The Nutritional Geometry of Resource Scarcity: Effects of Lean Seasons and Habitat Disturbance on Nutrient Intakes and Balancing in Wild Sifakas

Animals experience spatial and temporal variation in food and nutrient supply, which may cause deviations from optimal nutrient intakes in both absolute amounts (meeting nutrient requirements) and proportions (nutrient balancing). Recent research has used the geometric framework for nutrition to obtain an improved understanding of how animals respond to these nutritional constraints, among them free-ranging primates including spider monkeys and gorillas. We used this framework to examine macronutrient intakes and nutrient balancing in sifakas (Propithecus diadema) at Tsinjoarivo, Madagascar, in order to quantify how these vary across seasons and across habitats with varying degrees of anthropogenic disturbance. Groups in intact habitat experience lean season decreases in frugivory, amounts of food ingested, and nutrient intakes, yet preserve remarkably constant proportions of dietary macronutrients, with the proportional contribution of protein to the diet being highly consistent. Sifakas in disturbed habitat resemble intact forest groups in the relative contribution of dietary macronutrients, but experience less seasonality: all groups’ diets converge in the lean season, but disturbed forest groups largely fail to experience abundant season improvements in food intake or nutritional outcomes. These results suggest that: (1) lemurs experience seasonality by maintaining nutrient balance at the expense of calories ingested, which contrasts with earlier studies of spider monkeys and gorillas, (2) abundant season foods should be the target of habitat management, even though mortality might be concentrated in the lean season, and (3) primates’ within-group competitive landscapes, which contribute to variation in social organization, may vary in complex ways across habitats and seasons.     

Structure-activity relationship of the neurotransmitter alpha-bag cell peptide on Aplysia LUQ neurons: implications regarding its inactivation in the extracellular space.

Alpha-bag cell peptide [alpha-BCP (Ala-Pro-Arg-Leu-Arg-Phe-Tyr-Ser-Leu)] is a neurotransmitter that mediates bag cell-induced inhibition of left-upper-quadrant (LUQ) neurons L2, L3, L4, and L6 in the abdominal ganglion of Aplysia. Our recent biochemical studies have shown that alpha-BCP[1-9] is cleaved into alpha-BCP[1-2], [3-9], [1-5], [6-9], and [7-9] by a combination of three distinct peptidase activities located within the extracellular spaces of the CNS: A diaminopeptidase-IV (DAP-IV)-like enzyme cleaves alpha-BCP[1-9] at the 2-3 peptide bond; a neutral metalloendopeptidase (NEP)-like enzyme cleaves either alpha-BCP[1-9] or alpha-BCP[3-9] at the 5-6 bond; an aminopeptidase M-II (APM-II)-like enzyme cleaves alpha-BCP[6-9] at the 6-7 bond, but cleaves neither alpha-BCP[1-9], nor the other ganglionic peptidase products. To further understand the manner in which alpha-BCP is inactivated after release, that is loses its electrophysiological activity, we studied its structure-activity relationship by recording intracellularly from LUQ neurons in isolated abdominal ganglia that were arterially perfused with peptides dissolved in artificial sea water. The effects of alpha-BCP[1-9] and 15 of its fragments ([1-8], [1-7], [1-6], [1-5], [2-9], [3-9], [3-8], [6-9], [7-9], [8-9], [6-7], [6-8], [1-2], Phe, Tyr) indicated that the sequence Phe6-Tyr7 was both necessary and sufficient to produce LUQ inhibitory activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sources of Variability in Metabolite Measurements from Urinary Samples

Background

The application of metabolomics in epidemiological studies would potentially allow researchers to identify biomarkers associated with exposures and diseases. However, within-individual variability of metabolite levels caused by temporal variation of metabolites, together with technical variability introduced by laboratory procedures, may reduce the study power to detect such associations. We assessed the sources of variability of metabolites from urine samples and the implications for designing epidemiologic studies.

Methods

We measured 539 metabolites in urine samples from the Navy Colon Adenoma Study using liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectroscopy (GC-MS). The study collected 2–3 samples per person from 17 male subjects (age 38–70) over 2–10 days. We estimated between-individual, within-individual, and technical variability and calculated expected study power with a specific focus on large case-control and nested case-control studies.

Results

Overall technical reliability was high (median intraclass correlation = 0.92), and for 72% of the metabolites, the majority of total variance can be attributed to between-individual variability. Age, gender and body mass index explained only a small proportion of the total metabolite variability. For a relative risk (comparing upper and lower quartiles of “usual” levels) of 1.5, we estimated that a study with 500, 1,000, and 5,000 individuals could detect 1.0%, 4.5% and 75% of the metabolite associations.

Conclusions

The use of metabolomics in urine samples from epidemiological studies would require large sample sizes to detect associations with moderate effect sizes.     

Delayed-type cutaneous hypersensitivity to melanoma antigens and its implication in active specific immunotherapy in cancer

Summary In this study, we explored whether soluble tumor-cell surface-associated antigens (TAA) might be derived from autochthonous as well as allogeneic sources as immunogens for active specific immunotherapy. Using two popular cell membrane-bound antigen extraction techniques (3 M KCl and isotonic-hypotonic NaCl), we examined the immunogenic potential of such TAA and the specificity of immunologic host reactivity through a delayed-type cutaneous hypersensitivity reaction (DTH) as a guideline for their immunogenic potential in a human malignant melanoma model system. We found that either extraction technique could provide soluble TAA from both autochthonous and allogeneic sources capable of eliciting DTH. While evidence of positive DTH with autochthonous TAA reaffirms the immunogenicity of such TAA, the specificity of host reactivity against TAA derived from allogeneic sources is extremely difficult to establish, even with TAA partially purified by column chromatography in Sephadex G-200. Patients exhibited reactivity to other TAA derived from tumors of different histologies and often to more than one component isolated by column chromatography. Furthermore, when a group of melanoma patients was tested against a panel of melanoma antigens in any random combination, DTH to allogeneic TAA was seen in an unpredictable order and with inconsistent frequency. We conclude, therefore, that while autochthonous antigen immunizations may be justified, more careful studies will be necessary to define the antigenic profile of a given tumor (individual specificity vs shared specificity), establish specificity of alloantigens, and devise suitable methods for testing immunologic specificity for alloantigens, before rational immunotherapy with allogeneic tumor antigens will be feasible.     

Correction to: Reevaluation of Astrocyte‑Neuron Energy Metabolism with Astrocyte Volume Fraction Correction: Impact on Cellular Glucose Oxidation Rates,Glutamate–Glutamine Cycle Energetics,Glycogen Levels and Utilization Rates vs. Exercising Muscle,and Na+/K+ Pumping Rates

Neurochemical Research -     

The nutritional value of feeding on crops: Diets of vervet monkeys in a humanized landscape

Anthropogenic influences have dramatically altered the environments with which primates interact. In particular, the introduction of anthropogenic food sources to primate groups has implications for feeding behaviour, social behaviour, activity budgets, demography and life history. While the incorporation of anthropogenic foods can be beneficial to primates in a variety of nutritional ways including increased energetic return, they also carry risks associated with proximity to humans, such as risk of being hunted, disease risk and risk of conflict. Given such risks, we initiated a 3‐year study where we sought to understand the underlying nutritional motivations for anthropogenic food resource use by vervet monkeys (Cercopithecus aethiops) in the humanized matrix surrounding the Nabugabo Field Station in central Uganda. Feeding effort, defined as proportion of feeding scans spent on anthropogenic food, was not associated with ripe fruit availability nor with crop availability as determined by phenological monitoring. Likewise, there was no difference in the protein, fibre, or lipid composition of crop food items compared to wild food items. Individuals spent less time feeding overall in months over the 3 years with a higher proportion of time spent feeding on crop foods, suggesting a potential benefit in terms of accessibility (reduction in the proportion of activity budget devoted to feeding).     

Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption

We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4 × 10(-19)), near AHR, and 15q24 (P = 5.2 × 10(-14)), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2.     

Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore.

The overexpression of Bax kills cells by a mechanism that depends on induction of the mitochondrial permeability transition (MPT) (Pastorino, J. G., Chen, S.-T., Tafani, M., Snyder, J. W., and Farber, J. L. (1998) J. Biol. Chem. 273, 7770-7775). In the present study, purified, recombinant Bax opened the mitochondrial permeability transition pore (PTP). Depending on its concentration, Bax had two distinct effects. At a concentration of 125 nM, Bax caused the release of the intermembranous proteins cytochrome c and adenylate kinase and the release from the matrix of sequestered calcein, effects prevented by the inhibitor of the PTP cyclosporin A (CSA). At this concentration of Bax, there was no detectable mitochondrial swelling or depolarization. These effects of low Bax concentrations are interpreted as the consequence of transient, non-synchronous activation of the PTP followed by a prompt recovery of mitochondrial integrity. By contrast, Bax concentrations between 250 nM and 1 microM caused a sustained opening of the PTP with consequent persistent mitochondrial swelling and deenergization (the MPT). CSA prevented the MPT induced by Bax. Increasing concentrations of calcium caused a greater proportion of the mitochondria to undergo the MPT in the presence of Bax. Importantly, two known mediators of apoptosis, ceramide and GD3 ganglioside, potentiated the induction by Bax of the MPT. The data imply that Bax mediates the opening of the mitochondrial PTP with the resultant release of cytochrome c from the intermembranous space.     

LINE-1 methylation in granulocyte DNA and trihalomethane exposure is associated with bladder cancer risk

DNA methylation changes contribute to bladder carcinogenesis. Trihalomethanes (THM), a class of disinfection by-products, are associated with increased urothelial bladder cancer (UBC) risk. THM exposure in animal models produces DNA hypomethylation. We evaluated the relationship of LINE-1 5-methylcytosine levels (LINE-1%5mC) as outcome of long-term THM exposure among controls and as an effect modifier in the association between THM exposure and UBC risk. We used a case-control study of UBC conducted in Spain. We obtained personal lifetime residential THM levels and measured LINE-1%5mC by pyrosequencing in granulocyte DNA from blood samples in 548 incident cases and 559 hospital controls. Two LINE-1%5mC clusters (above and below 64%) were identified through unsupervised hierarchical cluster analysis. The association between THM levels and LINE-1%5mC was evaluated with β regression analyses and logistic regression was used to estimate odds ratios (OR) adjusting for covariables. LINE-1%5mC change between percentiles 75^th and 25^th of THM levels was 1.8% (95% confidence interval (CI): 0.1, 3.4%) among controls. THM levels above vs. below the median (26 μg/L) were associated with increased UBC risk, OR = 1.86 (95% CI: 1.25, 2.75), overall and among subjects with low levels of LINE-1%5mC (n = 975), OR = 2.14 (95% CI: 1.39, 3.30), but not associated with UBC risk among subjects’ high levels of LINE-1%5mC (n = 162), interaction P = 0.03. Results suggest a positive association between LINE-1%5mC and THM levels among controls, and LINE-1%5mC status may modify the association between UBC risk and THM exposure. Because reverse causation and chance cannot be ruled out, confirmation studies are warranted.     

Dissociation of clathrin coats coupled to the hydrolysis of ATP: role of an uncoating ATPase

ATP hydrolysis was used to power the enzymatic release of clathrin from coated vesicles. The 70,000-mol-wt protein, purified on the basis of its ATP-dependent ability to disassemble clathrin cages, was found to possess a clathrin-dependent ATPase activity. Hydrolysis was specific for ATP; neither dATP nor other ribonucleotide triphosphates would either substitute for ATP or inhibit the hydrolysis of ATP in the presence of clathrin cages. The ATPase activity is elicited by clathrin in the form of assembled cages, but not by clathrin trimers, the product of cage disassembly. The 70,000-mol-wt polypeptide, but not clathrin, was labeled by ATP in photochemical cross-linking, indicating that the hydrolytic site for ATP resides on the uncoating protein. Conditions of low pH or high magnesium concentration uncouple ATP hydrolysis from clathrin release, as ATP is hydrolyzed although essentially no clathrin is released. This suggests that the recognition event triggering clathrin-dependent ATP hydrolysis occurs in the absence of clathrin release, and presumably precedes such release.