Lactate transporters in the rat barrel cortex sustain whisker-dependent BOLD fMRI signal and behavioral performance

Lactate is an efficient neuronal energy source, even in presence of glucose. However, the importance of lactate shuttling between astrocytes and neurons for brain activation and function remains to be established. For this purpose, metabolic and hemodynamic responses to sensory stimulation have been measured by functional magnetic resonance spectroscopy and blood oxygen level-dependent (BOLD) fMRI after down-regulation of either neuronal MCT2 or astroglial MCT4 in the rat barrel cortex. Results show that the lactate rise in the barrel cortex upon whisker stimulation is abolished when either transporter is down-regulated. Under the same paradigm, the BOLD response is prevented in all MCT2 down-regulated rats, while about half of the MCT4 down-regulated rats exhibited a loss of the BOLD response. Interestingly, MCT4 down-regulated animals showing no BOLD response were rescued by peripheral lactate infusion, while this treatment had no effect on MCT2 down-regulated rats. When animals were tested in a novel object recognition task, MCT2 down-regulated animals were impaired in the textured but not in the visual version of the task. For MCT4 down-regulated animals, while all animal succeeded in the visual task, half of them exhibited a deficit in the textured task, a similar segregation into two groups as observed for BOLD experiments. Our data demonstrate that lactate shuttling between astrocytes and neurons is essential to give rise to both neurometabolic and neurovascular couplings, which form the basis for the detection of brain activation by functional brain imaging techniques. Moreover, our results establish that this metabolic cooperation is required to sustain behavioral performance based on cortical activation.

IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth

In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.

Metabolic and enzymatic elucidation of cooperative degradation of red seaweed agarose by two human gut bacteria

Various health beneficial outcomes associated with red seaweeds, especially their polysaccharides, have been claimed, but the molecular pathway of how red seaweed polysaccharides are degraded and utilized by cooperative actions of human gut bacteria has not been elucidated. Here, we investigated the enzymatic and metabolic cooperation between two human gut symbionts, Bacteroides plebeius and Bifidobacterium longum ssp. infantis, with regard to the degradation of agarose, the main carbohydrate of red seaweed. More specifically, B. plebeius initially decomposed agarose into agarotriose by the actions of the enzymes belonging to glycoside hydrolase (GH) families 16 and 117 (i.e., BpGH16A and BpGH117) located in the polysaccharide utilization locus, a specific gene cluster for red seaweed carbohydrates. Then, B. infantis extracted energy from agarotriose by the actions of two agarolytic β-galactosidases (i.e., Bga42A and Bga2A) and produced neoagarobiose. B. plebeius ultimately acted on neoagarobiose by BpGH117, resulting in the production of 3,6-anhydro-l-galactose, a monomeric sugar possessing anti-inflammatory activity. Our discovery of the cooperative actions of the two human gut symbionts on agarose degradation and the identification of the related enzyme genes and metabolic intermediates generated during the metabolic processes provide a molecular basis for agarose degradation by gut bacteria.

Synergistic coevolution accelerates genome evolution

Ecological interactions are key drivers of evolutionary change. Although it is welldocumented that antagonistic coevolution can accelerate molecular evolution, the evolutionary consequences of synergistic coevolution remain poorly understood. Here we show experimentally that also synergistic coevolution can speed up the rate of molecular evolution. Pairs of auxotrophic genotypes of the bacterium Escherichia coli, whose growth depended on a reciprocal exchange of amino acids, were experimentally coevolved, and compared to two control groups of independently growing cells. Coevolution drove the rapid emergence of a strong metabolic cooperation that correlated with a significantly increased number of mutations in coevolved auxotrophs as compared to monoculture controls. These results demonstrate that synergistic coevolution can cause rapid evolution that in the long run may drive diversification of mutualistically interacting species.

Structure and Functions of Gap Junctions and Their Constituent Connexins in the Mammalian CNS

Abstract— Numerous data obtained in the last 20 years indicate that all parts of the mature central nervous system, from the retina and olfactory bulb to the spinal cord and brain, contain cells connected by gap junctions (GJs). The morphological basis of the GJs is a group of joined membrane hemichannels called connexons, the subunit of each connexon is the protein connexin. In the central nervous system, connexins show specificity and certain types of them are expressed either in neurons or in glial cells. Connexins and GJs of neurons, combining certain types of inhibitory hippocampal and neocortical neuronal ensembles, provide synchronization of local impulse and rhythmic activity, thalamocortical conduction, control of excitatory connections, which reflects their important role in the processes of perception, concentration of attention and consolidation of memory, both on the cellular and at the system level. Connexins of glial cells are ubiquitously expressed in the brain, and the GJs formed by them provide molecular signaling and metabolic cooperation and play a certain role in the processes of neuronal migration during brain development, myelination, tissue homeostasis, and apoptosis. At the same time, mutations in the genes of glial connexins, as well as a deficiency of these proteins, are associated with such diseases as congenital neuropathies, hearing loss, skin diseases, and brain tumors. This review summarizes the existing data of numerous molecular, electrophysiological, pharmacological, and morphological studies aimed at progress in the study of the physiological and pathophysiological significance of glial and neuronal connexins and GJs for the central nervous system.

Anode Surface Bioaugmentation Enhances Deterministic Biofilm Assembly in Microbial Fuel Cells

ABSTRACT Microbial fuel cells (MFCs) generate energy while aiding the biodegradation of waste through the activity of an electroactive mixed biofilm. Metabolic cooperation is essential for MFCs’ efficiency, especially during early colonization. Thus, examining specific ecological processes that drive the assembly of anode biofilms is highly important for shortening startup times and improving MFC performance, making this technology cost-effective and sustainable. Here, we use metagenomics to show that bioaugmentation of the anode surface with a taxonomically defined electroactive consortium, dominated by Desulfuromonas, resulted in an extremely rapid current density generation. Conversely, the untreated anode surface resulted in a highly stochastic and slower biofilm assembly. Remarkably, an efficient anode colonization process was obtained only if wastewater was added, leading to a nearly complete replacement of the bioaugmented community by Geobacter lovleyi. Although different approaches to improve MFC startup have been investigated, we propose that only the combination of anode bioaugmentation with wastewater inoculation can reduce stochasticity. Such an approach provides the conditions that support the growth of specific newly arriving species that positively support the fast establishment of a highly functional anode biofilm. IMPORTANCE Mixed microbial communities play important roles in treating wastewater, in producing renewable energy, and in the bioremediation of pollutants in contaminated environments. While these processes are well known, especially the community structure and biodiversity, how to efficiently and robustly manage microbial community assembly remains unknown. Moreover, it has been shown that a high degree of temporal variation in microbial community composition and structure often occurs even under identical environmental conditions. This heterogeneity is directly related to stochastic processes involved in microbial community organization, similarly during the initial stages of biofilm formation on surfaces. In this study, we show that anode surface pretreatment alone is not sufficient for a substantial improvement in startup times in microbial fuel cells (MFCs), as previously thought. Rather, we have discovered that the combination of applying a well-known consortium directly on the anode surface together with wastewater (including the bacteria that they contain) is the optimized management scheme. This allowed a selected colonization process by the wastewater species, which improved the functionality relative to that of untreated systems.

Catalytic promiscuity in the RNA World may have aided the evolution of prebiotic metabolism

The Metabolically Coupled Replicator System (MCRS) model of early chemical evolution offers a plausible and efficient mechanism for the self-assembly and the maintenance of prebiotic RNA replicator communities, the likely predecessors of all life forms on Earth. The MCRS can keep different replicator species together due to their mandatory metabolic cooperation and limited mobility on mineral surfaces, catalysing reaction steps of a coherent reaction network that produces their own monomers from externally supplied compounds. The complexity of the MCRS chemical engine can be increased by assuming that each replicator species may catalyse more than a single reaction of metabolism, with different catalytic activities of the same RNA sequence being in a trade-off relation: one catalytic activity of a promiscuous ribozyme can increase only at the expense of the others on the same RNA strand. Using extensive spatially explicit computer simulations we have studied the possibility and the conditions of evolving ribozyme promiscuity in an initial community of single-activity replicators attached to a 2D surface, assuming an additional trade-off between replicability and catalytic activity. We conclude that our promiscuous replicators evolve under weak catalytic trade-off, relatively strong activity/replicability trade-off and low surface mobility of the replicators and the metabolites they produce, whereas catalytic specialists benefit from very strong catalytic trade-off, weak activity/replicability trade-off and high mobility. We argue that the combination of conditions for evolving promiscuity are more probable to occur for surface-bound RNA replicators, suggesting that catalytic promiscuity may have been a significant factor in the diversification of prebiotic metabolic reaction networks.