Geluksgevoel in Nederlandse provincies:oktober 2010 tot en met februari 2011

Samenvatting De GeluksWijzer is een combinatie van een zelf-help website en een langlopend wetenschappelijk onderzoek. Deelnemers beantwoorden hierbij regelmatig vragen over hun geluk. Van 16.125 deelnemers is bekend in welke provincie ze wonen. Daardoor kan nu worden nagegaan of mensen in alle provincies even gelukkig zijn. Wat is de meest en de minst gelukkige provincie in Nederland? In deze rapportage van de GeluksWijzer zijn verschillen in gemiddeld maandelijks en dagelijks geluk tussen de 12 Nederlandse provincies van 30 september 2010 tot en met 7 februari 2011 onderzocht. De belangrijkste bevindingen zijn: - Deelnemers uit Limburg zijn significant minder gelukkig dan deelnemers uit andere provincies in Nederland: Het rapportcijfer voor maandelijks en dagelijks geluk is er ongeveer een half punt lager. - Deelnemers uit Drenthe waren gemiddeld genomen het gelukkigst. - De (kleine) verschillen in gemiddeld geluk tussen provincies kunnen niet worden verklaard uit verschillen in levensomstandigheden op provincieniveau, zoals bijvoorbeeld het gemiddelde werkloosheidloosheidspercentage of de natuuroppervlakte per provincie. - Het minder hoge gelukscijfer in Limburg kan wel deels verklaard worden doordat meer deelnemers uit Limburg een ondermodaal inkomen hebben dan deelnemers uit de overige Nederlandse provincies. De GeluksWijzer is een geza

Theory and applications of differential scanning fluorimetry in early-stage drug discovery

Differential scanning fluorimetry (DSF) is an accessible, rapid, and economical biophysical technique that has seen many applications over the years, ranging from protein folding state detection to the identification of ligands that bind to the target protein. In this review, we discuss the theory, applications, and limitations of DSF, including the latest applications of DSF by ourselves and other researchers. We show that DSF is a powerful high-throughput tool in early drug discovery efforts. We place DSF in the context of other biophysical methods frequently used in drug discovery and highlight their benefits and downsides. We illustrate the uses of DSF in protein buffer optimization for stability, refolding, and crystallization purposes and provide several examples of each. We also show the use of DSF in a more downstream application, where it is used as an in vivo validation tool of ligand-target interaction in cell assays. Although DSF is a potent tool in buffer optimization and large chemical library screens when it comes to ligand-binding validation and optimization, orthogonal techniques are recommended as DSF is prone to false positives and negatives

Molecular mechanisms of resistance to classical and experimental anti-rheumatic drugs

Dijkmans, B.A.C. [Promotor]Scheper, R.J. [Promotor]Jansen, G. [Copromotor]Lems, W.F. [Copromotor

Finding the key to happy aging: A day reconstruction study of happiness

The main aim of this study was to examine the roles of physical passivity and extraversion in the relationship between daily engagement in activities and daily happiness among older adults. A day reconstruction method was used to accurately examine day-to-day activities and happiness. In total, 438 participants completed a monthly electronic diary survey over a 2-year period, generating 79,181 reported activities and momentary happiness scores. The results show that happiness increases when older adults combine effortful social, physical, cognitive, and household activities with restful activities. Furthermore, participation in social activities mediated the direct relationship between extraversion and happiness. Also, individuals who score high on extraversion derive greater happiness from social activities compared with their low-extravert counterparts. The study extends activity theory by demonstrating that combining effortful activities with restful activities leads to greater happiness among older adults. Also, personality traits such as extraversion play a decisive role in the kind of activities that contribute most to daily happiness

Comparison of the meteorology and surface energy balance at Storbreen and Midtdalsbreen, two glaciers in southern Norway

We compare 5 years of meteorological records from automatic weather stations (AWSs) on Storbreen and Midtdalsbreen, two glaciers in southern Norway, located approximately 120 km apart. The records are obtained from identical AWSs with an altitude difference of 120 m and cover the period September 2001 to September 2006. Air temperature at the AWS locations is found to be highly correlated, even with the seasonal cycle removed. The most striking difference between the two sites is the difference in wind climate. Midtdalsbreen is much more under influence of the large-scale circulation with wind speeds on average a factor 1.75 higher. On Storbreen, weaker katabatic winds are dominant. The main melt season is from May to September at both locations. During the melt season, incoming and net solar radiation are larger on Midtdalsbreen, whereas incoming and net longwave radiation are larger on Storbreen, primarily caused by thicker clouds on the latter. The turbulent fluxes are a factor 1.7 larger on Midtdalsbreen, mainly due to the higher wind speeds. Inter-daily fluctuations in the surface energy fluxes are very similar at the AWS sites. On average, melt energy is a factor 1.3 larger on Midtdalsbreen, a result of both larger net radiation and larger turbulent fluxes. The relative contribution of net radiation to surface melt is larger on Storbreen (76%) than on Midtdalsbreen (66%). As winter snow depth at the two locations is comparable in most years, the larger amount of melt energy results in an earlier disappearance of the snowpack on Midtdalsbreen and 70% more ice melt than on Storbreen. We compare the relative and absolute values of the energy fluxes on Storbreen and Midtdalsbreen with reported values for glaciers at similar latitudes. Furthermore, a comparison is made with meteorological variables measured at two nearby weather stations, showing that on-site measurements are essential for an accurate calculation of the surface energy balance and melt rate

Structural characterization and extended substrate scope analysis of two Mg<sup>2+</sup>-dependent O-methyltransferases from bacteria

Oxygen-directed methylation is a ubiquitous tailoring reaction in natural product pathways catalysed by O-methyltransferases (OMTs). Promiscuous OMT biocatalysts are thus a valuable asset in the toolkit for sustainable synthesis and optimization of known bioactive scaffolds for drug development. Here, we characterized two bacterial OMTs from Desulforomonas acetoxidans and Streptomyces avermitilis in terms of their enzymatic properties and substrate scope and determined their crystal structures. Both OMTs methylated a wide range of catechol-like substrates, including flavonoids, coumarins, hydroxybenzoic acids and their respective aldehydes, an anthraquinone and an indole. One enzyme also accepted a steroid. The product range included pharmaceutically relevant compounds such as (iso)fraxidin, iso(scopoletin), chrysoeriol, alizarin 1-methyl ether and 2-methoxyestradiol. Interestingly, certain non-catechol flavonoids and hydroxybenzoic acids were also methylated. This study expands the knowledge on substrate preference and structural diversity of bacterial catechol OMTs and paves the way for their use in (combinatorial) pathway engineering.Table of contents Two promiscuous O-methyltransferases from bacteria were found to methylate a panel of catechol substrates towards high-value medicinal compounds. Surprisingly, the non-catechol substrates 5-hydroxyflavonoids and o-hydroxybenzoic acids/aldehydes were also methylated at low conversion rates. The crystal structures reveal potential target sites for enzyme engineering for biocatalytic applications.Competing Interest StatementThe authors have declared no competing interest

Structural Characterization and Extended Substrate Scope Analysis of Two Mg²⁺-Dependent O-Methyltransferases from Bacteria**

Oxygen-directed methylation is a ubiquitous tailoring reaction in natural product pathways catalysed by O-methyltransferases (OMTs). Promiscuous OMT biocatalysts are thus a valuable asset in the toolkit for sustainable synthesis and optimization of known bioactive scaffolds for drug development. Here, we characterized the enzymatic properties and substrate scope of two bacterial OMTs from Desulforomonas acetoxidans and Streptomyces avermitilis and determined their crystal structures. Both OMTs methylated a wide range of catechol-like substrates, including flavonoids, coumarins, hydroxybenzoic acids, and their respective aldehydes, an anthraquinone and an indole. One enzyme also accepted a steroid. The product range included pharmaceutically relevant compounds such as (iso)fraxidin, iso(scopoletin), chrysoeriol, alizarin 1-methyl ether, and 2-methoxyestradiol. Interestingly, certain non-catechol flavonoids and hydroxybenzoic acids were also methylated. This study expands the knowledge on substrate preference and structural diversity of bacterial catechol OMTs and paves the way for their use in (combinatorial) pathway engineering.</p