Ginsenosides are the main active constituents of Panax ginseng. Ginsenoside Re is one of the major ginsenosides; whereas hydrolysis products such as Rd appear to have higher biological activity though are present in smaller amounts. Ginsenosides, from their early use in folk medicine to modern studies, appear to exert beneficial actions against aging and even neurodegenerative disorders. Parkinson’s disease is a progressive neurodegenerative movement disorder characterized by a profound loss of midbrain dopamine neurons in the substantia nigra pars compacta. Carbon tetrachloride (CCl4) exerts neurotoxic effects when present as an environmental pollutant. As a model compound it was used here to study the impact on primary nigrostriatal dopaminergic nerve cells and to investigate the neuroprotective potential of ginsenosides Rd and Re against this organic solvent. CCl4 (2.5 mM on day 12 in vitro for 48 h) significantly decreased the number of tyrosine hydroxylase (TH+) cells by 51% compared with untreated control cultures, reduced their neuritic lengths, and led to truncated degenerations of cell morphology. Ginsenosides Rd and Re (10 µM) strongly reduced cell loss and degeneration and significantly protected process lengths and numbers of neurites of TH+ cells. The anti-oxidative and anti-inflammatory potential of the cellular supernatant was lowered by CCl4 exposure. Inclusion of ginsenosides inhibited both oxidative stress and inflammation. Therefore the neuroprotective effects of ginsenosides at least partially depend on lowering oxidative stress and anti-inflammation.
Ginsenoside Rd; ginsenoside Re; CCl4; dopaminergic neurons; Parkinson’s disease
A series of recent reports has suggested PGC1α-driven upregulation of mitochondrial oxidative phosphorylation as a selective vulnerability of drug-resistant cancers. Accordingly, chemical inhibitors of respiration led to selective eradication of such cancer cells due to their preferential sensitivity to mitochondrial production of reactive oxygen species. These novel insights create a timely opportunity for a biomarker guided application of already existing and newly emerging mitochondrial inhibitors in recurrent drug resistant cancer, including lymphomas, melanomas, and other malignant diseases marked by increased mitochondrial respiration.
Increasing resistance to anti-tuberculosis drugs has driven the need for developing new drugs. Resources such as the tropical disease research (TDR) target database and AssessDrugTarget can help to prioritize putative drug targets. Hower, these resources do not necessarily map to metabolic pathways and the targets are not involved in dormancy. In this study, we specifically identify drug resistance pathways to allow known drug resistant mutations in one target to be offset by inhibiting another enzyme of the same metabolic pathway. One of the putative targets, Rv1712, was analysed by modelling its three dimensional structure and docking potential inhibitors.
We mapped 18 TB drug resistance gene products to 15 metabolic pathways critical for mycobacterial growth and latent TB by screening publicly available microarray data. Nine putative targets, Rv1712, Rv2984, Rv2194, Rv1311, Rv1305, Rv2195, Rv1622c, Rv1456c and Rv2421c, were found to be essential, to lack a close human homolog, and to share >67 % sequence identity and >87 % query coverage with mycobacterial orthologs. A structural model was generated for Rv1712, subjected to molecular dynamic simulation, and identified 10 compounds with affinities better than that for the ligand cytidine-5′-monophosphate (C5P). Each compound formed more interactions with the protein than C5P.
We focused on metabolic pathways associated with bacterial drug resistance and proteins unique to pathogenic bacteria to identify novel putative drug targets. The ten compounds identified in this study should be considered for experimental studies to validate their potential as inhibitors of Rv1712.
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Background and Purpose—
The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo.
This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90.
The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann–Whitney estimator, 0.71; 95% confidence interval, 0.63–0.79; P<0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann–Whitney estimator, 0.62; 95% confidence interval, 0.58–0.65; P<0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated.
Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial.
Clinical Trial Registration—
URL: http://www.clinicaltrialsregister.eu. Unique identifier: 2007-000870-21.
Cerebrolysin; randomized, double-blind, placebo-controlled trial; recovery of function; rehabilitation; stroke
Human NAD(P)H:quinone oxidoreductase 1 (NQO1) is essential for the antioxidant defense system, stabilization of tumor suppressors (e.g. p53, p33, and p73), and activation of quinone-based chemotherapeutics. Overexpression of NQO1 in many solid tumors, coupled with its ability to convert quinone-based chemotherapeutics into potent cytotoxic compounds, have made it a very attractive target for anticancer drugs. A naturally occurring single-nucleotide polymorphism (C609T) leading to an amino acid exchange (P187S) has been implicated in the development of various cancers and poor survival rates following anthracyclin-based adjuvant chemotherapy. Despite its importance for cancer prediction and therapy, the exact molecular basis for the loss of function in NQO1 P187S is currently unknown. Therefore, we solved the crystal structure of NQO1 P187S. Surprisingly, this structure is almost identical to NQO1. Employing a combination of NMR spectroscopy and limited proteolysis experiments, we demonstrated that the single amino acid exchange destabilized interactions between the core and C-terminus, leading to depopulation of the native structure in solution. This collapse of the native structure diminished cofactor affinity and led to a less competent FAD-binding pocket, thus severely compromising the catalytic capacity of the variant protein. Hence, our findings provide a rationale for the loss of function in NQO1 P187S with a frequently occurring single-nucleotide polymorphism.
antioxidant defense; cancer; flavin; quinones; single-nucleotide polymorphism
The Saccharomyces cerevisiae heat shock proteins Hsp31, Hsp32, Hsp33 and Hsp34 belong to the DJ-1/ThiJ/PfpI superfamily which includes the human protein DJ-1 (PARK7) as the most prominent member. Mutations in the DJ-1 gene are directly linked to autosomal recessive, early-onset Parkinson’s disease. DJ-1 acts as an oxidative stress-induced chaperone preventing aggregation and fibrillation of α-synuclein, a critical factor in the development of the disease. In vivo assays in Saccharomyces cerevisiae using the model substrate ΔssCPY*Leu2myc (ΔssCL*myc) as an aggregation-prone misfolded cytoplasmic protein revealed an influence of the Hsp31 chaperone family on the steady state level of this substrate. In contrast to the ubiquitin ligase of the N-end rule pathway Ubr1, which is known to be prominently involved in the degradation process of misfolded cytoplasmic proteins, the absence of the Hsp31 chaperone family does not impair the degradation of newly synthesized misfolded substrate. Also degradation of substrates with strong affinity to Ubr1 like those containing the type 1 N-degron arginine is not affected by the absence of the Hsp31 chaperone family. Epistasis analysis indicates that one function of the Hsp31 chaperone family resides in a pathway overlapping with the Ubr1-dependent degradation of misfolded cytoplasmic proteins. This pathway gains relevance in late growth phase under conditions of nutrient limitation. Additionally, the Hsp31 chaperones seem to be important for maintaining the cellular Ssa Hsp70 activity which is important for Ubr1-dependent degradation.
SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs.
castration-resistant prostate cancer; c-SRC kinase CSK; mouse xenografts; human prostate cancer tissue samples; siRNA screen
As a ubiquitin-like modifier, ISG15 is conjugated to many cellular proteins in a process termed protein ISGylation. However, the crosstalk between protein ISGylation and the ubiquitin proteasome system is not fully understood. Here, we report that cellular ubiquitin is a substrate of ISG15 and Lys 29 on ubiquitin is the major ISG15 acceptor site. Using a model substrate, we demonstrate that ISG15 can modify ubiquitin, which is immobilized on its substrate, to form ISG15-ubiquitin mixed chains. Furthermore, our results indicate that ISG15-ubiquitin mixed chains do not serve as degradation signals for a ubiquitin fusion degradation substrate. Accordingly, an ISG15-ubiquitin fusion protein, which mimics an ISG15-ubiquitin mixed chain, negatively regulates cellular turnover of ubiquitylated proteins. In addition, ISG15-ubiquitin mixed chains, which are detectable on endogenously ubiquitylated proteins, dampen cellular turnover of these proteins. Thus, our studies unveil an unanticipated interplay between two protein modification systems and highlight its role in coordinating protein homeostasis.
Imaging; Stroke; Recovery; CT; MRI; PET; DTI
In Saccharomyces cerevisiae the Gid-complex functions as an ubiquitin-ligase complex that regulates the metabolic switch between glycolysis and gluconeogenesis. In higher organisms six conserved Gid proteins form the CTLH protein-complex with unknown function. Here we show that Rmnd5, the Gid2 orthologue from Xenopus laevis, is an ubiquitin-ligase embedded in a high molecular weight complex. Expression of rmnd5 is strongest in neuronal ectoderm, prospective brain, eyes and ciliated cells of the skin and its suppression results in malformations of the fore- and midbrain. We therefore suggest that Xenopus laevis Rmnd5, as a subunit of the CTLH complex, is a ubiquitin-ligase targeting an unknown factor for polyubiquitination and subsequent proteasomal degradation for proper fore- and midbrain development.
To investigate potential mechanisms mediating the neuroprotective effect of thymoquinone (TQ) on dopaminergic neurons.
This study was conducted in the Chemistry and Biochemistry Institute, University of Veterinary Medicine, Vienna, Austria between June and August 2013. Primary cultures were prepared from embryonic mouse mesencephala (OFI/SPF) at gestation day 14. Four sets of cultures were kept untreated, treated with TQ on the eighth day in vitro (DIV) for 4 days, treated with 1-methyl-4-phenylpyridinium (MPP+) on the tenth DIV for 48 hours and co-treated with thymoquinone and MPP+. On the twelfth DIV, cultures were subjected to immunohistochemistry against tyrosine hydroxylase and fluorescent staining using LysoTracker® Deep Red, 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethyl benzimidazolylcarbocyanine (JC-1) and 4’,6-diamidino-2-phenylindole stains.
The MPP+ decreased the number of dopaminergic neurons by 40%, and increased the release of lactate dehydrogenase (LDH) into the culture medium. The TQ significantly rescued dopaminergic neurons and decreased the release of LDH at the concentrations of 0.1 and 1 µM. The TQ significantly shifted the red fluorescent intensity of the LysoTracker® Deep Red, increased the mitochondrial membrane potential as it increased the red:green florescent ratio of JC-1, and decreased MPP+-induced apoptotic cell death.
The TQ protects dopaminergic neurons in primary mesencephalic culture by enhancing lysosomal degradation that clears damaged mitochondria and inhibits mitochondria-mediated apoptotic cell death.
Long-distance migration is a rare phenomenon in European bats. Genetic analyses and banding studies show that females can cover distances of up to 1,600 km, whereas males are sedentary or migrate only short distances. The onset of this sex-biased migration is supposed to occur shortly after rousing from hibernation and when the females are already pregnant. We therefore predicted that the sexes are exposed to different energetic pressures in early spring, and this should be reflected in their behavior and physiology. We investigated this in one of the three Central European long-distance migrants, the common noctule (Nyctalus noctula) in Southern Germany recording the first individual partial migration tracks of this species. In contrast to our predictions, we found no difference between male and female home range size, activity, habitat use or diet. Males and females emerged from hibernation in similar body condition and mass increase rate was the same in males and females. We followed the first migration steps, up to 475 km, of radio-tagged individuals from an airplane. All females, as well as some of the males, migrated away from the wintering area in the same northeasterly direction. Sex differences in long-distance migratory behavior were confirmed through stable isotope analysis of hair, which showed greater variation in females than in males. We hypothesize that both sexes faced similarly good conditions after hibernation and fattened at maximum rates, thus showing no differences in their local behavior. Interesting results that warrant further investigation are the better initial condition of the females and the highly consistent direction of the first migratory step in this population as summering habitats of the common noctule occur at a broad range in Northern Europe. Only research focused on individual strategies will allow us to fully understand the migratory behavior of European bats.
Bacterial pyruvate decarboxylases (PDC) are rare. Their role in ethanol production and in bacterially mediated ethanologenic processes has, however, ensured a continued and growing interest. PDCs from Zymomonas mobilis (ZmPDC), Zymobacter palmae (ZpPDC) and Sarcina ventriculi (SvPDC) have been characterized and ZmPDC has been produced successfully in a range of heterologous hosts. PDCs from the Acetobacteraceae and their role in metabolism have not been characterized to the same extent. Examples include Gluconobacter oxydans (GoPDC), G. diazotrophicus (GdPDC) and Acetobacter pasteutrianus (ApPDC). All of these organisms are of commercial importance.
This study reports the kinetic characterization and the crystal structure of a PDC from Gluconacetobacter diazotrophicus (GdPDC). Enzyme kinetic analysis indicates a high affinity for pyruvate (KM 0.06 mM at pH 5), high catalytic efficiencies (1.3 • 106 M−1•s−1 at pH 5), pHopt of 5.5 and Topt at 45°C. The enzyme is not thermostable (T½ of 18 minutes at 60°C) and the calculated number of bonds between monomers and dimers do not give clear indications for the relatively lower thermostability compared to other PDCs. The structure is highly similar to those described for Z. mobilis (ZmPDC) and A. pasteurianus PDC (ApPDC) with a rmsd value of 0.57 Å for Cα when comparing GdPDC to that of ApPDC. Indole-3-pyruvate does not serve as a substrate for the enzyme. Structural differences occur in two loci, involving the regions Thr341 to Thr352 and Asn499 to Asp503.
This is the first study of the PDC from G. diazotrophicus (PAL5) and lays the groundwork for future research into its role in this endosymbiont. The crystal structure of GdPDC indicates the enzyme to be evolutionarily closely related to homologues from Z. mobilis and A. pasteurianus and suggests strong selective pressure to keep the enzyme characteristics in a narrow range. The pH optimum together with reduced thermostability likely reflect the host organisms niche and conditions under which these properties have been naturally selected for. The lack of activity on indole-3-pyruvate excludes this decarboxylase as the enzyme responsible for indole acetic acid production in G. diazotrophicus.
Electronic supplementary material
The online version of this article (doi:10.1186/s12900-014-0021-1) contains supplementary material, which is available to authorized users.
The aim of this exploratory study was to investigate the relationship between focal interictal epileptiform discharges (IEDs), intellectual disability and cortical information processing in children with partial epilepsy. Two groups of patients – Group 1 (n = 9 patients) with focal IEDs and normal IQ and Group 2 (n = 10 patients) with focal IEDs and intellectual disability – were compared with 14 healthy control participants. A computerized choice reaction time task (go/no-go paradigm) was performed and event-related potentials (ERPs) were recorded. When an IED occurred during the period between the presentation of the stimulus and the response, the response was defined as a response with IED. Omission errors, commission errors and reaction time were evaluated in temporal relationship to IEDs.
The Group 1 patients did not differ from the healthy children in neurophysiological functions and ERP amplitudes. The Group 2 children showed inferior performances in verbal learning and memory, cognitive flexibility and selective attention, and were characterized by low ERP amplitudes compared with the epilepsy patients with normal IQ and the healthy children. We were not able to identify any significant relationship between IEDs and cognitive functions in either group of patients. Our findings suggest that the impact of IEDs on the overall intellectual abilities of epilepsy patients may not be as significant as previously thought. Moreover, it is likely that abnormalities in cognitive information processing as revealed by lower ERP amplitudes, occurrence of IEDs, and intellectual disabilities may represent common abnormal processes and may not be causally related to each other.
epilepsy; go/no-go; intellectual disability; mismatch negativity; visual evoked potentials
The study of T cell memory and the target of vaccine design has focused on memory subsumed by T cells bearing the αβ T cell receptor. Alternatively, γδ T cells are thought to provide rapid immunity particularly at mucosal borders. Here we have shown that a distinct subset of mucosal γδ T cells mounts an immune response to oral Listeria monocytogenes (Lm) infection leading to the development of multifunctional memory T cells in the murine intestinal mucosa that is capable of simultaneously producing interferon-γ and interleukin-17A. Challenge infection with oral Lm, but not oral Salmonella or intravenous Lm, induced rapid expansion of memory γδ T cells suggesting contextual specificity to the priming pathogen. Importantly, memory γδ T cells were able to provide enhanced protection against infection. These findings illustrate a previously unrecognized role for γδ T cells with hallmarks of adaptive immunity in the intestinal mucosa.
Mg and Mg alloys are becoming more and more of interest for several applications. In the case of biomaterial applications, a special interest exists due to the fact that a predictable degradation should be given. Various investigations were made to characterize and predict the corrosion behavior in vitro and in vivo. Mostly, the simple oxidation of Mg to Mg2+ ions connected with adequate hydrogen development is assumed, and the negative difference effect (NDE) is attributed to various mechanisms and electrochemical results. The aim of this paper is to compare the different views on the corrosion pathway of Mg or Mg alloys and to present a neglected pathway based on thermodynamic data as a guideline for possible reactions combined with experimental observations of a delay of visible hydrogen evolution during cyclic voltammetry. Various reaction pathways are considered and discussed to explain these results, like the stability of the Mg+ intermediate state, the stability of MgH2 and the role of hydrogen overpotential. Finally, the impact of MgH2 formation is shown as an appropriate base for the prediction of the degradation behavior and calculation of the corrosion rate of Mg and Mg alloys.
magnesium; magnesium alloys; magnesium hydride; corrosion; degradation
The management of facial defects has rapidly changed in the last decade. Functional and esthetic requirements have steadily increased along with the refinements of surgery. In the case of advanced atrophy or jaw defects, extensive horizontal and vertical bone augmentation is often unavoidable to enable patients to be fitted with implants. Loss of vertical alveolar bone height is the most common cause for a non primary stability of dental implants in adults. At present, there is no ideal therapeutic approach to cure loss of vertical alveolar bone height and achieve optimal pre-implantological bone regeneration before dental implant placement. Recently, it has been found that specific populations of stem cells and/or progenitor cells could be isolated from different dental resources, namely the dental follicle, the dental pulp and the periodontal ligament. Our research group has cultured palatal-derived stem cells (paldSCs) as dentospheres and further differentiated into various cells of the neuronal and osteogenic lineage, thereby demonstrating their stem cell state. In this publication will be shown whether paldSCs could be differentiated into the osteogenic lineage and, if so, whether these cells are able to regenerate alveolar bone tissue in vivo in an athymic rat model. Furthermore, using these data we have started a proof of principle clinical- and histological controlled study using stem cell-rich palatal tissues for improving the vertical alveolar bone augmentation in critical size defects. The initial results of the study demonstrate the feasibility of using stem cell-mediated tissue engineering to treat alveolar bone defects in humans.
Human palatal-derived stem cells (paldSCs); Osteogenic differentiation; Athymic immunodeficient rats; Stem-cell enriched palatal-derived tissues; Proof of principle clinical-and histologically-con; Osteoplastic surgical methods
NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.
A novel and the shortest route, thus far, for preparing cytosporone B (Csn-B) is reported. Csn-B and two analogs were used to probe the importance of hydroxyl groups at the 3- and 5-positions of the Csn-B benzene ring in inhibiting the viability of human H460 lung cancer and LNCaP prostate cancer cells, inducing H460 cell apoptosis, and interacting with the NR4A1 (TR3) ligand-binding domain (LBD). These studies indicate that Csn-B and 5-Me-Csn-B, having a phenolic hydroxyl at the 3-position of their aromatic rings, had similar activities in inhibiting cancer cell viability and in inducing apoptosis, whereas 3,5-(Me)2-Csn-B was unable to do so. These results are in agreement with ligand-binding experiments showing that the interaction with the NR4A1 LBD required the presence of the 3-hydroxyl group.
Cullin 3, the core subunit of the CRL3 ubiquitin ligase family, is essential for development, but its substrates remain poorly defined. Here, Chen et al. (2009) report that CRL3BACURD targets the RhoA GTPase for degradation thereby maintaining actin cytoskeleton integrity.
Genome analysis of the yeast Saccharomyces cerevisiae identified 68 genes encoding flavin-dependent proteins (1.1% of protein encoding genes) to which 47 distinct biochemical functions were assigned. The majority of flavoproteins operate in mitochondria where they participate in redox processes revolving around the transfer of electrons to the electron transport chain. In addition, we found that flavoenzymes play a central role in various aspects of iron metabolism, such as iron uptake, the biogenesis of iron–sulfur clusters and insertion of the heme cofactor into apocytochromes. Another important group of flavoenzymes is directly (Dus1-4p and Mto1p) or indirectly (Tyw1p) involved in reactions leading to tRNA-modifications. Despite the wealth of genetic information available for S. cerevisiae, we were surprised that many flavoproteins are poorly characterized biochemically. For example, the role of the yeast flavodoxins Pst2p, Rfs1p and Ycp4p with regard to their electron donor and acceptor is presently unknown. Similarly, the function of the heterodimeric Aim45p/Cir1p, which is homologous to the electron-transferring flavoproteins of higher eukaryotes, in electron transfer processes occurring in the mitochondrial matrix remains to be elucidated. This lack of information extends to the five membrane proteins involved in riboflavin or FAD transport as well as FMN and FAD homeostasis within the yeast cell. Nevertheless, several yeast flavoproteins, were identified as convenient model systems both in terms of their mechanism of action as well as structurally to improve our understanding of diseases caused by dysfunctional human flavoprotein orthologs.
•Overview of flavin-dependent proteins in S. cerevisiae.•The role of yeast flavoproteins in iron metabolism.•Biosynthesis and transport of flavins.•Yeast as a model organism for investigating human diseases linked to flavoproteins.
DHAP, dihydroxy acetone phosphate; DHBP, 3,4-dihydroxy-2-butanone-4-phosphate; DRAP, 2,5-diamino-6-(ribosylamino)-4-(3H)-pyrimidinone 5′-phosphate; ER, endoplasmic reticulum; ETC, electron transport chain; Gly3p, glycerol 3-phosphate; gluSA, γ-glutamic acid semialdehyde; Mia(40), mitochondrial intermembrane space import and assay/oxidoreductase 40; ORF, open reading frame; Q, ubiquionone; Iron metabolism; Mitochondrion; Redox balance; tRNA-modifications; Membrane transporters
The bacterial pathogen Listeria monocytogenes spreads within human tissues using a motility process dependent on the host actin cytoskeleton. Cell-to-cell spread involves the ability of motile bacteria to remodel the host plasma membrane into protrusions, which are internalized by neighboring cells. Recent results indicate that formation of Listeria protrusions in polarized human cells involves bacterial antagonism of a host signaling pathway comprised of the scaffolding protein Tuba and its effectors N-WASP and Cdc42. These three human proteins form a complex that generates tension at apical cell junctions. Listeria relieves this tension and facilitates protrusion formation by secreting a protein called InlC. InlC interacts with a Src Homology 3 (SH3) domain in Tuba, thereby displacing N-WASP from this domain. Interaction of InlC with Tuba is needed for efficient Listeria spread in cultured human cells and infected animals. Recent structural data has elucidated the mechanistic details of InlC/Tuba interaction, revealing that InlC and N-WASP compete for partly overlapping binding surfaces in the Tuba SH3 domain. InlC binds this domain with higher affinity than N-WASP, explaining how InlC is able to disrupt Tuba/N-WASP complexes.
Listeria monocytogenes; cell-to-cell spread; protrusion; InlC; Tuba; SH3 domain; cortical tension; structural elucidation
Migraine is a disorder of central information processing which is characterized by a reduced habituation of event-related potentials. There might be positive effects of aerobic exercise on brain function and pain. The aim of this study was to investigate the influence of exercise on information processing and clinical course of migraine.
33 patients completed a ten-week aerobic exercise programme. To examine the influence of the treatment on information processing and attention, Trail Making Test (TMT) A and B, d2-Letter Cancellation Test (LCT) and recordings of the Contingent Negative Variation (CNV) were performed before and after the training.
Patients showed a significant reduction of the migraine attack frequency, the iCNV-amplitude and the processing time for TMT-A and TMT-B after treatment. Moreover, there was a significant increase of the habituation and positive changes in parameters of attention (d2-LCT) after the training.
This study demonstrates that aerobic exercise programme influences central information processing and leads to clinical effects on the migraine symptomatology. The results can be interpreted in terms of an improvement of a dysfunctional information processing and a stimulus selection under aerobic exercise.
Migraine; Sport; Exercise; Jogging; Walking; Contingent negative variation; CNV; Habituation; Dishabituation
PET and MRI provide complementary information in the study of the human brain. Simultaneous PET/MR data acquisition allows the spatial and temporal correlation of the measured signals, opening up opportunities impossible to realize using stand-alone instruments. This paper reviews the methodological improvements and potential neurological and psychiatric applications of this novel technology. We first present methods for improving the performance and information content of each modality by using the information provided by the other technique. On the PET side, we discuss methods that use the simultaneously acquired MR data to improve the PET data quantification. On the MR side, we present how improved PET quantification could be used to validate a number of MR techniques. Finally, we describe promising research, translational and clinical applications that could benefit from these advanced tools.
simultaneous PET/MRI; multimodal imaging; neurology
The combinatorial architecture of cullin 1-RING ubiquitin ligases (CRL1s), in which multiple F-box containing substrate receptors (FBPs) compete for access to CUL1, poses special challenges to assembling CRL1 complexes through high affinity protein interactions while maintaining the flexibility to dynamically sample the entire FBP repertoire. Here, using highly quantitative mass spectrometry, we demonstrate that this problem is addressed by CAND1, a factor that controls the dynamics of the global CRL1 network by promoting the assembly of newly synthesized FBPs with CUL1-RBX1 core complexes. Our studies of in vivo CRL1 dynamics and in vitro biochemical findings showing that CAND1 can displace FBPs from Cul1p suggest that CAND1 functions in a cycle that serves to exchange FBPs on CUL1 cores. We propose that this cycle assures comprehensive sampling of the entire FBP repertoire in order to maintain the CRL1 landscape, a function that we show to be critical for substrate degradation and normal physiology.