Mitochondrial Dysfunction and Psychiatric Disorders

Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders. Tissues with high energy demands, such as the brain, contain a large number of mitochondria, being therefore more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Bipolar disorder is a prevalent psychiatric disorder characterized by alternating episodes of mania and depression. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients and after amphetamine administration, an animal model of mania. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Schizophrenia is a devastating mental disorder characterized by disturbed thoughts and perception, alongside cognitive and emotional decline associated with a severe reduction in occupational and social functioning, and in coping abilities. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets. Abnormal mitochondrial morphology, size and density have all been reported in the brains of schizophrenic individuals. Considering that several studies link energy impairment to neuronal death, neurodegeneration and disease, this review article discusses energy impairment as a mechanism underlying the pathophysiology of some psychiatric disorders, like bipolar disorder, depression and schizophrenia.     

The mechano-gated K<Subscript>2P</Subscript> channel TREK-1

The versatility of neuronal electrical activity is largely conditioned by the expression of different structural and functional classes of K⁺ channels. More than 80 genes encoding the main K⁺ channel alpha subunits have been identified in the human genome. Alternative splicing, heteromultimeric assembly, post-translational modification and interaction with auxiliary regulatory subunits further increase the molecular and functional diversity of K⁺ channels. Mammalian two-pore domain K⁺ channels (K_2P) make up one class of K⁺ channels along with the inward rectifiers and the voltage- and/or calcium-dependent K⁺ channels. Each K_2P channel subunit is made up of four transmembrane segments and two pore-forming (P) domains, which are arranged in tandem and function as either homo- or heterodimeric channels. This novel structural arrangement is associated with unusual gating properties including “background” or “leak” K⁺ channel activity, in which the channels show constitutive activity at rest. In this review article, we will focus on the lipid-sensitive mechano-gated K_2P channel TREK-1 and will emphasize on the polymodal function of this “unconventional” K⁺ channel. EBSA Satellite meeting: Ion channels, Leeds, July 2007.     

Discovery of a new RNA-containing nuclear structure in UVC-induced apoptotic cells by integrated laser electron microscopy

Background information. Treatment of cells with UVC radiation leads to the formation of DNA cross‐links which, if not repaired, can lead to apoptosis. γ‐H2AX and cleaved caspase 3 are proteins formed during UVC‐induced DNA damage and apoptosis respectively. The present study sets out to identify early morphological markers of apoptosis using a new method of correlative microscopy, ILEM (integrated laser electron microscopy). Cleaved caspase 3 and γ‐H2AX were immunofluorescently labelled to mark the cells of interest. These cells were subsequently searched in the fluorescence mode of the ILEM and further analysed at high resolution with TEM (transmission electron microscopy). Results. Following the treatment of HUVECs (human umbilical vein endothelial cells) with UVC radiation, in the majority of the cells γ‐H2AX was formed, whereas only in a subset of cells caspase 3 was activated. In severely damaged cells with high levels of γ‐H2AX a round, electron‐dense nuclear structure was found, which was hitherto not identified in UV‐stressed cells. This structure exists only in nuclei of cells containing cleaved caspase 3 and is present during all stages of the apoptotic process. Energy‐loss imaging showed that the nuclear structure accumulates phosphorus, indicating that it is rich in nucleic acids. Because the nuclear structure did not label for DNA and was not affected by regressive EDTA treatment, it is suggested that the UV‐induced nuclear structure contains a high amount of RNA. Conclusions. Because the UV‐induced nuclear structure was only found in cells labelled for cleaved caspase 3 it is proposed as an electron microscopic marker for all stages of apoptosis. Such a marker will especially facilitate the screening for early apoptotic cells, which lack the well‐known hallmarks of apoptosis within a cell population. It also raises new questions on the mechanisms involved in the UV‐induced apoptotic pathway.     

Organotin meclofenamic complexes: Synthesis, crystal structures and antiproliferative activity of the first complexes of meclofenamic acid - Novel anti-tuberculosis agents

The complexes [Me₂(Meclo)SnOSn(Meclo)Me₂]₂ (2) and [Ph₃Sn(Meclo)] (3) where HMeclo is meclofenamic acid, N-(2,6-dichloro-m-tolylanthranilic acid)], have been prepared and structurally characterized by means of vibrational, ¹H and ¹³C NMR spectroscopies. The crystal structure of complexes (2) and (3) have been determined by X-ray crystallography. Three distannoxane rings are present to the dimeric tetraorganodistannoxane of planar ladder arrangement of (2). The structure is centro symmetric and features a central rhombus Sn₂O₂ unit two additional tin atoms linked at the oxygen atoms. Five- and six-coordinated tin centers are present in the dimer distannoxane. X-ray analysis of (3) revealed a penta-coordinated structure containing Ph₃Sn coordinated to the chelated carboxylato group. The polar imino hydrogen atom participates in intra-molecular hydrogen bonds. Complexes (2) and (3) are self-assembled via π → π, C-H-π, stacking interactions and intra-molecular hydrogen bonds. Meclofenamic acid and [Ph₃Sn(Meclo)] have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). The [Ph₃Sn(Meclo)] complex exhibited high cytotoxic activity against all the cancer cell lines. Meclofenamic and [Ph₃Sn(Meclo)] were tested for anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv. The [Ph₃Sn(Meclo)] complex was found to be a promising anti-mycobacterial lead compound, displaying high activity against M. tuberculosis H37Rv.     

Complex dynamics of microbial competition in the gradostat

We examine the conditions necessary for the emergence of complex dynamic behavior in systems of microbial competition. In particular, we study the effect of spatial heterogeneity and substrate-inhibition on the dynamics of such a system. This is accomplished through the study of a mathematical model of two microbial populations competing for a single nutrient in a configuration of two interconnected chemostats. Microbial growth is assumed to follow substrate-inhibited kinetics for both species. Such a system with sterile feed has been shown in a previous work to exhibit stable periodic states. In the present work we study the system for the case of non-sterile feed, i.e., when the two species are present in the feed of the chemostats. The analysis is done by numerical bifurcation theory methods. We demonstrate that, in addition to periodic states, the system possesses stable quasi-periodic states resulting from Neimark-Sacker bifurcations of limit cycles. Also, periodic states may undergo successive period doublings leading to periodic states of increasing period and indicating that chaotic states might be possible. Multistability is also observed, consisting in the coexistence of several stable steady states and possibly stable periodic or quasi-periodic states for given operating conditions. It appears that substrate-inhibition, spatial heterogeneity and presence of microorganisms in the inflow are all necessary conditions for complex dynamics to arise in a microbial system of pure and simple competition.     

Modeling denitrification in aquatic sediments

Sediment denitrification is a major pathway of fixed nitrogen loss from aquatic systems. Due to technical difficulties in measuring this process and its spatial and temporal variability, estimates of local, regional and global denitrification have to rely on a combination of measurements and models. Here we review approaches to describing denitrification in aquatic sediments, ranging from mechanistic diagenetic models to empirical parameterizations of nitrogen fluxes across the sediment-water interface. We also present a compilation of denitrification measurements and ancillary data for different aquatic systems, ranging from freshwater to marine. Based on this data compilation we reevaluate published parameterizations of denitrification. We recommend that future models of denitrification use (1) a combination of mechanistic diagenetic models and measurements where bottom-waters are temporally hypoxic or anoxic, and (2) the much simpler correlations between denitrification and sediment oxygen consumption for oxic bottom waters. For our data set, inclusion of bottom water oxygen and nitrate concentrations in a multivariate regression did not improve the statistical fit.     

The response regulator PhoP negatively regulates Yersinia pseudotuberculosis and Yersinia pestis biofilms

A few Yersinia pseudotuberculosis strains form biofilms on the head of the nematode Caenorhabditis elegans , but numerous others do not. We show that a widely used Y. pseudotuberculosis strain, YPIII, is biofilm positive because of a mutation in phoP , which encodes the response regulator of a two-component system. For two wild-type Y. pseudotuberculosis that do not make biofilms on C. elegans , deletion of phoP was sufficient to produce robust biofilms. In Yersinia pestis , a phoP mutant made more extensive biofilms in vitro than did the wild type. Expression of HmsT, a diguanylate cyclase that positively regulates biofilms, is diminished in Y. pseudotuberculosis strains with functional PhoP.     

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study

Background

Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality.

Methods

A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and “other”). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death.

Results

Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1–6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4–7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1–12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2–8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0–8.7).

Interpretation

Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.Osteoporosis-related fractures are a major health concern, affecting a growing number of individuals worldwide. The burden of fracture has largely been assessed by the impact on health-related quality of life and health care costs.^1,2 Fractures can also be associated with death. However, trials that have examined the relation between fractures and mortality have had limitations that may influence their results and the generalizability of the studies, including small samples,^3,4 the examination of only 1 type of fracture,^4–10 the inclusion of only women,^8,11 the enrolment of participants from specific areas (i.e., hospitals or certain geographic regions),^{3,4,7,8,10,12} the nonrandom selection of participants^3–11 and the lack of statistical adjustment for confounding factors that may influence mortality.^3,5–7,12We evaluated the relation between incident fractures and mortality over a 5-year period in a cohort of men and women 50 years of age and older. In addition, we examined whether other characteristics of participants were risk factors for death.     

Investigation of the antifouling constituents from the brown alga Sargassum muticum (Yendo) Fensholt

One of the most promising alternatives to toxic heavy metal-based paints is offered by the development of antifouling coatings in which the active ingredients are compounds naturally occurring in marine organisms and operating as natural antisettlement agents. Sessile marine macroalgae are remarkably free from settlement by fouling organisms. They produce a wide variety of chemically active metabolites in their surroundings, potentially as an aid to protect themselves against other settling organisms. In this study, a dichloromethane extract from the brown seaweed Sargassum muticum was tested in situ and, after 2 months of immersion, showed less fouling organisms on paints in which the extract was included, compared to paints containing only copper after 2 months of immersion. No barnacles or mussels have been observed on the test rack. Identification by NMR and GC/MS of the effective compound revealed the abundance of palmitic acid, a commonly found fatty acid. Pure palmitic acid showed antibacterial activity at 44 μg mL⁻¹, and also inhibited the growth of the diatom Cylindrotheca closterium at low concentration (EC₅₀ = 45.5 μg mL⁻¹), and the germination of Ulva lactuca spores at 3 μg mL⁻¹. No cytotoxicity was highlighted, which is promising in the aim of the development of an environmentally friendly antifouling paint.     

Differences in spatial predictions among species distribution modeling methods vary with species traits and environmental predictors

Prediction maps produced by species distribution models (SDMs) influence decision‐making in resource management or designation of land in conservation planning. Many studies have compared the prediction accuracy of different SDM modeling methods, but few have quantified the similarity among prediction maps. There has also been little systematic exploration of how the relative importance of different predictor variables varies among model types and affects map similarity. Our objective was to expand the evaluation of SDM performance for 45 plant species in southern California to better understand how map predictions vary among model types, and to explain what factors may affect spatial correspondence, including the selection and relative importance of different environmental variables. Four types of models were tested. Correlation among maps was highest between generalized linear models (GLMs) and generalized additive models (GAMs) and lowest between classification trees and GAMs or GLMs. Correlation between Random Forests (RFs) and GAMs was the same as between RFs and classification trees. Spatial correspondence among maps was influenced the most by model prediction accuracy (AUC) and species prevalence; map correspondence was highest when accuracy was high and prevalence was intermediate (average prevalence for all species was 0.124). Species functional type and the selection of climate variables also influenced map correspondence. For most (but not all) species, climate variables were more important than terrain or soil in predicting their distributions. Environmental variable selection varied according to modeling method, but the largest differences were between RFs and GLMs or GAMs. Although prediction accuracy was equal for GLMs, GAMs, and RFs, the differences in spatial predictions suggest that it may be important to evaluate the results of more than one model to estimate the range of spatial uncertainty before making planning decisions based on map outputs. This may be particularly important if models have low accuracy or if species prevalence is not intermediate.