Birth weight is inversely associated with central adipose tissue in healthy children and adolescents

Objective: Previous studies have explored the association between birth weight and excess childhood body fat, but few have used precise measures of body composition, leading to equivocal and sometimes contradictory results. Research Methods and Procedures: Subjects included 101 children who underwent DXA measurements between 1995 and 2000. Birth weight and gestational age were assessed using maternal recall. Multiple linear regression analysis was used to determine the relationship between birth weight and the following four outcome variables: total fat mass (FM), truncal fat mass (TrFM), percentage body fat (%BF), and TrFM adjusted for FM (TrFMadj), controlling for current weight and Tanner stage. Results: The mean age of the children studied was 12.9 ± 2.4 years, and the mean birth weight reported by subjects’ mothers was 3.3 ± 0.5 kg. The FM and TrFM were 12.8 ± 8.7 kg and 5.1 ± 4.1 kg, respectively, and the mean %BF was 22.9 ± 10.3%. Birth weight was a significant predictor of FM (p = 0.02) and %BF (p = 0.038). However, birth weight adjusted for gestational age (BWTadj) was a significant (p = 0.03) negative predictor of TrFMadj, independently of race, sex, Tanner stage, and current weight. Discussion: These results provide evidence that, even in childhood and adolescence, a higher birth weight is associated with higher FM and %BF, while a low birth weight is associated with TrFM, adjusted for FM.     

The quantification of erlotinib (OSI-774) and OSI-420 in human plasma by liquid chromatography-tandem mass spectrometry

An accurate and precise method was developed using HPLC-MS/MS to quantify erlotinib (OSI-774) and its O-desmethyl metabolite, OSI-420, in plasma. The advantages of this method include the use of a small sample volume, liquid-liquid extraction with high extraction efficiency and short chromatographic run times. The analytes were extracted from 100 microL plasma volume using hexane:ethyl acetate after midazolam was added to the sample for internal standardization. The compounds were separated on a Phenomenex C-18 Luna analytical column with acetonitrile:5 mM ammonium acetate as the mobile phase. All compounds were monitored by tandem mass spectrometry with electrospray positive ionization. The intra-day accuracy and precision (% coefficient of variation, % CV) estimates for erlotinib at 10 ng/mL were 90% and 9%, respectively. The intra-day accuracy and precision estimates for OSI-420 at 5 ng/mL were 80% and 4%, respectively. This method was used to quantify erlotinib and OSI-420 in plasma of patients (n=21) administered 150 mg erlotinib per day for non-small cell lung cancer.     

Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk

Common genetic variation could alter the risk for developing bladder cancer. We conducted a large-scale evaluation of single nucleotide polymorphisms (SNPs) in candidate genes for cancer to identify common variants that influence bladder cancer risk. An Illumina GoldenGate assay was used to genotype 1,433 SNPs within or near 386 genes in 1,086 cases and 1,033 controls in Spain. The most significant finding was in the 5′ UTR of VEGF (rs25648, p for likelihood ratio test, 2 degrees of freedom = 1 × 10⁻⁵). To further investigate the region, we analyzed 29 additional SNPs in VEGF, selected to saturate the promoter and 5′ UTR and to tag common genetic variation in this gene. Three additional SNPs in the promoter region (rs833052, rs1109324, and rs1547651) were associated with increased risk for bladder cancer: odds ratio (95% confidence interval): 2.52 (1.06–5.97), 2.74 (1.26–5.98), and 3.02 (1.36–6.63), respectively; and a polymorphism in intron 2 (rs3024994) was associated with reduced risk: 0.65 (0.46–0.91). Two of the promoter SNPs and the intron 2 SNP showed linkage disequilibrium with rs25648. Haplotype analyses revealed three blocks of linkage disequilibrium with significant associations for two blocks including the promoter and 5′ UTR (global p = 0.02 and 0.009, respectively). These findings are biologically plausible since VEGF is critical in angiogenesis, which is important for tumor growth, its elevated expression in bladder tumors correlates with tumor progression, and specific 5′ UTR haplotypes have been shown to influence promoter activity. Associations between bladder cancer risk and other genes in this report were not robust based on false discovery rate calculations. In conclusion, this large-scale evaluation of candidate cancer genes has identified common genetic variants in the regulatory regions of VEGF that could be associated with bladder cancer risk.     

Comparative visual acuity of coleoid cephalopods

The pelagic realm of the ocean is characterized by extremelyclear water and a lack of surfaces. Adaptations to the visualecology of this environment include transparency, fluorescence,bioluminescence, and deep red or black pigmentation. While thesignals that pelagic organisms send are increasingly well-understood,the optical capabilities of their viewers, especially for predatorswith camera-like vision such as fish and squid, are almost unknown.Aquatic camera-like vision is characterized by a spherical lensfocusing an image on the retina. Here, we measured the resolvingpower of the lenses of eight species of pelagic cephalopodsto obtain an approximation of their visual capabilities. Wedid this by focusing a standard resolution target through dissectedlenses and calculating their modulation transfer functions.The modulation transfer function (MTF) is the single most completeexpression of the resolving capabilities of a lens. Since theoptical and retinal capabilities of an eye are generally well-matched,we considered our measurements of cephalopod lens MTF to bea good proxy for their visual capabilities in vivo. In general,squid have optical capabilities comparable to other organismsgenerally assumed to have good vision, such as fish and birds.Surprisingly, the optical capability of the eye of Vampyroteuthisinfernalis rivals that of humans.     

Differential proteomics analysis of synaptic proteins identifies potential cellular targets and protein mediators of synaptic neuroprotection conferred by the slow Wallerian degeneration (Wlds) gene

Non-somatic synaptic and axonal compartments of neurons are primary pathological targets in many neurodegenerative conditions, ranging from Alzheimer disease through to motor neuron disease. Axons and synapses are protected from degeneration by the slow Wallerian degeneration (Wld(s)) gene. Significantly the molecular mechanisms through which this spontaneous genetic mutation delays degeneration remain controversial, and the downstream protein targets of Wld(s) resident in non-somatic compartments remain unknown. In this study we used differential proteomics analysis to identify proteins whose expression levels were significantly altered in isolated synaptic preparations from the striatum of Wld(s) mice. Eight of the 16 proteins we identified as having modified expression levels in Wld(s) synapses are known regulators of mitochondrial stability and degeneration (including VDAC1, Aralar1, and mitofilin). Subsequent analyses demonstrated that other key mitochondrial proteins, not identified in our initial screen, are also modified in Wld(s) synapses. Of the non-mitochondrial proteins identified, several have been implicated in neurodegenerative diseases where synapses and axons are primary pathological targets (including DRP-2 and Rab GDP dissociation inhibitor beta). In addition, we show that downstream protein changes can be identified in pathways corresponding to both Ube4b (including UBE1) and Nmnat1 (including VDAC1 and Aralar1) components of the chimeric Wld(s) gene, suggesting that full-length Wld(s) protein is required to elicit maximal changes in synaptic proteins. We conclude that altered mitochondrial responses to degenerative stimuli are likely to play an important role in the neuroprotective Wld(s) phenotype and that targeting proteins identified in the current study may lead to novel therapies for the treatment of neurodegenerative diseases in humans.     

Local adaptation in dispersal in multi‐resource landscapes

The distribution of resources in space has important consequences for the evolution of dispersal‐related traits. Dispersal moderates patterns of gene flow and, consequently, the potential for local adaptation to spatially differentiated resource types. We lack both models and experiments that evaluate how dispersal evolves in landscapes with multiple resources. Here, we investigate the evolution of dispersal in landscapes that contain two resource types that differ in their spatial autocorrelations. Individuals may possess ecological traits that give them a fitness advantage on one or the other resource. We find that resources differing in their spatial autocorrelation select for different optimal dispersal strategies and, further, that some multi‐resource landscapes can support the stable coexistence of distinct dispersal strategies. Whether divergence in dispersal strategies between resource specialists occurs depends on the underlying structure of the resources and the degree of linkage between dispersal strategies and ecological specialization. This work indicates that the spatial autocorrelation of resources is an important factor in determining when evolutionary branching is likely to occur, and sheds light on when secondary isolating mechanisms should arise between locally adapted specialists.     

Neomycin: An Effective Inhibitor of Jasmonate-Induced Reactions in Plants

Jasmonates are important phytohormones involved in both plant developmental processes as well as defense reactions. Many JA-mediated plant defense responses have been studied in model plants using mutants of the jasmonate signaling pathway. However, in plant species where JA-signaling mutants are not accessible, the availability of a tool targeting JA signaling is crucial to investigate jasmonate-dependent processes. Neomycin is a poly-cationic aminoglycoside antibiotic that blocks the release of Ca²⁺ from internal stores. We examined the inhibitory activities of neomycin on different jasmonate-inducible responses in eight different plant species: Intracellular calcium measurements in Nicotiana tabacum cell culture, Sporamin gene induction in Ipomoea batatas, PDF2.2 gene expression in Triticum aestivum, Nepenthesin protease activity measurement in Nepenthes alata, extrafloral nectar production in Phaseolus lunatus, nectary formation in Populus trichocarpa, terpene accumulation in Picea abies, and secondary metabolite generation in Nicotiana attenuata. We are able to show that neomycin, an easily manageable and commercially available compound, inhibits JA-mediated responses across the plant kingdom.

     

Synthesis and analysis of the enantiomers of calmidazolium,and a 1H NMR demonstration of a chiral interaction with calmodulin

Calmidazolium {R24571, 1-[bis(4-chlorophenyl)methyl]-3-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazolium chloride} is a potent calmodulin inhibitor. This paper describes the synthesis and properties of the enantiomers of calmidazolium from the enantiomers of miconazole {1(N)-(2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl))-ethyl imidazole}, prepared from the racemate by chiral preparative scale high performance liquid chromatography. Overlap between ligand and protein resonances in the aromatic region of the ¹H NMR spectrum of the calmidazolium-calmodulin complexes has been obviated by preparation of the protein with all of its nine phenylalanine rings deuterated (Phe-d₅ calmodulin). This has been accomplished by the overexpression of calmodulin derived from Trypanosoma brucei rhodiesiense in E. coli in a medium supplemented with ring-deuterated phenylalanine. The kinetics of binding of each enantiomer are slow on the ¹H NMR time scale as judged by the behaviour of the H2 resonance of Histidine-107, which is clearly visible under the sample conditions used. The aromatic spectral regions of the protein-bound (+) and (−) enantiomers contrast strikingly, reflecting differences in bound environment and/or conformation. Chirality 8:545–500, 1996. © 1997 Wiley-Liss, Inc.     

Regulation of bile acid synthesis. Isolation and characterization of microsomal phosphatases

In preliminary experiments, we have shown that rat liver microsomes possess phosphatase activity which was inhibited in the presence of sodium fluoride. We have now separated six microsomal phosphatase fractions appearing to be isoenzymes. They all possess different kinetic constants and are not equally inhibited by tartrate and fluoride ions, inhibitors of phosphatase activity. One phosphatase fraction, in fact, is almost completely unaffected by fluoride ion. More pertinent to our interest, these isoenzymes exhibit differing abilities to modulate the activities of hydroxymethylglutaryl CoA reductase, acyl-CoA:cholesterol O-acetyltransferase, and cholesterol 7 alpha-hydroxylase. Interaction of four of the fractions with rat liver microsomes resulted in a decrease in cholesterol 7 alpha-hydroxylase activity; two were without effect.