Plants from the family Orobanchaceae are widely used as a model to study different aspects of parasitic lifestyle including host-parasite interactions and physiological and genomic adaptations. Among ...the latter, the most prominent are those that occurred due to the loss of photosynthesis; they include the reduction of the photosynthesis-related gene set in both nuclear and plastid genomes. In Orobanchaceae, the transition to non-photosynthetic lifestyle occurred several times independently, but only one lineage has been in the focus of evolutionary studies. These studies included analysis of plastid genomes and transcriptomes and allowed the inference of patterns and mechanisms of genome reduction that are thought to be general for parasitic plants. Here we report the plastid genome of Lathraea squamaria, a holoparasitic plant from Orobanchaceae, clade Rhinantheae. We found that in this plant the degree of plastome reduction is the least among non-photosynthetic plants. Like other parasites, Lathraea possess a plastome with elevated absolute rate of nucleotide substitution. The only gene lost is petL, all other genes typical for the plastid genome are present, but some of them-those encoding photosystem components (22 genes), cytochrome b6/f complex proteins (4 genes), plastid-encoded RNA polymerase subunits (2 genes), ribosomal proteins (2 genes), ccsA and cemA-are pseudogenized. Genes for cytochrome b6/f complex and photosystems I and II that do not carry nonsense or frameshift mutations have an increased ratio of non-synonymous to synonymous substitution rates, indicating the relaxation of purifying selection. Our divergence time estimates showed that transition to holoparasitism in Lathraea lineage occurred relatively recently, whereas the holoparasitic lineage Orobancheae is about two times older.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. ...Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of β-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of β-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, β-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZ.
The brain extracellular matrix (ECM) is involved in crucial processes of neural support, neuronal and synaptic plasticity, extrasynaptic transmission, and neurotransmission. ECM is a tridimensional ...fibrillary meshwork composed of macromolecules that determine its bioactivity and give it unique characteristics. The characterization of the brain ECM is critical to understand its dynamic in SZ. Thus, a comparative study was developed with 71 patients with schizophrenia (SZ) and 70 healthy controls. Plasma of participants was analysed by label-free liquid chromatography–tandem mass spectrometry, and the results were validated using the classical western blot method. Lastly, immunostaining of post-mortem human brain tissue was performed to analyse the distribution of the brain ECM proteins by confocal microscopy. The analysis identified four proteins: fibronectin, lumican, nidogen-1, and secreted protein acidic and rich in cysteine (SPARC) as components of the brain ECM. Statistical significance was found for fibronectin (
P
= 0.0166), SPARC (
P
= 0.0003), lumican (
P
= 0.0012), and nidogen-1 (
P
< 0.0001) that were decreased in the SZ group. Fluorescence imaging of prefrontal cortex (PFC) sections revealed a lower expression of ECM proteins in SZ. Our study proposes a pathophysiological dysregulation of proteins of the brain ECM, whose abnormal composition leads to a progressive neuronal impairment and consequently to neurodegenerative processes due to lack of neurophysiological support and dysregulation of neuronal homeostasis. Moreover, the brain ECM and its components are potential pharmacological targets to develop new therapeutic approaches to treat SZ.
Instalado en la conciencia general de la humanidad el imperativo de impedir la impunidad de los más graves crímenes internacionales, la relevancia de la jurisdicción universal en la consecución de ...dicho fin resulta incuestionada desde el consenso internacional. Sin embargo, ese consenso desaparece cuando se profundiza en su alcance, contenido y aplicación. Estados que apostaron por ella están sucumbiendo ante fuerzas antagónicas favorecidas por el disenso internacional en su regulación. El caso de España y su reciente reforma legislativa sirve de ejemplo actual de la involución a la que se ve sometido el principio de jurisdicción universal. Entre tanto, la brecha de impunidad frente a las graves violaciones de los derechos humanos se amplía, a pesar de notables prácticas de tribunales estatales en el enjuiciamiento y castigo de los enemigos de la humanidad (hostis humani generis).
Schizophrenia is associated with patterns of aberrant neurobiological circuitry. The disease complexity is mirrored by multiple biological interactions known to contribute to the disease pathology. ...One potential contributor is the family of neurotrophins which are proteins involved in multiple functional processes in the nervous system, with crucial roles in neurodevelopment, synaptogenesis and neuroplasticity. With these roles in mind, abnormal neurotrophin profiles have been hypothesized to contribute to the pathology of schizophrenia.
We performed a systematic review and a meta-analysis to scrutinize the neurobiological hypothesis of neurotrophins in schizophrenia, examining the correlation between peripheral levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin 4/5 (NT-4/5) associated with schizophrenia.
Fifty-two studies were reviewed and twenty-two studies were included in this meta-analysis. Using a random effects model, we confirmed that decreased levels of neurotrophins (BDNF, NGF and NT-4/5) were associated with schizophrenia (Hedges's g = −0.846; SE = 0.058; 95% confidence interval: −0.960 to −0.733; Z-value = −14.632; p-value = 0.000). Subgroup analysis indicated that neurotrophin levels are significantly decreased in both medicated and drug-näive patients. Meta-regression of continuous variables such as mean age, duration of illness and PANSS total score did not show significant effects (p > 0.05) in relation to neurotrophins levels.
We confirm that decreased peripheral neurotrophin levels are significantly associated with schizophrenia, thereby confirming the neurobiological hypothesis of neurotrophins in schizophrenia. Low levels of neurotrophins in peripheral blood of patients with schizophrenia may explain, in part, the pathophysiology of schizophrenia.
•Neurotrophins are associated with the pathophysiology of schizophrenia.•Patients with schizophrenia have decreased levels of neurotrophins.•Peripheral levels of neurotrophins contribute to the neurobiological hypothesis of schizophrenia.
Major depressive disorder (MDD) is a multidimensional disorder that is characterized by the presence of alterations in mood, cognitive capacity, sensorimotor, and homeostatic functions. Given that ...about half of the patients diagnosed with MDD do not respond to the various current treatments, new techniques are being sought to predict not only the course of the disease but also the characteristics that differentiate responders from non-responders. Using the electroencephalogram, a noninvasive and inexpensive tool, most studies have proposed that patients with MDD have some lateralization in brain electrical activity, with alterations in alpha and theta rhythms being observed, which would be related to dysfunctions in emotional capacity such as the absence or presence of responses to the different existing treatments. These alterations help in the identification of subjects at high risk of suffering from depression, in the differentiation into responders and nonresponders to various therapies (pharmacological, electroconvulsive therapy, and so on), as well as to establish in which period of the disease the treatment will be more effective. Although the data are still inconclusive and more research is needed, these alpha and theta neurophysiological markers could support future clinical practice when it comes to establishing an early diagnosis and treating state disorders more successfully and accurately of mood disorders.
Schizophrenia is a severe and disabling psychiatric disorder with a complex and multifactorial etiology. The lack of consensus regarding the multifaceted dysfunction of this ailment has increased the ...need to explore new research lines. This research makes use of proteomics data to discover possible analytes associated with psychoneuroimmune signaling pathways in schizophrenia. Thus, we analyze plasma of 45 patients 10 patients with first-episode schizophrenia (FES) and 35 patients with chronic schizophrenia and 43 healthy subjects by label-free liquid chromatography-tandem mass spectrometry. The analysis revealed a significant reduction in the levels of glia maturation factor beta (GMF-β), the brain-derived neurotrophic factor (BDNF), and the 115-kDa isoform of the Rab3 GTPase-activating protein catalytic subunit (RAB3GAP1) in patients with schizophrenia as compared to healthy volunteers. In conclusion, GMF-β, BDNF, and 115-kDa isoform of RAB3GAP1 showed significantly reduced levels in plasma of patients with schizophrenia, thus making them potential biomarkers in schizophrenia.
Cancer cells exhibit mitochondrial cholesterol (mt-cholesterol) accumulation, which contributes to cell death resistance by antagonizing mitochondrial outer membrane (MOM) permeabilization. ...Hepatocellular mt-cholesterol loading, however, promotes steatohepatitis, an advanced stage of chronic liver disease that precedes hepatocellular carcinoma (HCC), by depleting mitochondrial GSH (mGSH) due to a cholesterol-mediated impairment in mGSH transport. Whether and how HCC cells overcome the restriction of mGSH transport imposed by mt-cholesterol loading to support mGSH uptake remains unknown. Although the transport of mGSH is not fully understood, SLC25A10 (dicarboxylate carrier, DIC) and SLC25A11 (2-oxoglutarate carrier, OGC) have been involved in mGSH transport, and therefore we examined their expression and role in HCC. Unexpectedly, HCC cells and liver explants from patients with HCC exhibit divergent expression of these mitochondrial carriers, with selective OGC upregulation, which contributes to mGSH maintenance. OGC but not DIC downregulation by siRNA depleted mGSH levels and sensitized HCC cells to hypoxia-induced ROS generation and cell death as well as impaired cell growth in three-dimensional multicellular HCC spheroids, effects that were reversible upon mGSH replenishment by GSH ethyl ester, a membrane permeable GSH precursor. We also show that OGC regulates mitochondrial respiration and glycolysis. Moreover, OGC silencing promoted hypoxia-induced cardiolipin peroxidation, which reversed the inhibition of cholesterol on the permeabilization of MOM-like liposomes induced by Bax or Bak. Genetic OGC knockdown reduced the ability of tumor-initiating stem-like cells to induce liver cancer. These findings underscore the selective overexpression of OGC as an adaptive mechanism of HCC to provide adequate mGSH levels in the face of mt-cholesterol loading and suggest that OGC may be a novel therapeutic target for HCC treatment.
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•OGC overexpression in HCC ensures unrestricted mGSH levels despite cholesterol loading.•OGC protects HCC cells against hypoxia-induced ROS generation, cardiolipin peroxidation and cell death.•OGC promotes mitochondrial oxygen consumption and glycolysis.•OGC silencing decreases in vivo liver tumorigenesis.
To understand how mitochondria are involved in malignant transformation we have generated a collection of transmitochondrial cybrid cell lines on the same nuclear background (143B) but with mutant ...mitochondrial DNA (mtDNA) variants with different degrees of pathogenicity. These include the severe mutation in the tRNALys gene, m.8363G>A, and the three milder yet prevalent Leber's hereditary optic neuropathy (LHON) mutations in the MT-ND1 (m.3460G>A), MT-ND4 (m.11778G>A) and MT-ND6 (m.14484T>C) mitochondrial genes. We found that 143B ρ0 cells devoid of mtDNA and cybrids harboring wild type mtDNA or that causing severe mitochondrial dysfunction do not produce tumors when injected in nude mice. By contrast cybrids containing mild mutant mtDNAs exhibit different tumorigenic capacities, depending on OXPHOS dysfunction.The differences in tumorigenicity correlate with an enhanced resistance to apoptosis and high levels of NOX expression. However, the final capacity of the different cybrid cell lines to generate tumors is most likely a consequence of a complex array of pro-oncogenic and anti-oncogenic factors associated with mitochondrial dysfunction.Our results demonstrate the essential role of mtDNA in tumorigenesis and explain the numerous and varied mtDNA mutations found in human tumors, most of which give rise to mild mitochondrial dysfunction.
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