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91.
Danila Caruso Manon Meyrel Karoline Krane-Gartiser Victoire Benard Chloé Benizri Héléna Brochard 《Chronobiology international》2020,37(1):101-110
ABSTRACTEveningness and sleep disturbances are considered as markers of Bipolar Disorder (BD) and influence mood and emotional or behavioral states. This study investigates the associations between circadian markers and sleep quality on residual depressive symptoms and inhibition/activation dimensions during the euthymic phase. A sample of 89 euthymic adult individuals with BD was assessed for circadian preference and typology using the Composite Scale of Morningness (CSM) and the Circadian Type Inventory (CTI) and for sleep quality using the Pittsburgh Sleep Quality Index (PSQI). The Montgomery and Asberg Depression Rating Scale (MADRS) and the Multidimensional Assessment of Thymic States (MAThyS) were used to measure residual depressive symptoms and the inhibition/activation dimensions. We examined any associations between these parameters using correlations and path analyses. We identified significant associations between eveningness and poorer sleep quality that correlated to higher depressive residual symptoms and a global inhibition. The use of path analyses led us to conclude that poor sleep quality mediated the relationship between eveningness and either residual mood symptoms or behavioral inhibition (motivation, sensory perception, interpersonal interaction, and cognition). These factors should be considered in the clinical evaluation of individuals with BD, with a specific attention during the euthymic phase, in order to achieve the best functional outcome possible. 相似文献
92.
93.
Evidence for a role of DNA polymerase beta in determining radiosensitivity is conflicting. In vitro assays show an involvement of DNA polymerase beta in single strand break repair and base excision repair of oxidative damages, both products of ionizing radiation. Nevertheless the lack of DNA polymerase beta has been shown to have no effect on radiosensitivity. Here we show that mouse embryonic fibroblasts deficient in DNA polymerase beta are considerably more sensitive to ionizing radiation than wild-type cells, but only when confluent. The inhibitor methoxyamine renders abasic sites refractory to the dRP lyase activity of DNA polymerase beta. Methoxyamine did not significantly change radiosensitivity of wild-type fibroblasts in log phase. However, DNA polymerase beta deficient cells in log phase were radiosensitized by methoxyamine. Alkaline comet assays confirmed repair inhibition of ionizing radiation induced damage by methoxyamine in these cells, indicating both the existence of a polymerase beta-dependent long patch pathway and the involvement of another methoxyamine sensitive process, implying the participation of a second short patch polymerase(s) other than DNA polymerase beta. This is the first evidence of a role for DNA polymerase beta in radiosensitivity in vivo. 相似文献
94.
J Benzler GK Ganjam M Krüger O Pinkenburg M Kutschke S Stöhr J Steger CE Koch R Olkrug MW Schwartz PR Shepherd DR Grattan A Tups 《The Biochemical journal》2012,447(1):175-184
GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lepob/ob mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance. 相似文献
95.
Sarrazin AF Villablanca EJ Nuñez VA Sandoval PC Ghysen A Allende ML 《Developmental biology》2006,295(2):534-545
The lateral line system comprises an array of mechanosensory organs, the neuromasts, distributed over the body surface. Each neuromast consists of a patch of mechanosensory hair cells surrounded by support cells. We show that, in the zebrafish, two proneural genes are essential for differentiation of the hair cells, neuroD (nrd) and atonal homolog 1 (ath1). Gene knockdown experiments demonstrate that loss of function of either gene, but not of the related proneural gene neurogenin1 (ngn1), abrogate the appearance of hair cell markers. This is in contrast to other sensory systems, such as the neurons of the lateral line ganglion, where nrd is regulated by ngn1 and not by ath1. Overexpression of ath1 can induce nrd, and the phenotype produced by loss of ath1 function can be partially rescued by injection of nrd mRNA. This supports the conclusion that the activation of nrd probably requires ath1 in the hair cell lineage, whereas in sensory neurons nrd activation requires ngn1. We propose that the emergence of two atonal homologs, ath1 and ngn1, allowed the cellular segregation of mechanoreception and signal transmission that were originally performed by a single cell type as found in insects. 相似文献
96.
The crystallographic structure of oxygenated trHbN from Mycobacterium tuberculosis showed an extended heme distal site hydrogen-bonding network that includes Y(B10), Q(E11), and the bound O(2) (Milani, M., et al. (2001) EMBO J. 20, 3902-3909). In the present work, we analyze the effects that substitutions at the B10 and E11 positions exert on the heme and its coordinated ligands, using steady-state resonance Raman spectroscopy, absorption spectroscopy and X-ray crystallography. Our results show that (1) residues Y(B10) and Q(E11) control the binding and the ionization state of the heme-bound water molecules in ferric trHbN and are important in keeping the sixth coordination position vacant in deoxy trHbN; (2) residue Q(E11) plays a role in maintaining the integrity of the proximal Fe-His bond in deoxy trHbN; (3) in wild-type oxy-trHbN, the size and hydrogen-bonding capability of residue E11 is important to sustain proper interaction between Y(B10) and the heme-bound O(2); (4) CO-trHbN is in a conformational equilibrium, where either the Y(B10) or the Q(E11) residue interacts with the heme-bound CO; and (5) Y(B10) and Q(E11) residues control the conformation (and likely the dynamics) of the protein matrix tunnel gating residue F(E15). These findings suggest that the functional processes of ligand binding and diffusion are controlled in trHbN through the dynamic interaction of residues Y(B10), Q(E11), F(E15), and the heme ligand. 相似文献
97.
Michael D. L. Suits Jérôme Lang Gour P. Pal Manon Couture Zongchao Jia 《Protein science : a publication of the Protein Society》2009,18(4):825-838
For many pathogenic microorganisms, iron acquisition from host heme sources stimulates growth, multiplication, ultimately enabling successful survival and colonization. In gram‐negative Escherichia coli O157:H7, Shigella dysenteriae and Yersinia enterocolitica the genes encoded within the heme utilization operon enable the effective uptake and utilization of heme as an iron source. While the complement of proteins responsible for heme internalization has been determined in these organisms, the fate of heme once it has reached the cytoplasm has only recently begun to be resolved. Here we report the first crystal structure of ChuX, a member of the conserved heme utilization operon from pathogenic E. coli O157:H7 determined at 2.05 Å resolution. ChuX forms a dimer which remarkably given low sequence homology, displays a very similar fold to the monomer structure of ChuS and HemS, two other heme utilization proteins. Absorption spectral analysis of heme reconstituted ChuX demonstrates that ChuX binds heme in a 1:1 manner implying that each ChuX homodimer has the potential to coordinate two heme molecules in contrast to ChuS and HemS where only one heme molecule is bound. Resonance Raman spectroscopy indicates that the heme of ferric ChuX is composed of a mixture of coordination states: 5‐coordinate and high‐spin, 6‐coordinate and low‐spin, and 6‐coordinate and high‐spin. In contrast, the reduced ferrous form displays mainly a 5‐coordinate and high‐spin state with a minor contribution from a 6‐coordinate and low‐spin state. The νFe‐CO and νC‐O frequencies of ChuX‐bound CO fall on the correlation line expected for histidine‐coordinated hemoproteins indicating that the fifth axial ligand of the ferrous heme is the imidazole ring of a histidine residue. Based on sequence and structural comparisons, we designed a number of site‐directed mutations in ChuX to probe the heme binding sites and dimer interface. Spectral analysis of ChuX and mutants suggests involvement of H65 and H98 in heme coordination as mutations of both residues were required to abolish the formation of the hexacoordination state of heme‐bound ChuX. 相似文献
98.
Maika Deffieu Ingrid Bhatia-Ki??ová Bénédicte Salin Anne Galinier Stéphen Manon Nadine Camougrand 《The Journal of biological chemistry》2009,284(22):14828-14837
The antioxidant N-acetyl-l-cysteine prevented the
autophagy-dependent delivery of mitochondria to the vacuoles, as examined by
fluorescence microscopy of mitochondria-targeted green fluorescent protein,
transmission electron microscopy, and Western blot analysis of mitochondrial
proteins. The effect of N-acetyl-l-cysteine was specific
to mitochondrial autophagy (mitophagy). Indeed, autophagy-dependent activation
of alkaline phosphatase and the presence of hallmarks of non-selective
microautophagy were not altered by N-acetyl-l-cysteine.
The effect of N-acetyl-l-cysteine was not related to its
scavenging properties, but rather to its fueling effect of the glutathione
pool. As a matter of fact, the decrease of the glutathione pool induced by
chemical or genetical manipulation did stimulate mitophagy but not general
autophagy. Conversely, the addition of a cell-permeable form of glutathione
inhibited mitophagy. Inhibition of glutathione synthesis had no effect in the
strain Δuth1, which is deficient in selective mitochondrial
degradation. These data show that mitophagy can be regulated independently of
general autophagy, and that its implementation may depend on the cellular
redox status.Autophagy is a major pathway for the lysosomal/vacuolar delivery of
long-lived proteins and organelles, where they are degraded and recycled.
Autophagy plays a crucial role in differentiation and cellular response to
stress and is conserved in eukaryotic cells from yeast to mammals
(1,
2). The main form of autophagy,
macroautophagy, involves the non-selective sequestration of large portions of
the cytoplasm into double-membrane structures termed autophagosomes, and their
delivery to the vacuole/lysosome for degradation. Another process,
microautophagy, involves the direct sequestration of parts of the cytoplasm by
vacuole/lysosomes. The two processes coexist in yeast cells but their extent
may depend on different factors including metabolic state: for example, we
have observed that nitrogen-starved lactate-grown yeast cells develop
microautophagy, whereas nitrogen-starved glucose-grown cells preferentially
develop macroautophagy (3).Both macroautophagy and microautophagy are essentially non-selective, in
the way that autophagosomes and vacuole invaginations do not appear to
discriminate the sequestered material. However, selective forms of autophagy
have been observed (4) that
target namely peroxisomes (5,
6), chromatin
(7,
8), endoplasmic reticulum
(9), ribosomes
(10), and mitochondria
(3,
11–13).
Although non-selective autophagy plays an essential role in survival by
nitrogen starvation, by providing amino acids to the cell, selective autophagy
is more likely to have a function in the maintenance of cellular structures,
both under normal conditions as a “housecleaning” process, and
under stress conditions by eliminating altered organelles and macromolecular
structures
(14–16).
Selective autophagy targeting mitochondria, termed mitophagy, may be
particularly relevant to stress conditions. The mitochondrial respiratory
chain is both the main site and target of
ROS4 production
(17). Consequently, the
maintenance of a pool of healthy mitochondria is a crucial challenge for the
cells. The progressive accumulation of altered mitochondria
(18) caused by the loss of
efficiency of the maintenance process (degradation/biogenesis de
novo) is often considered as a major cause of cellular aging
(19–23).
In mammalian cells, autophagic removal of mitochondria has been shown to be
triggered following induction/blockade of apoptosis
(23), suggesting that
autophagy of mitochondria was required for cell survival following
mitochondria injury (14).
Consistent with this idea, a direct alteration of mitochondrial permeability
properties has been shown to induce mitochondrial autophagy
(13,
24,
25). Furthermore, inactivation
of catalase induced the autophagic elimination of altered mitochondria
(26). In the yeast
Saccharomyces cerevisiae, the alteration of
F0F1-ATPase biogenesis in a conditional mutant has been
shown to trigger autophagy
(27). Alterations of
mitochondrial ion homeostasis caused by the inactivation of the
K+/H+ exchanger was shown to cause both autophagy and
mitophagy (28). We have
reported that treatment of cells with rapamycin induced early ROS production
and mitochondrial lipid oxidation that could be inhibited by the hydrophobic
antioxidant resveratrol (29).
Furthermore, resveratrol treatment impaired autophagic degradation of both
cytosolic and mitochondrial proteins and delayed rapamycin-induced cell death,
suggesting that mitochondrial oxidation events may play a crucial role in the
regulation of autophagy. This existence of regulation of autophagy by ROS has
received molecular support in HeLa cells
(30): these authors showed
that starvation stimulated ROS production, namely H2O2,
which was essential for autophagy. Furthermore, they identified the cysteine
protease hsAtg4 as a direct target for oxidation by
H2O2. This provided a possible connection between the
mitochondrial status and regulation of autophagy.Investigations of mitochondrial autophagy in nitrogen-starved lactate-grown
yeast cells have established the existence of two distinct processes: the
first one occurring very early, is selective for mitochondria and is dependent
on the presence of the mitochondrial protein Uth1p; the second one occurring
later, is not selective for mitochondria, is not dependent on Uth1p, and is a
form of bulk microautophagy
(3). The absence of the
selective process in the Δuth1 mutant strongly delays and
decreases mitochondrial protein degradation
(3,
12). The putative protein
phosphatase Aup1p has been also shown to be essential in inducing mitophagy
(31). Additionally several Atg
proteins were shown to be involved in vacuolar sequestration of mitochondrial
GFP (3,
12,
32,
33). Recently, the protein
Atg11p, which had been already identified as an essential protein for
selective autophagy has also been reported as being essential for mitophagy
(33).The question remains as to identify of the signals that trigger selective
mitophagy. It is particularly intriguing that selective mitophagy is activated
very early after the shift to a nitrogen-deprived medium
(3). Furthermore, selective
mitophagy is very active on lactate-grown cells (with fully differentiated
mitochondria) but is nearly absent in glucose-grown cells
(3). In the present paper, we
investigated the relationships between the redox status of the cells and
selective mitophagy, namely by manipulating glutathione. Our results support
the view that redox imbalance is a trigger for the selective elimination of
mitochondria. 相似文献
99.
FluBlok, a recombinant trivalent hemagglutinin (rHA) vaccine produced in insect cell culture using the baculovirus expression system, provides an attractive alternative to the current egg-based trivalent inactivated influenza vaccine (TIV). Its manufacturing process presents the possibility for safe and expeditious vaccine production. FluBlok contains three times more HA than TIV and does not contain egg-protein or preservatives. The high purity of the antigen enables administration at higher doses without a significant increase in side-effects in human subjects.The insect cell–baculovirus production technology is particularly suitable for influenza where annual adjustment of the vaccine is required. The baculovirus–insect expression system is generally considered a safe production system, with limited growth potential for adventitious agents. Still regulators question and challenge the safety of this novel cell substrate as FluBlok continues to advance toward product approval. This review provides an overview of cell substrate characterization for expresSF cell line used for the manufacturing of FluBlok.In addition, this review includes an update on the clinical development of FluBlok. The highly purified protein vaccine, administered at three times higher antigen content than TIV, is well tolerated and results in stronger immunogenicity, a long lasting immune response and provides cross-protection against drift influenza viruses. 相似文献
100.
Pilar Junier Manon Frutschi Nicholas S. Wigginton Eleanor J. Schofield John R. Bargar Rizlan Bernier‐Latmani 《Environmental microbiology》2009,11(12):3007-3017
The bioremediation of uranium‐contaminated sites is designed to stimulate the activity of microorganisms able to catalyze the reduction of soluble U(VI) to the less soluble mineral UO2. U(VI) reduction does not necessarily support growth in previously studied bacteria, but it typically involves viable vegetative cells and the presence of an appropriate electron donor. We characterized U(VI) reduction by the sulfate‐reducing bacterium Desulfotomaculum reducens strain MI‐1 grown fermentatively on pyruvate and observed that spores were capable of U(VI) reduction. Hydrogen gas – a product of pyruvate fermentation – rather than pyruvate, served as the electron donor. The presence of spent growth medium was required for the process, suggesting that an unknown factor produced by the cells was necessary for reduction. Ultrafiltration of the spent medium followed by U(VI) reduction assays revealed that the factor's molecular size was below 3 kDa. Pre‐reduced spent medium displayed short‐term U(VI) reduction activity, suggesting that the missing factor may be an electron shuttle, but neither anthraquinone‐2,6‐disulfonic acid nor riboflavin rescued spore activity in fresh medium. Spores of D. reducens also reduced Fe(III)‐citrate under experimental conditions similar to those for U(VI) reduction. This is the first report of a bacterium able to reduce metals while in a sporulated state and underscores the novel nature of the mechanism of metal reduction by strain MI‐1. 相似文献