Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB ( 1 ). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties. 相似文献
Inspired by the incorporation of metallocene functionalities into a variety of bioactive structures, particularly antimicrobial peptides, we endeavored to broaden the structural variety of quaternary ammonium compounds (QACs) by the incorporation of the ferrocene moiety. Accordingly, 23 ferrocene-containing mono- and bisQACs were prepared in high yields and tested for activity against a variety of bacteria, including Gram-negative strains and a panel of clinically isolated MRSA strains. Ferrocene QACs were shown to be effective antiseptics with some displaying single-digit micromolar activity against all bacteria tested, demonstrating yet another step in the expansion of structural variety of antiseptic QACs. 相似文献
With the cessation of milk quotas in the European Union, dairy herd sizes increased in some countries, including Ireland, with an associated increase in labor requirement. Second to feed costs, labor has been identified as one of the highest costs on pasture-based dairy farms. Compared with other European Union countries, Ireland has historically had low milk production per labor unit; thus, optimization of labor efficiency on farm should be addressed before or concurrently with herd expansion. The objective of this study was to quantify current levels of labor input and labor efficiency on commercial pasture-based dairy farms and to identify the facilities and management practices associated with increased labor efficiency. Thirty-eight dairy farms of varying herd sizes, previously identified as labor-efficient farms, were enrolled on the study and data were collected over 3 consecutive days each month over a 12-mo period, starting in May 2015 and finishing in August of 2016. This was achieved through the use of a smartphone application. For analysis purposes, farms were categorized into 1 of 3 herd size categories (HSC): farms with <150 cows (HSC 1), 150–249 cows (HSC 2), or ≥250 cows (HSC 3). Overall farm labor input increased with HSC with 3,015, 4,499, and 6,023 h worked on HSC 1, 2, and 3, respectively. A higher proportion of work was carried out by hired staff as herd size increased. Labor efficiency was measured as total hours input to the dairy enterprise divided by herd size. Labor efficiency improved as herd size increased above 250 cows with 17.3 h/cow per yr observed for HSC 3; labor efficiency was similar for HSC 1 and 2, at 23.8 and 23.3 h/cow per yr, respectively. A large range of efficiency was observed within HSC. The labor requirements had a distinct seasonal pattern across the 3 HSC with the highest input observed in springtime (February to April) primarily due to calving and calf-care duties, milking, and winter feeding. The lowest input was observed in wintertime (November to January) when cows were dry. Particular facilities and management practices were associated with efficiency within certain tasks, the most notable in regard to milking and winter feeding practices. Additionally, the most efficient farms used contractors to perform a higher proportion of machinery work on farm than the least efficient farms. 相似文献
Cocaine is one of the most widely abused illicit drugs worldwide and has long been recognised as an agent of cardiac dysfunction in numerous cases of drug overdose. Cocaine has previously been shown to up-regulate cytoskeletal rearrangements and morphological changes in numerous tissues; however, previous literature observes such changes primarily in clinical case reports and addiction studies. An investigation into the fundamental cytoskeletal parameters of migration, adhesion and proliferation were studied to determine the cytoskeletal and cytotoxic basis of cocaine in cardiac cells. Treatment of cardiac myocytes with cocaine increased cell migration and adhesion (p < 0.05), with no effect on cell proliferation, except with higher doses eliciting (1–10 μg/mL) its diminution and increase in cell death. Cocaine downregulated phosphorylation of cofilin, decreased expression of adhesion modulators (integrin-β3) and increased expression of ezirin within three hours of 1 μg/mL treatments. These functional responses were associated with changes in cellular morphology, including alterations in membrane stability and a stellate-like phenotype with less compaction between cells. Higher dose treatments of cocaine (5–10 μg/mL) were associated with significant cardiomyocyte cell death (p < 0.05) and loss of cellular architecture. These results highlight the importance of cocaine in mediating cardiomyocyte function and cytotoxicity associated with the possible loss of intercellular contacts required to maintain normal cell viability, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis. 相似文献
The implementation of periodic boundary conditions (PBCs) is one of the most important and difficult steps in the computational analysis of structures and materials. This is especially true in cases such as mechanical metamaterials which typically possess intricate geometries and designs which makes finding and implementing the correct PBCs a difficult challenge. In this work, we analyze one of the most common PBCs implementation technique, as well as implement and validate an alternative generic method which is suitable to simulate any possible 2D microstructural geometry with a quadrilateral unit cell regardless of symmetry and mode of deformation. A detailed schematic of how both these methods can be employed to study 3D systems is also presented.
The burgeoning interest in archaic, traditional, and novel beer styles has coincided with a growing appreciation of the role of yeasts in determining beer character as well as a better understanding of the ecology and biogeography of yeasts. Multiple studies in recent years have highlighted the potential of wild Saccharomyces and non-Saccharomyces yeasts for production of beers with novel flavour profiles and other desirable properties. Yeasts isolated from spontaneously fermented beers as well as from other food systems (wine, bread, and kombucha) have shown promise for brewing application, and there is evidence that such cross-system transfers have occurred naturally in the past. We review here the available literature pertaining to the use of nonconventional yeasts in brewing, with a focus on the origins of these yeasts, including methods of isolation. Practical aspects of utilizing nondomesticated yeasts are discussed, and modern methods to facilitate discovery of yeasts with brewing potential are highlighted. 相似文献
Mysis diluviana is a major component of prey fish diets in the Great Lakes, so annual production of M. diluviana is important for understanding and modeling energy flow through Great Lakes food webs. However, only three lake-wide measurements of M. diluviana annual production in Lake Ontario are currently available (1971, 1990, 1995). During 2013, lake-wide coverage of Lake Ontario was achieved during four periods from April to November. Annual mean density and biomass of M. diluviana in 2013 were 99?#/m2 (SE: 8) and 318?mg?dw/m2 (SE: 28) – approximately half of values observed in 1990s. M. diluviana comprised 13–30% of offshore zooplankton biomass in each period. Reproduction peaked in fall, with mean brood size of 32 embryos (range: 11–49), at least 10% larger than in 1990s. Generation time was two years from embryo to initial reproduction. Growth rates were 0.052?mm/d for the age-0 cohort and 0.027?mm/d for the age-1 cohort. Age-0 growth rate was significantly higher than in 1980s–90s (0.035?mm/d). Annual production in 2013 was 0.85?g?dw/m2/yr (SE: 0.03) which was 30–40% of values observed in 1990 and 1995 (2.23 and 2.53?g/m2/yr). Annual production to biomass ratio (P/B) in 2013 was 2.65?/yr which was 80–85% of values observed in 1990 and 1995 (3.24 and 3.11?/yr), but this difference was not statistically significant. Our results suggest that changes in annual production over time can be estimated using changes in biomass over time and a mean P/B ratio. 相似文献
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
Diffuser plates in exhaust system manifolds are designed to provide uniform flow pattern within the manifold for maximum utilization of the catalytic converter substrate during high-temperature applications. In this paper, failure analysis of a diffuser which survived only 20% duration of a manifold crack test and various design optimization studies of the diffuser plate using computer-aided engineering (CAE) analyses are presented. During the manifold crack test, the failure occurred at the inner and outer periphery of the diffuser. Metallurgical failure analysis coupled with CAE thermal fatigue analysis of the component concluded that thermal fatigue was the root cause of the failure. The new recommended robust design showed considerable improvement in the thermal durability of the diffuser plate assembly. 相似文献