Role of the cyclic lipopeptide massetolide A in biological control of Phytophthora infestans and in colonization of tomato plants by Pseudomonas fluorescens

Pseudomonas strains have shown promising results in biological control of late blight caused by Phytophthora infestans. However, the mechanism(s) and metabolites involved are in many cases poorly understood. Here, the role of the cyclic lipopeptide massetolide A of Pseudomonas fluorescens SS101 in biocontrol of tomato late blight was examined. Pseudomonas fluorescens SS101 was effective in preventing infection of tomato (Lycopersicon esculentum) leaves by P. infestans and significantly reduced the expansion of existing late blight lesions. Massetolide A was an important component of the activity of P. fluorescens SS101, since the massA-mutant was significantly less effective in biocontrol, and purified massetolide A provided significant control of P. infestans, both locally and systemically via induced resistance. Assays with nahG transgenic plants indicated that the systemic resistance response induced by SS101 or massetolide A was independent of salicylic acid signalling. Strain SS101 colonized the roots of tomato seedlings significantly better than its massA-mutant, indicating that massetolide A was an important trait in plant colonization. This study shows that the cyclic lipopeptide surfactant massetolide A is a metabolite with versatile functions in the ecology of P fluorescens SS101 and in interactions with tomato plants and the late blight pathogen P. infestans

Dynamic Correlation between Intrahost HIV-1 Quasispecies Evolution and Disease Progression

Quantifying the dynamics of intrahost HIV-1 sequence evolution is one means of uncovering information about the interaction between HIV-1 and the host immune system. In the chronic phase of infection, common dynamics of sequence divergence and diversity have been reported. We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants. The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces. Analysis of the model suggested that the previously observed saturation of divergence and decrease of diversity in later stages of infection can be explained by a decrease in the proportion of offspring that are mutants as the distance from the founder strain increases rather than due to an increase of viral fitness. The prediction of the model was examined by performing phylogenetic analysis to estimate the change in the rate of evolution during infection. In agreement with our modeling, in 13 out of 15 patients (followed for 3–12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline. The correlation between the dynamics of the evolutionary rate and the rate of CD4+ T-cell decline, coupled with our HIV-1 sequence evolution model, explains previously conflicting observations of the relationships between the rate of HIV-1 quasispecies evolution and disease progression

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction

Advances in the clinical management of pediatric B cell Acute Lymphoblastic Leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL

Stop Making Sense(s) : Some late medieval and very late medieval views on faculty psychology

Peer reviewe

Generalized Geometry and M theory

We reformulate the Hamiltonian form of bosonic eleven dimensional supergravity in terms of an object that unifies the three-form and the metric. For the case of four spatial dimensions, the duality group is manifest and the metric and C-field are on an equal footing even though no dimensional reduction is required for our results to hold. One may also describe our results using the generalized geometry that emerges from membrane duality. The relationship between the twisted Courant algebra and the gauge symmetries of eleven dimensional supergravity are described in detail.Comment: 29 pages of Latex, v2 References added, typos fixed, v3 corrected kinetic term and references adde

The Rotterdam Scan Study: design and update up to 2012

Neuroimaging plays an important role in etiologic research on neurological diseases in the elderly. The Rotterdam Scan Study was initiated as part of the ongoing Rotterdam Study with the aim to unravel causes of neurological disease by performing neuroimaging in a population-based longitudinal setting. In 1995 and 1999 random subsets of the Rotterdam Study underwent neuroimaging, whereas from 2005 onwards MRI has been implemented into the core protocol of the Rotterdam Study. In this paper, we discuss the background and rationale of the Rotterdam Scan Study. We also describe the imaging protocol and post-processing techniques, and highlight the main findings to date. Finally, we make recommendations for future research, which will also be the main focus of investigation in the Rotterdam Scan Study

A Unified Algebraic Approach to Few and Many-Body Correlated Systems

The present article is an extended version of the paper {\it Phys. Rev.} {\bf B 59}, R2490 (1999), where, we have established the equivalence of the Calogero-Sutherland model to decoupled oscillators. Here, we first employ the same approach for finding the eigenstates of a large class of Hamiltonians, dealing with correlated systems. A number of few and many-body interacting models are studied and the relationship between their respective Hilbert spaces, with that of oscillators, is found. This connection is then used to obtain the spectrum generating algebras for these systems and make an algebraic statement about correlated systems. The procedure to generate new solvable interacting models is outlined. We then point out the inadequacies of the present technique and make use of a novel method for solving linear differential equations to diagonalize the Sutherland model and establish a precise connection between this correlated system's wave functions, with those of the free particles on a circle. In the process, we obtain a new expression for the Jack polynomials. In two dimensions, we analyze the Hamiltonian having Laughlin wave function as the ground-state and point out the natural emergence of the underlying linear $W_{1+\infty}$ symmetry in this approach.Comment: 18 pages, Revtex format, To appear in Physical Review

Technique of anterior colporrhaphy: a Dutch evaluation

Contains fulltext : 96395.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: To evaluate the variation in techniques of anterior colporrhaphy among members of the Dutch Urogynecologic Society. METHODS: A questionnaire evaluating the technique of anterior colporrhaphy, preoperative and postoperative care, and use of the POP-Q score was sent out by e-mail. RESULTS: One hundred thirty-three completed questionnaires were received. The response rate was 65%. There are large variations in incisions, use of hydrodissection, method of plication, and excision of redundant vaginal epithelium. The urinary catheter was generally removed on day 2 after surgery and the vaginal pack on day 1. Less than half of the respondents used the POP-Q score routinely. CONCLUSIONS: Dutch gynecologists use a variety of surgical techniques to operate on a cystocele. This suggests that there is no widely accepted opinion on the best surgical approach. The lack of differentiation between central and lateral defects is striking and in contrast with the, mostly, American literature

Prerequisites for a dry powder inhaler for children with cystic fibrosis

Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7-14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion