased significantly with N fertilizer application. In the maize-supplemented farmlet, N outputs in milk were 31% higher than in the corresponding non-supplemented 400 N farmlet, whereas leaching losses averaged 17% lower during the 2 years of supplementation. In the N-fertilized farmlets, estimated N balances were influenced by inclusion of the transitional N processes of immobilization of fertilizer N into the soil organic N pool (estimated using 15N at 42–94 kg N/ha per year) and the contribution from mineralization of residual clover-fixed N in soil not accounted for in the current estimates of N2 fixation (estimated at up to 70% of measured N2 fixation or 46 kg N/ha per year). However, these processes were counteracting and together were calculated to have only a small net effect on total N balances. The output of N in products (milk, meat and feed) relative to the total N input averaged 26% in the 400 N farmlets, and is compared to that measured for commercial intensively-managed dairy farms in England and the Netherlands (14–20%). The 0 N farmlet, which was reliant on N2 fixation as the sole N input, was relatively very N-efficient with the milk production being 83% of that in the 400 N farmlet (at 3·3 cows/ha) and the N output in products relative to total N input averaging 52%.
Detecting and estimating density dependence in wildlife populations

We review methods for detecting and assessing the strength of density dependence based on 2 types of approaches: surveys of population size and studies of life history traits, in particular demographic parameters. For the first type of studies, methods neglecting uncertainty in population size should definitely be abandoned. Bayesian approaches to simple state-space models accounting for uncertainty in population size are recommended, with some caution because of numerical difficulties and risks of model misspecification. Realistic state-space models incorporating features such as environmental covariates, age structure, etc., may lack power because of the shortness of the time series and the simultaneous presence of process and sampling variability. In all cases, complementing the population survey data with some external information, with priority on the intrinsic growth rate, is highly recommended. Methods for detecting density dependence in life history traits are generally conservative (i.e., tend to underestimate the strength of density dependence). Among approaches to correct for this effect, the state-space formulation of capture–recapture models is again the most promising. Foreseeable developments will exploit integrated monitoring combining population size surveys and individual longitudinal data in refined state-space models, for which a Bayesian approach is the most straightforward statistical treatment. One may thus expect an integration of various types of models that will make it possible to look at density dependence as a complex biological process interacting with other processes rather than in terms of a simple equation; modern statistical and modeling tools make such a synthesis within reach. © 2012 The Wildlife Society.
Diluted seawater promoted the green tide of Ulva prolifera (Chlorophyta, Ulvales)

Ulva prolifera (Müller) J. Agardh is the main causative species of the 2008 Yellow Sea green tide incident. We investigated the influences of diluted seawater on the vegetative growth and reproductive cell formation of the alga. The thalli that were cultivated under low salinities (10‰ and 20‰) and low pH values (pH around 7.0) showed obvious and steady biomass gain, while those cultivated under high salinities (40‰) and relatively higher pH conditions (pH around 8.0) manifested significant biomass loss. The trend was, however, completely the opposite for reproductive cell formation and there were indications that enrichment, over very wide concentration ranges of both nitrogen and phosphate, could significantly promote vegetative growth. Results also indicated that relatively low salinity and low pH regimes boosted vegetative growth but were unfavorable for reproductive cell formation and vice versa. Based on these results, the possible origin and development mechanisms of the green tide event are discussed. Eutrophication in the Changjiang River estuary and adjacent sea areas, as well as extremely high freshwater inflows before, and during, the flood of 2007 – due to the full operation of large‐scale water facilities in the area – may have both played an important role in the formation and development of the green tide event.
Analysis of Textual and Non-Textual Sources of Sentiment in Github

Github is a collaborative platform that is used primarily for the development of software. In order to gain more insight into how teams work on Github, we wish to analyze the sentiment content available via communication on the platform. In order to do so, we first use existing sentiment analysis classifiers and compare the Github data to other social networks, Twitter and Reddit. By identifying that users are able to provide reactions to other users posts on Github, we use this as an indicator or label of sentiment information. Using this we first investigate whether repeated user interaction has an impact on sentiment and find that it is positively correlated to the amount of prior interaction as well as the directness of interaction. We also investigate if metrics corresponding to a user’s status or power in a project correlate with positive sentiment received and find that it does. We then build sentiment classifiers using both textual and non textual information, both which outperform the generic sentiment scorer systems. In addition we show that a sentiment classifier built using only non-textual information can perform at a comparable level to that of a text-based classifier, indicating that there is significant sentiment information contained in non-textual information in the Github network.
The learning rate of vector-valued ranking with least square loss

: In the present paper, we give an investigation on the quantitative convergence analysis of the kernel regularized vector ranking with least square loss. We present with G ˆ ateaux derivative the qualitative relation between the solution and the hiding distribution and quantitatively show the robustness for the solution. Finally, we provide a learning rate in terms of the approximation ability and capacity of the involved vector-valued RKHS.
Mining Public Databases for Discovery of Structure and Function within the Hotdog-fold Thioesterase and HAD Phosphatase Enzyme Families

For my doctoral work, I have developed strategies to mine public databases for data that can be used to infer structural and functional information for the hotdog-fold and HADSF superfamilies. For the hotdog-fold superfamily, I used curated and automatically applied annotations of structure, taxonomic lineage, function, and subfamily membership from the UniProtKB, gene context and taxonomic information from the NCBI, and the results of several in-depth explorations of subfamily/function and structural class membership. Based on the distribution of the aforementioned annotations mapped onto a sequence similarity network (SSN), I applied structural assignments to sequences and/or specific function/subfamily assignments to ~143,000 sequences and general subfamily assignments to an additional ~61,000 sequences. I also identified 52 clusters containing nearly 9,000 uncharacterized sequences lacking any annotations whatsoever and several
Detecting nutritional state and food source use in field‐collected insects that synthesize honeydew oligosaccharides

1. During the adult stage many arthropod species, including aphid predators and parasitoids, depend on nectar and honeydew as a source of carbohydrates. Despite the importance of sugar feeding for these organisms, we know little about their energy and nutrient provision under field conditions. 2. Here we assessed the nutritional state of adult parasitoids, hoverflies and lacewings in a Swiss winter wheat (WW) and a spring wheat (SW) field and studied the contribution of honeydew to the diet of these aphidophagous insects. The total sugar level and the glucose-fructose ratio were used as indicators for nutritional state and sugar feeding. 3. Over 76% of the collected individuals from each of the three insect groups in both fields had recently consumed carbohydrates. The average nutritional state was significantly higher in the SW field for Chrysoperla carnea and Aphidius spp. 4. Honeydew consumption by insects is commonly investigated by analyzing target insects for the presence of honeydew 'signature' sugars, such as melezitose and erlose. However, our laboratory studies show that adults of the three insect orders investigated synthesize these 'honeydew-specific' sugars after sucrose feeding. 5. As the erlose-melezitose ratio of sucrose-fed Aphidius spp. and the hoverfly Episyrphus balteatus differed clearly from the honeydew sugar profiles of wheat infesting aphids, this ratio could be used as an alternative indicator of honeydew feeding. However, this method could not be used for the lacewing C. carnea. 6. Our data show that 55% (WW) and 59% (SW) of field-collected Aphidius spp. which showed evidence of sugar feeding could be classified as having consumed honeydew within the 24–48 h before collection. Evidence of honeydew feeding by hoverflies, on the other hand, was found to be much more variable, ranging from 0% in the WW field to 44% in the SW field. 7. This study shows that the detection of honeydew consumption in field-collected insects based on honeydew oligosaccharides can be feasible even when insects synthesize these oligosaccharides themselves.
Climatic determinants of budburst seasonality in four temperate‐zone tree species

summary Several physiological processes controlling tree phenology remain poorly understood and in particular bud dormancy. Many studies have emphasised the action of chilling temperatures in breaking dormancy. However, the eect of the preceding summer temperatures has rarely been investigated although there is some evidence that they may be involved in the settlement and intensity of dormancy as well as cold acclimation. In this paper, thermal time to budburst in relation to the duration of chilling outdoors, preceding summer temperatures and forcing temperatures was studied by outdoors experiments in seedlings of Platanus acerifolia, Vitis vinifera, Quercus pubescens and Castanea sativa. Results showed that temperatures of the preceding summer had no significant eect on the timing of budburst, P. acerifolia and Q. pubescens showed a very weak response to the duration of chilling, and the phenological characteristics of each species were found to be adapted to the climate conditions of its own geographical area. The phenological model used in this study explained 82‐100% of the variance of the data without taking into account summer temperatures. Thus, although summer temperatures may be well involved in the intensity of dormancy and cold hardiness, they do not significantly aect budburst and therefore may not need to be considered in phenological models for predicting budburst.
Impact of Culture Filtrate of Piriformospora indica on Biomass and Biosynthesis of Active Ingredient Aristolochic Acid in Aristolochia elegans Mart

The mycorrhiza plant partnership is the basic, essential and integral part of plant survival and growth. In the present investigation we are reporting the effect of culture filtrate of Piriformospora indica, a growth promoter and bioprotector fungus on Aristolochia elegans Mart. The culture filtrate of the fungus increased overall growth, biomass, and active ingredient-aristolochic acid in the leaves of plants. In untreated control plants, the overall growth was reduced. P. indica culture filtrate application increased root number, root length, and root dry weightby 28%, 98%, and 123% respectivelyin plants of Aristolochia. Also stem height and shoot length was enhanced by 43% and 155% respectively.There was increase in number of leaves by 79% and length of leaves by 36%. The increase in total biomass was 136%. The improvement in content of aristolochic acid in leaves was between7.6% and 28.8%in treated plants as against untreated control plants