Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection

Many new gene copies emerged by gene duplication in hominoids, but little is known with respect to their functional evolution. Glutamate dehydrogenase (GLUD) is an enzyme central to the glutamate and energy metabolism of the cell. In addition to the single, GLUD-encoding gene present in all mammals (GLUD1), humans and apes acquired a second GLUD gene (GLUD2) through retroduplication of GLUD1, which codes for an enzyme with unique, potentially brain-adapted properties. Here we show that whereas the GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. Using evolutionary analysis and resurrected ancestral protein variants, we demonstrate that the enhanced mitochondrial targeting specificity of GLUD2 is due to a single positively selected glutamic acid-to-lysine substitution, which was fixed in the N-terminal mitochondrial targeting sequence (MTS) of GLUD2 soon after the duplication event in the hominoid ancestor ~18–25 million years ago. This MTS substitution arose in parallel with two crucial adaptive amino acid changes in the enzyme and likely contributed to the functional adaptation of GLUD2 to the glutamate metabolism of the hominoid brain and other tissues. We suggest that rapid, selectively driven subcellular adaptation, as exemplified by GLUD2, represents a common route underlying the emergence of new gene functions

Flexible inhibitory control of visually evoked defensive behavior by the ventral lateral geniculate nucleus

Animals can choose to act upon, or to ignore, sensory stimuli, depending on circumstance and prior knowledge. This flexibility is thought to depend on neural inhibition, through suppression of inappropriate and disinhibition of appropriate actions. Here, we identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic area, as a critical node for control of visually evoked defensive responses in mice. The activity of vLGN projections to the medial superior colliculus (mSC) is modulated by previous experience of threatening stimuli, tracks the perceived threat level in the environment, and is low prior to escape from a visual threat. Optogenetic stimulation of the vLGN abolishes escape responses, and suppressing its activity lowers the threshold for escape and increases risk-avoidance behavior. The vLGN most strongly affects visual threat responses, potentially via modality-specific inhibition of mSC circuits. Thus, inhibitory vLGN circuits control defensive behavior, depending on an animal’s prior experience and its anticipation of danger in the environment

Flexible inhibitory control of visually evoked defensive behavior by the ventral lateral geniculate nucleus

Animals can choose to act upon, or to ignore, sensory stimuli, depending on circumstance and prior knowledge. This flexibility is thought to depend on neural inhibition, through suppression of inappropriate and disinhibition of appropriate actions. Here, we identified the ventral lateral geniculate nucleus (vLGN), an inhibitory prethalamic area, as a critical node for control of visually evoked defensive responses in mice. The activity of vLGN projections to the medial superior colliculus (mSC) is modulated by previous experience of threatening stimuli, tracks the perceived threat level in the environment, and is low prior to escape from a visual threat. Optogenetic stimulation of the vLGN abolishes escape responses, and suppressing its activity lowers the threshold for escape and increases risk-avoidance behavior. The vLGN most strongly affects visual threat responses, potentially via modality-specific inhibition of mSC circuits. Thus, inhibitory vLGN circuits control defensive behavior, depending on an animal’s prior experience and its anticipation of danger in the environment

Chromosome looping at the human alpha-globin locus is mediated via the major upstream regulatory element (HS-40)

Previous studies in the mouse have shown that high levels of alpha-globin gene expression in late erythropoiesis depend on long-range, physical interactions between remote upstream regulatory elements and the globin promoters. Using quantitative chromosome conformation capture (q3C), we have now analyzed all interactions between 4 such elements lying 10 to 50 kb upstream of the human alpha cluster and their interactions with the alpha-globin promoter. All of these elements interact with the alpha-globin gene in an erythroid-specific manner. These results were confirmed in a mouse model of human alpha globin expression in which the human cluster replaces the mouse cluster in situ (humanized mouse). We have also shown that expression and all of the long-range interactions depend largely on just one of these elements; removal of the previously characterized major regulatory element (called HS -40) results in loss of all the interactions and alpha-globin expression. Reinsertion of this element at an ectopic location restores both expression and the intralocus interactions. In contrast to other more complex systems involving multiple upstream elements and promoters, analysis of the human alpha-globin cluster during erythropoiesis provides a simple and tractable model to understand the mechanisms underlying long-range gene regulation

Exact Solutions of the Klein-Gordon Equation in the Presence of a Dyon, Magnetic Flux and Scalar Potential in the Specetime of Gravitational Defects

In this paper we analyse the relativistic quantum motion of a charged spin-0 particle in the presence of a dyon, Aharonov-Bohm magnetic field and scalar potential, in the spacetimes produced by an idealized cosmic string and global monopole. In order to develop this analysis, we assume that the dyon and the Aharonov-Bohm magnetic field are superposed to both gravitational defects. Two distinct configurations for the scalar potential, $S(r)$, are considered: $i)$ the potential proportional to the inverse of the radial distance, i.e., $S\propto1/r$, and $ii)$ the potential proportional to this distance, i.e., $S\propto r$. For both cases the center of the potentials coincide with the dyon's position. In the case of the cosmic string the Aharonov-Bohm magnetic field is considered along the defect, and for the global monopole this magnetic field pierces the defect. The energy spectra are computed for both cases and explicitly shown their dependence on the electrostatic and scalar coupling constants. Also we analyse scattering states of the Klein-Gordon equations, and show how the phase shifts depend on the geometry of the spacetime and on the coupling constants parameter.Comment: To be published in CQG. Minor comments adde

Nonrelativistic Quantum Analysis of the Charged Particle-Dyon System on a Conical Spacetime

In this paper we develop the nonrelativistic quantum analysis of the charged particle-dyon system in the spacetime produced by an idealized cosmic string. In order to do that, we assume that the dyon is superposed to the cosmic string. Considering this peculiar configuration {\it conical} monopole harmonics are constructed, which are a generalizations of previous monopole harmonics obtained by Wu and Yang(1976 {\it Nucl. Phys. B} {\bf 107} 365) defined on a conical three-geometry. Bound and scattering wave functions are explicitly derived. As to bound states, we present the energy spectrum of the system, and analyze how the presence of the topological defect modifies obtained result. We also analyze this system admitting the presence of an extra isotropic harmonic potential acting on the particle. We show that the presence of this potential produces significant changes in the energy spectrum of the system.Comment: Paper accepted for publication in Classical and Quantum Gravit

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System.

Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory-autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves' disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves' disease) and PTC

Gene polymorphism of interleukin 1 and 8 in chronic gastritis patients infected with Helicobacter pylori

Background: Epidemiological investigations have indicated that Helicobacter pylori induces inflammation in the gastric mucosa regulated by several interleukins. The genes IL1B and IL8 are suggested as key factors in determining the risk of gastritis. The aim of this paper was to evaluate the association of gene polymorphism of interleukin-1 and interleukin-8 with chronic gastrits in H. pylori infected patients. A total of 60 patients underwent endoscopic procedure. Biopsy samples were collected for urease test, histopathological and molecular exams. The DNA of theses samples was extracted for detection of H. pylori and analysis of the genes mentioned above. Patients with gastritis had a higher frequency of H. pylori-positive samples. Result: H. pylori was detected in 30/60 patients (50%) by PCR. As for polymorphism of interleukin 8 (-251) gene we observed a statistical difference when analyzed TA (p = 0.039) and TT (p = 0.047) genotypes. In the IL1B31 there was a statistical difference in TT (p = 0.01) genotype and in theIL1B-511 there wasn’t any statistical difference. Conclusion: Our results suggest a strong correlation between the presence of chronic gastritis and infection byH. pylori and that IL1B-31TT and IL8-251TT genotypes appear to act as protective factors againstH. pylori infection while IL8-251TA genotype may comprise a risk factor for infection with this bacterium.Marília Medical School FAMEMA Blood Center Department of GeneticsSacred Heart UniversityMarília Medical School Department of Digestive System SurgeryFederal University of São Paulo Department of MorphologyMarília Medical School Department of Radiotherapy and OncologyFAMEMA Hemocentro Laboratório de GenéticaUNIFESP, Department of MorphologySciEL