Increased Oxidative Metabolism and Neurotransmitter Cycling in the Brain of Mice Lacking the Thyroid Hormone Transporter Slc16a2 (Mct8)

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T₄ and T₃) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T₄ and T₃. Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-¹³C) glucose and brain extracts prepared and analyzed by ¹³C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T₃ by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.     

Assessing the performance of nonparametric estimators of species richness in meadows

To accurately measure the number of species in a biological community, a complete inventory should be performed, which is generally unfeasible; hopefully, estimators of species richness can help. Our main objectives were (i) to assess the performance of nonparametric estimators of plant species richness with real data from a small set of meadows located in the Basque campiña (northern Spain), and (ii) to apply the best estimator to a larger dataset to test the effects on plant species richness caused by environmental conditions and human practices. Two non-asymptotic and seven asymptotic accumulation functions were fitted to a randomized sample-based rarefaction curve computed with data from three well sampled meadows, and information theoretic methods were used to select the best fitting model; this was the Morgan-Mercer-Flodin, and its asymptote was taken as our best guess of true richness. Then, five nonparametric estimators were computed: ICE, Chao 2, Jackknife 1 and 2, and Bootstrap; MMRuns and MMMeans were also assessed. According to the criteria set for our performance assessment (i.e., bias, precision, and accuracy), the best estimator was Jackknife 1. Finally, Jackknife 1 was applied to assess the effects of terrain slope and soil parent material, and also fertilization, grazing, and mowing, on plant species richness from a larger dataset (20 meadows). Results suggested that grass cutting was causing a loss of richness close to 30%, as compared to unmowed meadows. It is concluded that the use of nonparametric estimators of species richness can improve the evaluation of biodiversity responses to human management practices.     

<Emphasis Type="Italic">MICA</Emphasis> response to gliadin in intestinal mucosa from celiac patients

MHC class I chain-related gene A (MICA), a putative independent susceptibility gene in autoimmune diseases, encodes a surface protein present in epithelial cells that binds to NKG2D, an activating receptor of NK, and T cells, and could function as a stress-inducible activator of the innate immune response. There is no evidence of a long-term implication of MICA in the celiac autoimmune process. However, it could be that gliadin activation of MICA occurs only during the initial stages of the disease. In order to determine whether MICA is activated in response to gliadin in patients with celiac disease (CD), small intestinal mucosa biopsy samples from ten long-standing celiac patients on a gluten-free diet and from five non-celiac individuals were incubated with and without gliadin for 4 h. Total RNA was purified and MICA, IFNG and NKG2D mRNA were quantified by fluorescent real-time RT-PCR. Expression levels were calculated relative to GAPDH. MICA expression was detected in both patients and controls, but incubation with gliadin induced a strong increase in samples from the treated CD group compared with the non-CD controls (P=0.028), while no differences were observed for IFNG or NKG2D mRNA levels. The gliadin-provoked over-expression of MICA in normalized tissues from CD patients suggests a role for this stress-induced activator of the immune response in the early stages of organ-specific autoimmune destruction, probably preceding the onset of inflammation.     

Neuronal Hyperactivity Disturbs ATP Microgradients,Impairs Microglial Motility,and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.     

A standardized reanalysis of molecular phylogenetic hypotheses of Gobioidei

Gobioidei is a suborder of perciform fishes with about 2000 species distributed worldwide. Despite the evolutionary and ecological importance of gobioids, their phylogenetic inter- and intrarelationships are still poorly understood. Only a few studies (either morphological or molecular) have tackled the phylogeny of Gobioidei as a whole. Of these, only six studies thus far have addressed gobioid intrarelationships based on molecular data (each using different taxon sampling, genes, outgroups and method of phylogenetic inference), yielding contrasting results regarding the phylogenetic relationships among major lineages. In this study, we have reanalysed data from four of these molecular phylogenetic studies of Gobioidei under standardization criteria (same outgroup and methods of phylogenetic inference) in order to assess the robustness of their results, as well as to identify which parts of the gobioid tree are least resolved. Results from all datasets reanalysed in this study are generally similar to those of the respective original studies, and suggest broad patterns of phylogenetic relationships among gobioid lineages. However, there are numerous topological discrepancies among the four studies, support is low for many phylogenetic relationships and topology tests are unable to reject the vast majority of alternative topologies tested. The concatenation of datasets yields a relatively robust phylogeny of major lineages of Gobioidei, but there are some issues of overlap and missing data, which are ameliorated with the inclusion of additional homologous sequences from GenBank that increase dataset completeness. Because both monophyly of major gobioid groups and phylogenetic relationships among them cannot be fully resolved, it is clear that further phylogenetic research is needed, and this should be accompanied by a major taxonomic revision of the Gobioidei. Nevertheless, even with the relatively unstable nature of the available molecular phylogenies, there are some monophyletic units that can be identified, and a basic structure of the gobioid tree appears evident.