Synthesis and SAR of 2,3-diarylpyrrole inhibitors of parasite cGMP-dependent protein kinase as novel anticoccidial agents

Several analogs of 2,3-diaryl pyrroles were synthesized and evaluated as inhibitors of Eimeria tenella cGMP-dependent protein kinase and in in vivo anticoccidial assays. A 4-fluorophenyl group enhances both in vitro and in vivo activities. The most potent analogs are the 5-(N-methyl, N-ethyl, and N-methylazetidine methyl) piperidyl derivatives 12, 23, and 34. These compounds have a broad spectrum of activity. Based on the in vivo efficacy and cost of synthesis, the N-ethyl analog 23 was chosen as a novel anticoccidial agent for a field trial.     

Effect of serum concentration on the cytotoxicity of clay particles

Nanoparticle cytotoxicity testing based on in vitro methods frequently lack consistency. Even the inclusion of the commonly employed growth supplement, FCS (fetal calf serum), generates variable results. Thus, our object was to investigate the effect of FCS concentration on the cytotoxic behaviour of the unmodified nanoclay, Cloisite® Na⁺. Human monocytic U937 cells in medium supplemented with 5% FCS, 2.5% FCS or serum‐free medium were treated with 1 mg/ml Cloisite Na⁺. Cell growth in 2.5% FCS was significantly inhibited by Cloisite Na⁺ within 48 h, whereas little effect was seen with a supplement of 5% FCS. Without serum, cell growth was inhibited and Cloisite Na⁺ had a detrimental effect on these cells. In media supplemented with FCS, the nanoclays agglomerated together to form large bundles, whereas they were evenly dispersed throughout the medium in the absence of serum. Clay particles, therefore, have cytotoxic properties that may be linked to their dispersion pattern. These adverse effects seem to be masked by 5% FCS. Serum supplementation is an important consideration in the toxicological assessments of nanomaterials on cells, which needs to be addressed in the standardization of in vitro testing methods.     

Functional organization of adult motor cortex is dependent upon continued protein synthesis

The functional organization of adult cerebral cortex is characterized by the presence of highly ordered sensory and motor maps. Despite their archetypical organization, the maps maintain the capacity to rapidly reorganize, suggesting that the neural circuitry underlying cortical representations is inherently plastic. Here we show that the circuitry supporting motor maps is dependent upon continued protein synthesis. Injections of two different protein synthesis inhibitors into adult rat forelimb motor cortex caused an immediate and enduring loss of movement representations. The disappearance of the motor map was accompanied by a significant reduction in synapse number, synapse size, and cortical field potentials and caused skilled forelimb movement impairments. Further, motor skill training led to a reappearance of movement representations. We propose that the circuitry of adult motor cortex is perpetually labile and requires continued protein synthesis in order to maintain its functional organization.     

Mitochondrial genomes of a bandicoot and a brushtail possum confirm the monophyly of australidelphian marsupials.

Recent molecular analyses suggest that the position of bandicoots is the major difficulty in determining the root of the tree of extant marsupials. To resolve this, we analyse mitochondrial genome sequences of a bandicoot (Isoodon macrourus) and a brushtail possum (Trichosurus vulpecula) together with the previously available marsupial mitochondrial genomes, the Virginia opossum (Didelphis virginiana) and the wallaroo (Macropus robustus). Analyses of mitochondrial protein-coding and RNA genes strongly support the bandicoot as sister to the wallaroo and the brushtail possum. This result, combined with other recent molecular analyses, confirms the monophyly of Australidelphia (Australasian marsupials plus Dromiciops from South America). Further, RY coding was found to nullify AGCT coding nucleotide composition bias.     

Maternal obesity is associated with younger age at obesity onset in U.S. adolescent offspring followed into adulthood

Objective: The objective was to test the hypothesis that maternal obesity is associated with younger age of offspring's obesity onset. Research Methods and Procedures: We used prospective, nationally representative, longitudinal data collected across Waves I (1995; 12 to 20 years), II (1996; 13 to 20 years), and III (2001; 18 to 28 years) of the National Longitudinal Study of Adolescent Health (N = 14,654; 49% female). Interval regression analysis was used to assess the association between maternal obesity and age at offspring's obesity onset (International Obesity Task Force BMI ≥30 equivalent age‐ and sex‐specific cut‐off points for adolescents and BMI ≥30 for young adults) using self‐reported heights and weights, adjusting for race/ethnicity, sex, parental education, and family income, accounting for complex sampling design. Results: The net effect of having an obese mother varied by race/ethnicity and was associated with a significantly earlier age at obesity onset (p = 0.0001) for whites [β= ?8.1 year, 95% confidence interval (CI), ?9.3; ?6.9)], blacks (β = ?10.8 years, 95% CI, ?12.4; ?9.2), Hispanics (β = ?7.0 years, 95% CI, ?9.2; ?4.8), and Asians (β = ?8.6 years, 95% CI, ?13.3; ?3.9). Earlier obesity onset (<18 years) was associated with increased severity at young adulthood (mean BMI, 36.0 ± 0.3 kg/m²) vs. onset after age 18 (mean BMI, 34.4 ± 0.2 kg/m²; p = 0.0001). There were no sex differences in the association of maternal obesity to age at obesity onset. Conclusions: Having an obese mother was associated with earlier age at obesity onset across all race/ethnic groups, particularly non‐Hispanic blacks. Early obesity onset has important health consequences because of its association with more severe adult obesity.     

An invasive species may be better than none: invasive signal and native noble crayfish have similar community effects

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A portable surface plasmon resonance sensor system for real-time monitoring of small to large analytes

Many environmental applications exist for biosensors capable of providing real-time analyses. One pressing current need is monitoring for agents of chemical- and bio-terrorism. These applications require systems that can rapidly detect small organics including nerve agents, toxic proteins, viruses, spores and whole microbes. A second area of application is monitoring for environmental pollutants. Processing of grab samples through chemical laboratories requires significant time delays in the analyses, preventing the rapid mapping and cleanup of chemical spills. The current state of development of miniaturized, integrated surface plasmon resonance (SPR) sensor elements has allowed for the development of inexpensive, portable biosensor systems capable of the simultaneous analysis of multiple analytes. Most of the detection protocols make use of antibodies immobilized on the sensor surface. The Spreeta 2000 SPR biosensor elements manufactured by Texas Instruments provide three channels for each sensor element in the system. A temperature-controlled two-element system that monitors for six analytes is currently in use, and development of an eight element sensor system capable of monitoring up to 24 different analytes will be completed in the near future. Protein toxins can be directly detected and quantified in the low picomolar range. Elimination of false positives and increased sensitivity is provided by secondary antibodies with specificity for different target epitopes, and by sensor element redundancy. Inclusion of more than a single amplification step can push the sensitivity of toxic protein detection to femtomolar levels. The same types of direct detection and amplification protocols are used to monitor for viruses and whole bacteria or spores. Special protocols are required for the detection of small molecules. Either a competition type assay where the presence of analyte inhibits the binding of antibodies to surface-immobilized analyte, or a displacement assay, where antibodies bound to analyte on the sensor surface are displaced by free analyte, can be used. The small molecule detection assays vary in sensitivity from the low micromolar range to the high picomolar.     

Interference with withdrawal signs of naloxone-induced opiate withdrawal under anesthesia is anesthetic-specific in opiate-dependent rats.

We hypothesized that interference of opiate antagonist-precipitated withdrawal signs under anesthesia is anesthetic-specific. Three groups of morphine-dependent rats were compared in different experimental conditions using a protocol of rapid withdrawal induction by an antagonist under anesthesia. We observed that ketamine and midazolam have different effects on the expression of withdrawal. This brings specific insights into the pharmacological basis of therapy with induction of opiate antagonist.     

Analysis of lambda receptor and beta-lactamase synthesis and export using cloned genes in a minicell system

Summary We have cloned lamB, the gene for receptor (an outer membrane protein), on a small plasmid which also carries the gene for -lactamase (a periplasmic protein). We have identified a promoter in the region of malK, the gene immediately preceding lamB, which is active in minicells but relatively inactive in vitro. Using a minicell system, we have found that both receptor and -lactamase are made as full length precursors which are subsequently processed. We also show that the receptor precursor can be exported to the outer membrane before it is processed. Mature -lactamase is found only in the periplasm, suggesting that processing may be a requirement for export to the periplasm.