Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism

Modeling Biological Membranes with Circuit Boards and Measuring Electrical Signals in Axons: Student Laboratory Exercises

This is a demonstration of how electrical models can be used to characterize biological membranes. This exercise also introduces biophysical terminology used in electrophysiology. The same equipment is used in the membrane model as on live preparations. Some properties of an isolated nerve cord are investigated: nerve action potentials, recruitment of neurons, and responsiveness of the nerve cord to environmental factors

Reliability of Fronto-Amygdala Coupling during Emotional Face Processing.

One of the most exciting translational prospects for brain imaging research is the potential use of functional magnetic resonance imaging (fMRI) 'biomarkers' to predict an individual's risk of developing a neuropsychiatric disorder or the likelihood of responding to a particular intervention. This proposal depends critically on reliable measurements at the level of the individual. Several previous studies have reported relatively poor reliability of amygdala activation during emotional face processing, a key putative fMRI 'biomarker'. However, the reliability of amygdala connectivity measures is much less well understood. Here, we assessed the reliability of task-modulated coupling between three seed regions (left and right amygdala and the subgenual anterior cingulate cortex) and the dorsomedial frontal/cingulate cortex (DMFC), measured using a psychophysiological interaction analysis in 29 healthy individuals scanned approximately two weeks apart. We performed two runs on each day of three different emotional face-processing tasks: emotion identification, emotion matching, and gender classification. We tested both between-day reliability and within-day (between-run) reliability. We found good-to-excellent within-subject reliability of amygdala-DMFC coupling, both between days (in two tasks), and within day (in one task). This suggests that disorder-relevant regional coupling may be sufficiently reliable to be used as a predictor of treatment response or clinical risk in future clinical studies

Assessing the potential for egg chemoattractants to mediate sexual selection in a broadcast spawning marine invertebrate

In numerous species, egg chemoattractants play a critical role in guiding sperm towards unfertilized eggs (sperm chemotaxis). Until now, the known functions of sperm chemotaxis include increasing the effective target size of eggs, thereby promoting sperm–egg encounters, and facilitating species recognition. Here, we report that in the broadcast spawning mussel, Mytilus galloprovincialis, egg chemoattractants may play an unforeseen role in sexual selection by enabling sperm to effectively ‘choose’ between the eggs of different conspecific females. In an initial experiment, we confirmed that sperm chemotaxis occurs in M. galloprovincialis by showing that sperm are attracted towards unfertilized eggs when given the choice of eggs or no eggs in a dichotomous chamber. We then conducted two cross-classified mating experiments, each comprising the same individual males and females crossed in identical male × female combinations, but under experimental conditions that offered sperm ‘no-choice’ (each fertilization trial took place in a Petri dish and involved a single male and female) or a ‘choice’ of a female's eggs (sperm were placed in the centre of a dichotomous choice chamber and allowed to choose eggs from different females). We show that male-by-female interactions characterized fertilization rates in both experiments, and that there was remarkable consistency between patterns of sperm migration in the egg-choice experiment and fertilization rates in the no-choice experiment. Thus, sperm appear to exploit chemical cues to preferentially swim towards eggs with which they are most compatible during direct sperm-to-egg encounters. These results reveal that sperm differentially select eggs on the basis of chemical cues, thus exposing the potential for egg chemoattractants to mediate mate choice for genetically compatible partners. Given the prevalence of sperm chemotaxis across diverse taxa, our findings may have broad implications for sexual selection in other mating systems

Dramatic Plays as a Tool to Educate Young African-American Females about HIV/AIDS

Rates of HIV/AIDS transmission have increased substantially, particularly among young African American women. According to the Centers for Disease Control and Prevention (CDC), HIV/AIDS is the number one killer for African American women aged 25 to 34. Given that many of these young women are contracting the disease in their late teens and early twenties, there is a need to develop interventions that directly address the needs of this group. The current study sought to assess the effectiveness of theater in increasing knowledge of HIV/AIDS and the likelihood of healthier sexual behavior and choices among 219 young African American women 18 to 39 years of age. Paired sample t-tests revealed that there were significant mean differences in knowledge and intended safe sex behavior after viewing the play. Young women who viewed the play reported increased knowledge of HIV and reported a higher likelihood of engaging in safer sex. Given the high rates of HIV/AIDS among young African American women, more innovative educational and prevention techniques are needed

A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome

The collection of proteins secreted from a cell—the secretome—is of particular interest in cancer pathophysiology due to its diagnostic potential and role in tumorigenesis. However, cancer secretome studies are often limited to one tissue or cancer type or focus on biomarker prediction without exploring the associated functions. We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes. Using transcriptomic data spanning 32 cancer types and 30 healthy tissues, we quantified the relative diagnostic potential of secretome proteins for each cancer. Furthermore, we offer a potential mechanism by which cancer cells relieve secretory pathway stress by decreasing the expression of tissue-specific genes, thereby facilitating the secretion of proteins promoting invasion and proliferation. These results provide a more systematic understanding of the cancer secretome, facilitating its use in diagnostics and its targeting for therapeutic development

Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation, but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in vivo. Genome-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell types. Here, we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion model. In addition, we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human cells. The combined modeling reproduced severe hypoxic conditions and the Warburg effect, and we found that limitations in enzymatic capacity contribute to cancer cells’ preferential use of glutamine as a substrate to the citric acid cycle. Furthermore, we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer cells. We identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts, but when limiting to metabolites previously identified to participate in such collaboration, no growth advantage was observed. Our work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments

The evolution of culture and institutions: evidence from the Kuba Kingdom

We use variation in historical state centralization to examine the long-term impact of institutions on cultural norms. The Kuba Kingdom, established in Central Africa in the early 17th century by King Shyaam, had more developed state institutions than the other independent villages and chieftaincies in the region. It had an unwritten constitution, separation of political powers, a judicial system with courts and juries, a police force, a military, taxation, and significant public goods provision. Comparing individuals from the Kuba Kingdom to those from just outside the Kingdom, we find that centralized formal institutions are associated with weaker norms of rule following and a greater propensity to cheat for material gain. This finding is consistent with recent models where endogenous investments to inculcate values in children decline when there is an increase in the effectiveness of formal institutions that enforce socially desirable behavior. Consistent with such a mechanism, we find that Kuba parents believe it is less important to teach children values related to rule-following behaviors

A Millisecond Pulsar Optical Counterpart with Large-Amplitude Variability in the Globular Cluster 47 Tucanae

Using extensive HST imaging, combined with Chandra X-ray and Parkes radio data, we have detected the optical binary companion to a second millisecond pulsar (MSP) in the globular cluster 47 Tucanae. This faint (V=22.3) blue (V-I=0.7) star shows a large amplitude (60-70%) sinusoidal variation in both V and I. The period (3.19066 hr) and phase of the variation match those of the MSP 47 Tuc W (which does not have an accurate radio timing position) to within 0.5 seconds and 1.2 minutes respectively, well within the ~1sigma errors. The phase dependence of the intensity and color implies that heating of a tidally locked companion causes the observed variations. The eclipsing nature of this MSP in the radio, combined with the relatively large companion mass (> 0.13 solar masses) and the companion's position in the color-magnitude diagram, suggest that the companion is a main sequence star, a rare circumstance for an MSP companion. This system is likely to have had a complex evolution and represents an interesting case study in MSP irradiation of a close companion. We present evidence for another optical variable with similar properties to the companion of 47 Tuc W. This variable may also be an MSP companion, although no radio counterpart has yet been detected.Comment: 11 pages, 9 figures, accepted for publication in Ap

Phylogenetic relationships of Indian caecilians (Amphibia: Gymnophiona) inferred from mitochondrial rRNA gene sequences

India has a diverse caecilian fauna, including representatives of three of the six currently recognized families, the Caeciliidae, Ichthyophiidae, the endemic Uraeotyphlidae, but previous molecular phylogenetic studies of caecilians have not included sequences for any Indian caecilians. Partial 12S and 16S mitochondrial gene sequences were obtained for a single representative of each of the caecilian families found in India and aligned against previously reported sequences for 13 caecilian species. The resulting alignment (16 taxa, 1200 sites, of which 288 cannot be aligned unambiguously) was analyzed using parsimony, maximum-likelihood, and distance methods. As judged by bootstrap proportions, decay indices, and leaf stabilities, well-supported relationships of the Indian caecilians are recovered from the alignment. The data (1) corroborate the hypothesis, based on morphology, that the Uraeotyphlidae and Ichthyophiidae are sister taxa, (2) recover a monophyletic Ichthyophiidae, including Indian and South East Asian representatives, and (3) place the Indian caeciliid Gegeneophis ramaswamii as the sister group of the caeciliid caecilians of the Seychelles. Rough estimates of divergence times suggest an origin of the Uraeotyphlidae and Ichthyophiidae while India was isolated from Laurasia and Africa and are most consistent with an Indian origin of these families and subsequent dispersal of ichthyophiids into South East Asia