Miracle-dz/UniFAR-FTUs huggingface dataset:
Renal elimination of a novel and potent αvβ3 integrin antagonist in animals

Compound A (3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]napthyridin-2-yl)propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid), a hydrophilic zwitterion, is a potent and selective αvβ3 integrin antagonist currently under clinical development for the treatment of osteoporosis. The mechanism of renal excretion of compound A was investigated using a combination of in vivo and in vitro approaches. In rats, renal excretion of compound A involved tubular secretion; ratios between renal clearance, corrected for unbound fraction in plasma (CLr,u) and glomerular filtration rate (GFR) were greater than unity (2–5). The tubular secretion of compound A was saturable at high plasma levels (> 26 μM), and was inhibited significantly, although modestly (about twofold) by relatively high plasma concentrations of the organic anion PAH (160 µM) and the cation cimetidine (about 400 μM), but not by the P-gp inhibitor quinidine (about 50 μM). However, compound A (about 100 μM) had a minimal effect on CLr/GFRs for cimetidine and PAH. In rhesus monkeys, renal elimination of compound A also involved tubular secretion, with a CLr,u/GFR ratio of about 30. The renal secretion of compound A was not affected by either cimetidine (about 120 μM) or PAH (about 80 μM). Similarly, compound A (about 40 μM) had a minimal effect on the renal tubular secretion of both cimetidine and PAH. At the doses studied, neither rat nor monkey plasma protein binding of compound A, cimetidine or PAH was affected in the presence of each other. In vitro transport studies showed that compound A was not a substrate for P-gp in the Caco-2, human MDR1 and mouse mdr1a transfected LLC-PK1 cell lines. In an uptake study using rOAT1 and rOAT3 transfected HEK cell lines, compound A was shown to be a substrate for rat OAT3 (Km = 15 μM), but not rat OAT1. The results suggest that the tubular secretion of compound A is not mediated by P-gp, but rather is mediated, at least in part, via the organic anion transporter OAT3, the renal transporter shown to be capable of transporting both the organic anion PAH and the organic cation cimetidine. Although there is a possibility for pharmacokinetic interactions between compound A and substrates or inhibitors of OAT3, at the renal excretion level, the magnitude of interaction would likely be modest in humans at clinically relevant doses.
Comparative Evaluation of Amino Acid Composition and Volatile Organic Compounds of Selected Nigerian Cucurbit Seeds

2 Abstract: Amino acid composition and volatile organic compounds (VOCS) of five Nigerian cucurbits namely: Luffa aegyptiaca (Mill.), Citrullus lanatus (Thunb. Matsum), Cucurbita maxima (Duchesne, ex Lam), Cucumis metuliferus (E.Mey. ex Naudin) and Momordica balsamina (L.) were investigated using Amino acid Analyzer and Gas Chromatography-Mass Spectrometry (GC-MS). The proportion of essential amino acids ranged from 22.75- 30.23 g/100 g protein with the highest content in M. balsamina with 30.23 g/100 g protein and the least in C. lanatus with 22.75 g/100 g protein. High content of leucine was found in C. maxima and M. balsamina with 7.04 and 6.11 g /100 g protein respectively. The GC-MS analysis revealed the presence of thirty-one compounds, the most abundant classes of organic compounds in L. aegyptiaca comprised of esters with 65.17% and Fatty Acids (FA) had 32.62% while hydrocarbons amounted to 29%. In C. lanatus , seve n compounds were identified dominated by FA and hydrocarbons with 91.5 and 7.25% respectively. In C. maxima, ten compounds were identified dominated by FA (52.24%) and hydrocarbons (43.46%). In C. metuliferus, FA had 30.74% while aromatic compounds and alcohol had 9.18 and 0.68%, respectively. Among the five seeds studied, the most abundant compounds identified were linoleic acid methyl ester in L. aegyptiaca with 63.72%. Cis-cis linoleic acid is most abundant in M. balsamina (62.03%) totaling the fatty acid portion to 86.41%. These results suggest the potential of the seeds as a source of amino acids and fatty acids that could be useful in food and feed fortification strategies. The unique VOCS could be useful as biomarkers for delimitation of the studied species.
Leaf analysis as a guide to the nutrition of fruit crops. VII.†—Sand culture N, P, K, Mg experiments with red raspberry (Rubus idaeus)

The main effects and interactions of N, P, K and Mg on cane growth, leaf nutrient composition and crop yield of red raspberry, grown in sand culture, were investigated. Results indicated that leaf-lamina samples taken from non-fruiting canes from late June to early August may be used as an index of the nutritional status of the crop. Leaf nutrient concentrations at this growth stage were related to crop yield in the following season. Optimum leaf-lamina concentrations in late July were thought to be: K, 1.5%; Mg, 0.3%; N, > 2.3%; P, > 0.2% in dry weight.
Comparison of models using different censoring scenarios for days open in Spanish Holstein cows

Abstract Days open data from 113 569 lactation records in 774 Spanish Holstein herds were analysed using standard linearmodels under two different editing procedures, and with two alternative methodologies that account for censoring: acensored linear model (CLM) and a Weibull survival analysis (SA) model. The ﬁrst editing procedure excluded from thelinear model all censored records for days open (LM nc ), and the second deﬁned days open as days from calving to thelast known insemination or culling date, treating censored records as complete (LM). Sire variance estimates for daysopen were 61, 70 and 139 for LM nc , LM and CLM, respectively, and 0·026 for SA on a logarithmic scale. Heritabilityestimates were 0·05, 0·06 and 0·08 with LM nc , LM and CLM, respectively. Rankings of sires varied betweenmethodologies: sire evaluations from LMnc and LM had rank correlations with evaluations from SA equal to 20·65 and20·82, respectively, and of 0·71 and 0·87 with evaluations from CLM. The rank correlation between evaluations from SAand CLM was 20·98, suggesting stronger agreement of sire rankings between models that take censoring intoaccount.The SA model had a better predictive ability of daughter fertility at early stages of lactation than the othermethods, as measured by chi-squared statistics for predicted pregnancy status at 75, 103, 140, or 200 days post partumin a split data set. The CLM also predicted daughter fertility more accurately than any of the two standard linear models.Keywords: dairy cows, fertility, linear models, survival analysis.
Structural basis of AZD9291 selectivity for EGFR T790M.

AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose with EGFR T790M remains unclear. Here we report unbiased, atomic-level molecular dynamics (MD) simulations in which spontaneous association of AZD9291 with EGFR kinases having WT and T790M mutant gatekeepers was observed. Simulation-generated structural models suggest that the binding pose of AZD9291 with T790M differs from its binding pose with the WT, and that AZD9291 interacts extensively with the gatekeeper residue (Met790) in T790M but not with Thr790 in the WT, which explain why AZD9291 binds T790M with higher affinity. The MD simulation-generated models were confirmed by experimentally determined EGFR/T790M complex crystal structures. This work may facilitate the rational design of drugs that overcome resistance mutations to AZD9291, and more generally it suggests the potential of using unbiased MD simulation to elucidate small-molecule binding poses.
Metformin directly suppresses atherosclerosis in normoglycaemic mice via haematopoietic adenosine monophosphate-activated protein kinase

Abstract Aims Atherosclerotic vascular disease has an inflammatory pathogenesis. Heme from intraplaque haemorrhage may drive a protective and pro-resolving macrophage M2-like phenotype, Mhem, via AMPK and activating transcription factor 1 (ATF1). The antidiabetic drug metformin may also activate AMPK-dependent signalling. Hypothesis: Metformin systematically induces atheroprotective genes in macrophages via AMPK and ATF1, thereby suppresses atherogenesis. Methods and results Normoglycaemic Ldlr−/− hyperlipidaemic mice were treated with oral metformin, which profoundly suppressed atherosclerotic lesion development (P < 5 × 10−11). Bone marrow transplantation from AMPK-deficient mice demonstrated that metformin-related atheroprotection required haematopoietic AMPK [analysis of variance (ANOVA), P < 0.03]. Metformin at a clinically relevant concentration (10 μM) evoked AMPK-dependent and ATF1-dependent increases in Hmox1, Nr1h2 (Lxrb), Abca1, Apoe, Igf1, and Pdgf, increases in several M2-markers and decreases in Nos2, in murine bone marrow macrophages. Similar effects were seen in human blood-derived macrophages, in which metformin-induced protective genes and M2-like genes, suppressible by si-ATF1-mediated knockdown. Microarray analysis comparing metformin with heme in human macrophages indicated that the transcriptomic effects of metformin were related to those of heme, but not identical. Metformin-induced lesional macrophage expression of p-AMPK, p-ATF1, and downstream M2-like protective effects. Conclusion Metformin activates a conserved AMPK-ATF1-M2-like pathway in mouse and human macrophages, and results in highly suppressed atherogenesis in hyperlipidaemic mice via haematopoietic AMPK.
Revision of the genus Glyphotmethis Bey-Bienko, 1951 (Orthoptera: Pamphagidae)

The complicated genus Glyphotmethis Bey-Bienko, 1951 is revised using the previous materials including the type specimens preserved in Museums and an abundance of new material collected mainly in Turkey. Diagnoses, ecology, distribution and taxonomic characters for the genus are provided. The function of Krauss’ organ is discussed. The followingseven taxa are proposed as junior synonyms: Glyphotmethis holtzi spinosus Karabag, 1956 is synonym with G. holtzi pulchripes (Uvarov, 1943), Glyphotmethis holtzi extimus Bey-Bienko, 1951 is synonym with G. holtzi holtzi (Werner, 1901), Glyphotmethis escherichi coloripes Cejchan, 1965 is synonym with G. escherichi elatior (Ramme, 1951), Glyphotmethis guichardi Cejchn, 1964 is synonym with G. escherichi escherichi (Krauss, 1896), Glyphotmethis raggei Cejchan, 1965 and Glyphotmethis adaliae angorensis Cejchan, 1965 are synonyms with G. escherichi inermis (Uvarov, 1934) and Glyphotmethis heldreichi macedonicus, Bey-Bienko, 1951 is synonym with G. heldreichi heldreichi (Brunner, 1882). One species, Glyphotmethis arasi, is removed from the genus and three new taxa, Glyphotmethis holtzi brachypterus ssp.n. , Glyphotmethis holtzi turcicus ssp.n. and Glyphotmethis efe sp.n. are described. The taxonomical status of some taxa are rearranged. A neotype is designated for Glyphotmethis eshcerichi escherichi (Krauss, 1896) from Ankara known as the type locality. Misidentified specimens and inaccurate records for taxa in previous papers are corrected and their geographical distributions adjusted. Many records are provided for new localities. Keys for the identification of species and subspecies are prepared using traditional and some new distinctive characters. A short description and comparison with close allies are given for each taxon. Distribution areas of the taxa and the contact zones between some subspecies are determined. In addition, 126 figures and 3 distributional maps are given.
Adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research Recommendations and Breast Cancer in the SUN Project

A proportion of breast cancer cases are attributable to combined modifiable risk factors. The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) has recently updated the recommendations for cancer prevention and a standard scoring system has been published. The aim of this study was to evaluate the association between compliance with the 2018 WCRF/AICR cancer prevention recommendations (Third Expert Report) and the risk of breast cancer in the SUN (“Seguimiento Universidad de Navarra”) prospective cohort. Spanish female university graduates, initially free of breast cancer, were included (n = 10,930). An 8-item score to measure compliance to the recommendations was built: body fat, physical activity, consumption of wholegrains/vegetables/fruit/beans, “fast foods”, red/processed meat consumption, sugar-sweetened drinks consumption, alcohol intake, and breastfeeding. A stratified analysis was conducted according to menopausal status. A non-significant inverse association was observed for overall breast cancer. The inverse association became statistically significant for post-menopausal breast cancer after multivariable adjustment (hazard ratio for > 5 vs. ≤ 3 points = 0.27; 95% CI: 0.08-0.93). The results suggested that the possible inverse association with breast cancer was attributable to the combined effects of the different nutritional and lifestyle components.
CYCLIC CO2 RELEASE IN DIAPAUSING AGAPEMA PUPAE

1. Forcing a few of the spiracles of the Agapema pupa to remain open abolishes the alternate retention and release ("burst") of CO2 and greatly augments water loss. The effects are reversed by sealing the inactivated spiracles.2. Pupae exposed to N2 after a normal CO2 burst has been produced release an additional volume of CO2 twice that of the original burst. The first cycle after such a "purge" is nearly twice as long as normal. These results further implicate the spiracles in CO2 retention and favor the idea that accumulation of CO2 triggers the burst.3. A statistical analysis of successive cycles within individual pupae indicates that burst volume tends to be constant, and comparison of individuals in a population shows significant inverse relations between metabolic rate and cycle length, and possibly between burst volume and cycle length. The significance of these findings is discussed in relation to the triggering of CO2 release and the rationale of the cycle.4. Mechanical disturbances may also tri.
The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome

Abstract Isoforms of the receptor for advanced glycation end-product (RAGE) protein, which lack the transmembrane and the signaling (soluble RAGE or sRAGE) domains are hypothesized to counteract the detrimental action of the full-length receptor by acting as a decoy, and they provide a potential tool to treat RAGE-associated diseases. Multiple studies have explored the relationship between sRAGE and endogenous secretory RAGE and its polymorphism and obesity, metabolic syndrome, atherosclerosis, kidney function, and increased mortality in the general population. In addition, sRAGE may be a key player in the pathogenesis of diabetes mellitus and its microvascular (e.g. kidney disease) as well as macrovascular (e.g. cardiovascular disease) complications. In this review, we focus on the role of sRAGE as a biomarker in these specific areas. As there is a lack of an underlying unifying hypothesis about how sRAGE changes according to the disease condition or risk factor, there is a call to incorporate all three players of the AGE-RAGE axis into a new universal biomarker/risk marker: (AGE + RAGE)/sRAGE. However, the measurement of RAGE in humans is not practical as it is a cell-bound receptor for which tissue is required for analysis. A high AGE/sRAGE ratio may be a valuable alternative and practical universal biomarker/risk marker for diseases associated with the AGE-RAGE axis, irrespective of low or high serum sRAGE concentrations.
Diversity and ecology of carrion- and fruit-feeding butterflies in Bornean rain forest

Tropical rain forests are well known as centres of insect diversity and much effort has focused on the role of larval host plant specificity in generating and maintaining this diversity, but fewer studies have examined the exploitation of different food resources by adults in this context. Tropical butterflies feed as adults on a wide range of resources and we examined the diversity and ecology of species feeding on rotting fruit and carrion in a tropical lowland rain forest in Sabah, Borneo. We found that species richness and diversity were significantly higher on carrion than on fruit, and that this pattern was repeated at genus and family level. There was little similarity in species assemblages on the two substrates and β-diversity between carrion and fruit comprised 33% of the total diversity of butterflies feeding on decaying matter. β-diversity between canopy gap and shade microhabitats comprised 21% of total species diversity on carrion but only 7% of the total on fruit, indicating greater functional diversity on carrion in terms of light preferences. Captures were strongly male-biased on carrion but not on fruit, and recapture rates were much lower on carrion than on fruit. Species from two subfamilies (Nymphalinae and Charaxinae) exploited both substrates and for Charaxinae, there was evidence from adult flight morphology that species on carrion were capable of faster more-powerful flight. These results support the notion of a distinctive carrion-feeding fauna comprising more mobile species, which may use carrion to meet additional nitrogen requirements resulting from greater musculature. However there was no relationship between flight morphology and substrate choice in the Nymphalinae, and carrion-feeding may not have a unitary explanation.
Performance of Four Fosfomycin Susceptibility Testing Methods against an International Collection of Clinical Pseudomonas aeruginosa Isolates

Fosfomycin has been shown to have a wide spectrum of activity against multidrug-resistant Gram-negative bacteria; however, breakpoints have been established only for Escherichia coli or Enterobacterales per the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), respectively. A lack of additional organism breakpoints limits clinical use of this agent and has prompted extrapolation of these interpretive categories to other organisms like Pseudomonas aeruginosa without supporting evidence. ABSTRACT Fosfomycin has been shown to have a wide spectrum of activity against multidrug-resistant Gram-negative bacteria; however, breakpoints have been established only for Escherichia coli or Enterobacterales per the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), respectively. A lack of additional organism breakpoints limits clinical use of this agent and has prompted extrapolation of these interpretive categories to other organisms like Pseudomonas aeruginosa without supporting evidence. Further complicating the utility of fosfomycin is the specified method for MIC determination, namely, agar dilution, which is not widely available and is both labor and time intensive. We therefore sought to determine the susceptibility of a large international collection of P. aeruginosa isolates (n = 198) to fosfomycin and to compare testing agreement rates across four methods: agar dilution, broth microdilution, disk diffusion, and Etest. Results were interpreted according to CLSI E. coli breakpoints, with 49.0 to 85.8% considered susceptible, dependent upon the testing method used. Epidemiological cutoff values were calculated and determined to be 256 μg/ml and 512 μg/ml for agar dilution and broth microdilution, respectively. Agreement rates were analyzed using both agar dilution and broth microdilution with a resulting high essential agreement rate of 91.3% between the two susceptibility testing methods. These results indicate that broth microdilution may be a reliable method for fosfomycin susceptibility testing against P. aeruginosa and stress the need for P. aeruginosa-specific breakpoints.
Heavy Metals in the Sea Cucumber Holothuria tubulosa (Echinodermata) from the Mediterranean Posidonia oceanica Ecosystem: Body Compartment, Seasonal, Geographical and Bathymetric Variations

The concentrations of Cd, Cu, Fe, Pb and Zn were measured in holothuroids Holothuria tubulosa collected during different seasons and at several depths in three N W Mediterranean Posidonia oceanica meadows (Calvi, Corsica; Ischia, Italy; Marseille, France). Metals were found to be selectively distributed among the holothuroid body compartments (i.e. body wall, gut, and haemal system). Among the sources of variation taken into account, the major part of the variability observed in metal concentrations was associated to the body compartment factor, then to the seasonal one and, finally, to the geographical and bathymetric factors. Our results suggest that, if one uses H. tubulosa as a bioindicator species for surveying and monitoring metal contamination in the Mediterranean P. oceanica meadows, attention should be paid to compare only concentrations measured in the same body compartments of individuals collected during the same period of the year. Body compartments that should be preferably considered for me.
From Physical Violence to Intensified Economic Abuse: Transitions Between the Types of IPV Over Survivors’ Life Courses

Scholars of intimate partner violence (IPV) cite the various forms of IPV perpetrated by violent male partners to establish their coercive control over women. This scholarship emphasizes IPV’s long-term destructive effects on survivors’ lives. However, until recently, the role of the state in the relationship between different manifestations of IPV has received little attention, leaving hazy the meaning of absent formal legislation. An opportunity to clarify the significance of this condition lies in Israel, where economic abuse is not yet recognized as grounds for legal and social sanctions. Based on in-depth interviews with 33 IPV survivors, the present study explores state actions involved in transitions between types of violence as revealed in cases of ongoing economic abuse.
Combined effects of five prothrombotic genotypes and cancer on the risk of a first venous thromboembolic event

The role of combined prothrombotic genotypes in cancer‐related venous thromboembolism (VTE) is scarcely studied. We aimed to investigate the impact of a 5‐single nucleotide polymorphism (SNP) score on the risk of VTE in patients with and without cancer using a population‐based case‐cohort.
Ultrasonographic findings of child acute appendicitis incorporated into a scoring system.

INTRODUCTION This study aimed to investigate the ultrasonographic features of child acute appendicitis and incorporate them into a scoring algorithm that will quantify the risk of complications and the strength of recommendation for surgical intervention. METHODS 179 patients with suspected appendicitis and who had undergone ultrasonographic examination were included in this study. Based on their medical evaluation and post-surgical histopathological results, patients were categorised into the confirmed appendicitis (n = 101); and non-appendicitis (n = 78) groups. RESULTS In the appendicitis group, the appendix was visualised in 66 (65.3%) patients. In cases where the appendix was not visualised, we looked out for secondary inflammatory signs, which were present in 32 (31.7%) patients. Using stepwise logistic regression, Blumberg's sign, free fluid or collection, hyperaemia, non-compressible appendix and an appendix diameter > 7 mm were found to be significant predictive factors for appendicitis. A new scoring system called POPs was developed, combining inflammatory predictors and ultrasonography findings, with an area under the receiving operating characteristic curve of 0.958 (95% confidence interval 0.929-0.986). CONCLUSION The newly developed POPs-based diagnosis scheme proved a promising alternative to existing scoring systems, such as the Alvarado score. Although further calibration would be beneficial, the proposed scoring scheme is simple and easy to understand, memorise and apply in the emergency room.