Galactosylsphingamides : new α-GalCer analogues to probe the F’-pocket of CD1d

Invariant Natural Killer T-cells (iNKT-cells) are an attractive target for immune response modulation, as upon CD1d-mediated stimulation with KRN7000, a synthetic alpha-galactosylceramide, they produce a vast amount of cytokines. Here we present a synthesis that allows swift modification of the phytosphingosine side chain by amidation of an advanced methyl ester precursor. The resulting KRN7000 derivatives, termed alpha-galactosylsphingamides, were evaluated for their capacity to stimulate iNKT-cells. While introduction of the amide-motif in the phytosphingosine chain is tolerated for CD1d binding and TCR recognition, the studied alpha-galactosylsphingamides showed compromised antigenic properties

Beroepsprofiel geriatriefysiotherapeut

Een Geriatriefysiotherapeut is een geschoolde en vakbekwame fysiotherapeut die zich, middels een, door de NVAO Geaccrediteerde en KNGF en NVFG erkende, opleiding, heeft gespecialiseerd in de zorg voor kwetsbare ouderen. Het specialisme richt zich op verbetering en behoud van gezondheid, zelfredzaamheid, participatie en kwaliteit van leven van kwetsbare ouderen of ouderen die het risico lopen kwetsbaar te worden, met de focus op het bewegend functioneren. Het domein van de geriatriefysiotherapie valt onder de medische, bewegings- en gedragswetenschappen en baseert zich op actuele wetenschappelijke inzichten, methoden en technieken uit deze kennisgebieden

1-(1-Arylethylpiperidin-4-yl)thymine analogs as antimycobacterial TMPK inhibitors

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM)

Ageing in rural China: migration and care circulation

This article applies the concept of care circulation (Baldassar and Merla, Transnational families, migration and the circulation of care: understanding mobility and absence in family life, 2013) to the processes involved in the care of old people in rural China,an area which has hitherto been predominantly located in a quantitatively based intergenerational transfer framework. Drawing upon a qualitative study of rural families in the context of rural to urban migration, this article examines the multidirectional and asymmetrical exchanges of caregiving and care-receiving and seeks to provide a more nuanced understanding of the impact of migration upon ageing and familial care in rural China. First, going beyond a unidirectional flow or two-way transfer, this article reveals that care circulates between different family members, in different locations, to differing degrees, over the life course. This circulation framework enables an examination of intra-generational dynamics as well as intergenerational relations. Second, this article draws attention to the mediating factors that impact upon the ways in which adult children care for the older generation. It reveals how the employment status of migrating adult children, the temporal dimension of migration and family life cycle of migrating children as well as family relations between the older generation and adult child generation are critical factors. These factors also contribute to the quality of care provided. Finally, while confirming existing scholarship that gender is an important dimension in structuring old age support in rural China, this article calls for a more differentiated approach among generations of women and between regions, revealing the ways in which local migration history interacts with intergenerational dynamics to determine the cohort of women that endure the greatest burden of care

The Impact of Perceived Expectations and Uncertainty on Firm Investment

This paper analyses the (differential) impact of perceived expectations and uncertainty on investment spending in small and large firms. We analyse two types of investment, viz. aggregate investment and investment in energy-saving technologies, using Dutch firm level data. The results show that expectations and uncertainty about input- and output prices and domestic demand have substantial but different effects on investment spending in firms of different sizes. Furthermore, we find evidence, at least for small firms, that there are important differences between the effects of uncertainty about input and output variable

Origin and Evolution of GALA-LRR, a New Member of the CC-LRR Subfamily: From Plants to Bacteria?

The phytopathogenic bacterium Ralstonia solanacearum encodes type III effectors, called GALA proteins, which contain F-box and LRR domains. The GALA LRRs do not perfectly fit any of the previously described LRR subfamilies. By applying protein sequence analysis and structural prediction, we clarify this ambiguous case of LRR classification and assign GALA-LRRs to CC-LRR subfamily. We demonstrate that side-by-side packing of LRRs in the 3D structures may control the limits of repeat variability within the LRR subfamilies during evolution. The LRR packing can be used as a criterion, complementing the repeat sequences, to classify newly identified LRR domains. Our phylogenetic analysis of F-box domains proposes the lateral gene transfer of bacterial GALA proteins from host plants. We also present an evolutionary scenario which can explain the transformation of the original plant LRRs into slightly different bacterial LRRs. The examination of the selective evolutionary pressure acting on GALA proteins suggests that the convex side of their horse-shoe shaped LRR domains is more prone to positive selection than the concave side, and we therefore hypothesize that the convex surface might be the site of protein binding relevant to the adaptor function of the F-box GALA proteins. This conclusion provides a strong background for further functional studies aimed at determining the role of these type III effectors in the virulence of R. solanacearum