Reducing the stimulation of CD8+ T cells during infection with intracellular bacteria promotes differentiation primarily into a central (CD62LhighCD44high) subset

During infection with lymphocytic choriomeningitis virus, CD8(+) T cells differentiate rapidly into effectors (CD62L(low)CD44(high)) that differentiate further into the central memory phenotype (CD62L(high)CD44(high)) gradually. To evaluate whether this CD8(+) T cell differentiation program operates in all infection models, we evaluated CD8(+) T cell differentiation during infection of mice with recombinant intracellular bacteria, Listeria monocytogenes (LM) and Mycobacterium bovis (BCG), expressing OVA. We report that CD8(+) T cells primed during infection with the attenuated pathogen BCG-OVA differentiated primarily into the central subset that correlated to reduced attrition of the primed cells subsequently. CD8(+) T cells induced by LM-OVA also differentiated into central phenotype cells first, but the cells rapidly converted into effectors in contrast to BCG-OVA. Memory CD8(+) T cells induced by both LM-OVA as well as BCG-OVA were functional in that they produced cytokines and proliferated extensively in response to antigenic stimulation after adoptive transfer. During LM-OVA infection, if CD8(+) T cells were guided to compete for access to APCs, then they received reduced stimulation that was associated with increased differentiation into the central subset and reduced attrition subsequently. Similar effect was observed when CD8(+) T cells encountered APCs selectively during the waning phase of LM-OVA infection. Taken together, our results indicate that the potency of the pathogen can influence the differentiation and fate of CD8(+) T cells enormously, and the extent of attrition of primed CD8(+) T cells correlates inversely to the early differentiation of CD8(+) T cells primarily into the central CD8(+) T cell subset.     

Symposium De toekomst van de informele zorg

Due to the reform of long term care in 2015, there is growing concern about whether groups at risk receive the care they need. People in need of care have to rely more on help from their social network. The increased need for informal care requires resilience and organizational skills of families, but also of volunteers, professionals and employers. What does this mean for the provision of informal care in the next decennia? The symposium ‘The future of informal care’, organized on January 26 2017 by the National Institute for Social Research and the Institute for Societal Resilience of the Vrije Universiteit, addressed possible answers to this question. In her inaugural speech Alice de Boer discussed social inequality as possible determinant and outcome of informal care. Some conclusions:Until 2050 the absolute number of 75-plus doubled to about 3 million persons, but the number of informal caregivers will decrease. In addition to the importance of social and economic resources (the ‘have & have-nots’), the ability to arrange care (the ‘can & can-nots’) gains importance.Almost half of the older employers provides informal care just before retirement. Flexibility in working hours and work location facilitates combining work and care, but about half of the employers indicates that partial retirement and working at home are no options.Informal caregivers and professionals often provide care from comparable perspectives and identities. Addressing similarities rather than differences improves their chances for collaboration.The number of adult children providing household care to older parents increased between 2002 and 2014. This suggests an increase in family solidarity, but current reform policies may increase the gender inequality in caregiving families.Spouses and children remain primary caregivers in the future, preferably supported by many different types of caregivers. Not everybody has the capabilities to organize and direct such a large care network.Providing informal care increases the risk for overburden and absence at work or education. Informal caregivers at risk remain, also in the future, women, spouses, migrants, and younger carers.     

Functional Imaging of Plants: A Nuclear Magnetic Resonance Study of a Cucumber Plant

Functional magnetic resonance imaging was used to study transients of biophysical parameters in a cucumber plant in response to environmental changes. Detailed flow imaging experiments showed the location of xylem and phloem in the stem and the response of the following flow characteristics to the imposed environmental changes: the total amount of water, the amount of stationary and flowing water, the linear velocity of the flowing water, and the volume flow. The total measured volume flow through the plant stem was in good agreement with the independently measured water uptake by the roots. A separate analysis of the flow characteristics for two vascular bundles revealed that changes in volume flow of the xylem sap were accounted for by a change in linear-flow velocities in the xylem vessels. Multiple-spin echo experiments revealed two water fractions for different tissues in the plant stem; the spin-spin relaxation time of the larger fraction of parenchyma tissue in the center of the stem and the vascular tissue was down by 17% in the period after cooling the roots of the plant. This could point to an increased water permeability of the tonoplast membrane of the observed cells in this period of quick recovery from severe water loss.     

Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo

The precise assembly of the highly organized filament systems found in muscle is critically important for its function. It has been hypothesized that nebulin, a giant filamentous protein extending along the entire length of the thin filament, provides a blueprint for muscle thin filament assembly. To test this hypothesis, we generated a KO mouse model to investigate nebulin functions in vivo. Nebulin KO mice assemble thin filaments of reduced lengths and approximately 15% of their Z-disks are abnormally wide. Our data demonstrate that nebulin functions in vivo as a molecular ruler by specifying pointed- and barbed-end thin filament capping. Consistent with the shorter thin filament length of nebulin deficient mice, maximal active tension was significantly reduced in KO animals. Phenotypically, the murine model recapitulates human nemaline myopathy (NM), that is, the formation of nemaline rods combined with severe skeletal muscle weakness. The myopathic changes in the nebulin KO model include depressed contractility, loss of myopalladin from the Z-disk, and dysregulation of genes involved in calcium homeostasis and glycogen metabolism; features potentially relevant for understanding human NM.     

Caffeinated soft drinks reduce bacterial prevalence in voice prosthetic biofilms

Laryngectomized patients use indwelling silicone rubber voice prostheses, placed in a surgically created fistula in between the trachea and the esophagus, for voice and speech rehabilitation. At the esophageal side, these voice prostheses rapidly become colonized by a thick biofilm consisting of a variety of oral and skin bacteria and yeasts, and on average, after 3–4 months a prosthesis has to be replaced. In this study, the influence of caffeinated soft drinks on biofilm formation on silicone rubber voice prostheses has been investigated in a modified Robbins device. Robbins devices were first inoculated with the total cultivable microflora from an explanted voice prosthesis for 3 d, after which the devices were perfused three times daily over a 12 day period with 650 ml of either phosphate buffered saline or carbonated mineral water (controls), caffeinated soft drinks (two types), or a decaffeinated and a sugar‐free version of one of the caffeinated soft drinks. At the end of a day, during the experimental period, the devices were filled with growth medium for 30 min. Both caffeinated soft drinks reduced bacterial prevalence in the biofilms to 1–5% of the control, while yeasts thrived in voice prosthetic biofilms exposed to caffeinated soft drinks. Neither the controls, nor the decaffeinated soft drink, nor the sugar‐free version of this showed these effects on bacterial prevalence.     

Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study

Introduction  

Identifying ankylosing spondylitis (AS) patients who are likely to benefit from tumor necrosis factor-alpha (TNF-α) blocking therapy is important, especially in view of the costs and potential side effects of these agents. Recently, the AS Disease Activity Score (ASDAS) has been developed to assess both subjective and objective aspects of AS disease activity. However, data about the predictive value of the ASDAS with respect to clinical response to TNF-α blocking therapy are lacking. The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-α blocking therapy in AS patients in daily clinical practice.