Stochastic modeling of cargo transport by teams of molecular motors

Many different types of cellular cargos are transported bidirectionally along microtubules by teams of molecular motors. The motion of this cargo-motors system has been experimentally characterized in vivo as processive with rather persistent directionality. Different theoretical approaches have been suggested in order to explore the origin of this kind of motion. An effective theoretical approach, introduced by M\"uller et al., describes the cargo dynamics as a tug-of-war between different kinds of motors. An alternative approach has been suggested recently by Kunwar et al., who considered the coupling between motor and cargo in more detail. Based on this framework we introduce a model considering single motor positions which we propagate in continuous time. Furthermore, we analyze the possible influence of the discrete time update schemes used in previous publications on the system's dynamic.Comment: Cenference proceedings - Traffic and Granular Flow 1

Structural Insights into the Methane-Generating Enzyme from a Methoxydotrophic Methanogen Reveal a Restrained Gallery of Post-Translational Modifications

Methanogenic archaea operate an ancient, if not primordial, metabolic pathway that releases methane as an end-product. This last step is orchestrated by the methyl-coenzyme M reductase (MCR), which uses a nickel-containing F430-cofactor as the catalyst. MCR astounds the scientific world by its unique reaction chemistry, its numerous post-translational modifications, and its importance in biotechnology not only for production but also for capturing the greenhouse gas methane. In this report, we investigated MCR natively isolated from Methermicoccus shengliensis. This methanogen was isolated from a high-temperature oil reservoir and has recently been shown to convert lignin and coal derivatives into methane through a process called methoxydotrophic methanogenesis. A methoxydotrophic culture was obtained by growing M. shengliensis with 3,4,5-trimethoxybenzoate as the main carbon and energy source. Under these conditions, MCR represents more than 12% of the total protein content. The native MCR structure refined at a resolution of 1.6-Å precisely depicts the organization of a dimer of heterotrimers. Despite subtle surface remodeling and complete conservation of its active site with other homologues, MCR from the thermophile M. shengliensis contains the most limited number of post-translational modifications reported so far, questioning their physiological relevance in other relatives

Kinderanästhesie zur Protonenbestrahlung: Medizin fernab der Klinik

Zusammenfassung: Die Betreuung von Kleinkindern für die Protonentherapie stellt fachlich und menschlich hohe Anforderungen an das Anästhesieteam. Das Anästhesiepersonal soll in Kinderanästhesie speziell ausgebildet und erfahren sein, insbesondere da die Kinder sich oft in einem reduzierten Allgemeinzustand befinden. Die Infrastruktur soll gemäß den aktuellen anästhesiologischen Standards eingerichtet sein. Die ständige visuelle Überwachung des sedierten Patienten und das lückenlose Monitoring der Vitaldaten müssen gewährleistet sein. Propofol eignet sich ideal für die Sedierung von Kleinkindern in Spontanatmung für die Protonentherapie. Auch bei repetitiver Gabe über mehrere Wochen wird Propofol sehr gut toleriert. Eine enge Zusammenarbeit zwischen Radioonkologe, Onkologe und Anästhesist ist notwendig, um interkurrent auftretende medizinische Probleme optimal zu behandeln. Die besonderen Belange onkologischer Patienten müssen bei der Therapieplanung berücksichtigt werde

Single gene enables plant pathogenic Pectobacterium to overcome host-specific chemical defence

Plants of the Brassicales order, including Arabidopsis and many common vegetables, produce toxic isothiocyanates to defend themselves against pathogens. Despite this defence, plant pathogenic microorganisms like Pectobacterium cause large yield losses in fields and during storage of crops. The bacterial gene saxA was previously found to encode isothiocyanate hydrolase that degrades isothiocyanates in vitro. Here we demonstrate in planta that saxA is a virulence factor that can overcome the chemical defence system of Brassicales plants. Analysis of the distribution of saxA genes in Pectobacterium suggests that saxA from three different phylogenetic origins are present within this genus. Deletion of saxA genes representing two of the most common classes from P. odoriferum and P. versatile resulted in significantly reduced virulence on Arabidopsis thaliana and Brassica oleracea. Furthermore, expressing saxA from a plasmid in a potato-specific P. parmentieri strain that does not naturally harbour this gene significantly increased the ability of the strain to macerate Arabidopsis. These findings suggest that a single gene may have a significant role in defining the host range of a plant pathogen.Peer reviewe

The structure of porin from Rhodobacter capsulatus at 1.8 Å resolution

AbstractThe structure of the porin from Rhodobacter capsulanus was determined at a resolution of 1.8 Å. The analysis started from a closely related crystal structure that had been solved at a medium resolution of 3 Å using multiple isomorphous replacement and solvent flattening. The new structure contains the complete sequence of 301 amino acid residues. Refinement of the model is under way: the present R-factor is 22% with good geometry. Except for the lengths of several loops, the resulting chain fold corresponds to the medium resolution model. The membrane channel is lined by a large number of ionogenic side chains with characteristic segregation of differently charged groups

Cancer stem cells in melanoma

The identification of cancer stem cells in various malignancies led to the hypothesis that these cells have the exclusive ability of self-renewal, contribute to the plasticity of the tumours and may be the cause for ineffective cancer therapies. Several markers of melanoma stem cells have been described in recent studies including CD133, CD166, Nestin and BMI-1. Further studies are necessary to identify, better define and understand the origin and function of cancer stem cells. If confirmed that cancer stem cells play an important role in malignancy, therapeutic strategies may need to be redirected towards these cells to circumvent the failure of conventional therapies

Efficacy and safety of ceftobiprole in patients aged 65 years or older:a post hoc analysis of three Phase III studies

Lay abstract Infections are a common cause of severe disease and death in older patients. Antibiotic treatment may also be complicated by age-related changes within the body. The present study analyzed results from three large clinical trials that assessed the benefits of the novel antibiotic ceftobiprole in the older population. In patients aged over 65 years with skin infections or with pneumonia acquired either in the community or in a hospital setting, ceftobiprole offered similar benefits to established antibiotics. There was also some preliminary evidence that older patients may respond more quickly to ceftobiprole compared with the other antibiotics used in these studies. Overall, ceftobiprole was well tolerated and will be a useful treatment option for infections in older patients. Aim: To evaluate the efficacy and safety of ceftobiprole in patients aged >= 65 years. Materials & methods: We conducted a post hoc analysis of three randomized, double-blind, Phase III studies in patients with acute bacterial skin and skin structure infections, community-acquired pneumonia and hospital-acquired pneumonia. Results: Findings for patients aged >= 65 years (n = 633) were consistent with those for the overall study populations, although a trend toward improved outcomes was reported in some subgroups, for example, patients aged >= 75 years with community-acquired pneumonia were more likely to achieve an early clinical response with ceftobiprole than comparator (treatment difference 16.3% [95% CI:1.8-30.8]). The safety profile was similar between treatment groups in all studies. Conclusion: This analysis further supports the efficacy and safety of ceftobiprole in older patients with acute bacterial skin and skin structure infections or pneumonia. Clinicaltrials.gov trial identifiers: , ,

Action du sulfite de sodium sur la concentration en composés organohalogénés et sur l'activité mutagène de solutions chlorées de substances humiques

Cette étude a eu pour but de déterminer l'effet d'un traitement par le sulfite de sodium sur la concentration en composés organohalogénés totaux (TOX) et sur l'activité mutagène de solutions chlorées de substances humiques d'origine aquatique (SHA), après avoir cherché à préciser l'influence du pH et du temps sur la concentration en TOX.Les résultats obtenus à partir d'échantillons chlorés de SHA en absence de chlore résiduel ont permis de mettre en évidence une diminution de la concentration en composés organohalogénés totaux, soit par stockage en milieu neutre ou basique, soit par addition de sulfite de sodium. L'intensité de cette réduction de la concentration en TOX augmente avec le pH, le temps de réaction et la dose de sulfite de sodium introduite.Les résultats obtenus à partir d'échantillons contenant du chlore libre indiquent que seule une déchloration totale avec un excès de sulfite de sodium peut conduire, en milieu neutre, à une diminution de l'activité mutagène et de la concentration en TOX des solutions diluées de SHA. La comparaison des pourcentages d'abattement obtenus sur le paramètre TOX et sur l'activité mutagène indique que la diminution de la génotoxicité par déchloration totale est due à l'action du sulfite sur des composés mutagènes non chlorés ou sur des composés chlorés fortement mutagènes et ne représentant qu'une très faible fraction du TOX.If is a well known tact that mimerous organohalogenated compounds are formed during the chlorination (preoxidation or final disinfection) of drinking water. Some of these compounds have been shown to be mutagenic. Recent studies have suggested that a treatment with oxygenated derivatives of SIV (SO2, NaHSO3 and Na2SO3) could reduce the genotoxicity of chlorinated drinking water.The general aim of Ibis study was to determine the effect of dechlorination treatments on the mutagenic activity of chlorinated drinking water. The following experiments were carried out in order to point out the effect of a treatment with sodium sulfite on the concentration of total organohalogenated compounds (TOX) and on the mutagenic activity of chlorinated dilute solutions of Aquatic Humic Substances (AHS).At first, the affects of pH, sodium sulfite dose and contact time on TOX concentration were investigated. Then, the importance of the dechlorination rate (partial or complete) on TOX concentration and also on the mutagenic activity could be studied.ExperimentalAquatic Humic Substances (natural mixture of fulvic and humic acids) were dissolved in phosphate-buffered ultra-pure water at 5 and 15 mg l-1 concentrations (pH 6.1 and 6.9 respectively). Stock solutions of chlorine were prepared in the laboratory and titrated by iodometry. Chlorination and dechlorination treatments were carried out in headspace-free baffles, at 20± 1 °C in the dark. Residual chlorine was determined by spectrophotometric measurements at 510 nm, following the calorimetric method using N,N-diethylphenylene-1,4-diamine (DPD). To avoid the slow oxidation of Slv into Svl by dissolved oxygen, the sodium sulfite solutions were prepared freshly before use. TOX concentrations were measured using a DOHRMAN DX-20 TOX analyser equipped with a MC-1 microcoulometric cell and with an AD-2 adsorption module. Before analysis, the residual chlorine was neutralized with sodium thiosulfate and samples were acidified to pH 1.4.The mutagenic activity was determined using acetone-dichloromethane extracts (AMBERLITE XAD-8 and XAD-2 resins) of the aqueous samples of chlorinated and dechlorinated solutions of AHS, acidified to pH 2.0 before extraction. The mutagenicity tests were carried out on TA 98 and TA 100 tester strains, following the method described by MARON and AMES (1983).Results-Effect of pH, addition of sodium sulfite and storage time on the TOX concentrationThe experiments carried out with dilute solutions of AHS ([AHS] = 5 mg 1-1; DOC = 2.5 mg Cl-1; pH = 6.1) showed a linear relationship between TOX production and chlorine consumption in the range 0-2.0 mg Cl2 l-1 (fig. 2).15 % of the chlorine demand was incorporated as organic chlorine in molecules.Experiments performed on solutions containing no residual free chlorine showed that organohatogenated compounds could be partially destroyed upon storage at neutral or basic pH (table 1). Reductions in TOX concentrations of 10 % at pH 6.1-8.5 in 24 hours and of 20 % at pH 11.5 in 2 hours were observed. This was enhanced by increasing the storage time.The addition of sodium sulfite (100 µmol l-1) in solutions containing no residual free chlorine significantly reduced the TOX concentration (10 % in 2 hours at pH 6.1-8.5; table 1). This reduction was enhanced by increasing sulfite dose and storage time and by increasing pH (30 % in 2 hours at pH 11.5). Furthermore, at a given pH value and for a reaction time of 2 hours, the decrease in TOX concentration was larger in presence of sulfite.- Effect of a dechlorination treatment on the TOX concentrationAs shown in figure 3, a dechlorination treatment (reduction of the residual free chlorine concentration) with sodium sulfite could significantly reduce the TOX concentration of the dilute solutions of AHS at pH 6.1 only if an excess of the dechlorinating agent was added. This effect was enhanced by increasing the excess of sulfite but nevertheless seemed to be limited (less than 15 % of reduction for the highest doses used; table 2).The free chlorine residuals measured after a 2 hours partial dechlorination confirmed the stoichiometric factor of 1 mole/mole for the reaction between chlorine and sodium sulfite.- Effect of a dechlorination treatment on the mutagenic activity and on the TOX concentrationThe dechlorination treatments were carried out on chlorinated dilute solutions of AHS ([AHS] = 15 mg l-1; DOC 7.5 mg C l-1; pH = 6.9). The TOX concentrations were measured on aqueous solutions and mutagenicity tests were performed on the corresponding acetone-dichloromethane extracts following a solvent exchange (dimethylsulfoxide). The results obtained showed again that only a total dechlorination treatment could reduce the TOX concentration of the aqueous chlorinated solutions and was able to destroy a significant part of the mutagenic activity of the extracts (table 3 and fig. 4).Although the effect of sulfite on TOX concentration seemed limited (less than 7 % reduction for the highest sulfite dose tested), the reduction in the genotoxicity was more important when the excess of sulfite was increased. No correlation between the TOX concentration and the mutagenic activity could be established. The mutagenic compounds destroyed by sodium sulfite do not appear to be organohalogenated ones. If they are, they are present at trace levels and thus are extremely patent and account for a very little part of the TOX concentration

Molecular characterization of signalling pathways in cancer stem cells

To avoid artefacts introduced by culturing cells for extended periods of time, it is crucial to use low-passage patient-derived tumour cells. The ability to enrich, isolate and assay sub-populations of cells that behave as cancer stem cells (CSCs) from these primary cell lines is essential before performing characterizations such as gene-expression profiling. We have isolated cells from glioblastomas which show characteristics of CSCs. Although glioblastomas contain only a relatively small amount of putative CSCs, these cells express many genes which seem to be worthy targets for future therapies