Chemical genetic approaches for target validation

Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression. One of the essential steps in this process is to validate that pharmacological modulation (e.g. inhibition) of the target leads to the desired phenotype, a process which is collectively referred to as target validation. Target validation heavily relies on the availability of suitable chemical tools to study engagement of the compound to the intended biological target. The development of selective chemical tools can be challenging to achieve due to the off-target activity towards structurally and/or functionally related homologs, e.g. other members within the same protein class. The field of chemical genetics combines the specificity of genetics with benefits of acute, pharmacological modulation by small molecules. This thesis describes chemical genetic approaches that can be used for target engagement and target validation studies of two different enzyme classes: kinases and serine hydrolases. Molecular Physiolog

Risk and resilience: health inequalities, working conditions and sickness benefit arrangements: an analysis of the 2010 European Working Conditions survey

In this article we ask whether the level of sickness benefit provision protects the health of employees, particularly those who are most exposed to hazardous working conditions or who have a little education. The study uses the European Working Condition Survey that includes information on 20,626 individuals from 28 countries. Health was measured by self-reported mental wellbeing and self-rated general health. Country-level sickness benefit provision was constructed using spending data from Eurostat. Group-specific associations were fitted using cross-level interaction terms between sickness benefit provision and physical and psychosocial working conditions respectively, as well as those with little education. The mental wellbeing of employees exposed to psychosocial job strain and physical hazards, or who had little education, was better in countries that offer more generous sickness benefit. These results were found in both men and women and were robust to the inclusion of GDP and country fixed effects. In the analyses of self-reported general health, few group-specific associations were found. This article concludes that generous sickness benefit provision may strengthen employee's resilience against mental health risks at work and risks associated with little education. Consequently, in countries with a generous provision of sickness benefit, social inequalities in mental health are smaller

Can dry merging explain the size evolution of early-type galaxies?

The characteristic size of early-type galaxies (ETGs) of given stellar mass is observed to increase significantly with cosmic time, from redshift z>2 to the present. A popular explanation for this size evolution is that ETGs grow through dissipationless ("dry") mergers, thus becoming less compact. Combining N-body simulations with up-to-date scaling relations of local ETGs, we show that such an explanation is problematic, because dry mergers do not decrease the galaxy stellar-mass surface-density enough to explain the observed size evolution, and also introduce substantial scatter in the scaling relations. Based on our set of simulations, we estimate that major and minor dry mergers increase half-light radius and projected velocity dispersion with stellar mass (M) as M^(1.09+/-0.29) and M^(0.07+/-0.11), respectively. This implies that: 1) if the high-z ETGs are indeed as dense as estimated, they cannot evolve into present-day ETGs via dry mergers; 2) present-day ETGs cannot have assembled more than ~45% of their stellar mass via dry mergers. Alternatively, dry mergers could be reconciled with the observations if there was extreme fine tuning between merger history and galaxy properties, at variance with our assumptions. Full cosmological simulations will be needed to evaluate whether this fine-tuned solution is acceptable.Comment: 5 pages, 2 figures. Accepted for publication in ApJ Letter

Lipid membrane-mediated attraction between curvature inducing objects

The interplay of membrane proteins is vital for many biological processes, such as cellular transport, cell division, and signal transduction between nerve cells. Theoretical considerations have led to the idea that the membrane itself mediates protein self-organization in these processes through minimization of membrane curvature energy. Here, we present a combined experimental and numerical study in which we quantify these interactions directly for the first time. In our experimental model system we control the deformation of a lipid membrane by adhering colloidal particles. Using confocal microscopy, we establish that these membrane deformations cause an attractive interaction force leading to reversible binding. The attraction extends over 2.5 times the particle diameter and has a strength of three times the thermal energy (−3.3 kBT). Coarse-grained Monte-Carlo simulations of the system are in excellent agreement with the experimental results and prove that the measured interaction is independent of length scale. Our combined experimental and numerical results reveal membrane curvature as a common physical origin for interactions between any membrane-deforming objects, from nanometre-sized proteins to micrometre-sized particles

The Detection of a Red Sequence of Massive Field Galaxies at z~2.3 and its Evolution to z~0

The existence of massive galaxies with strongly suppressed star formation at z~2.3, identified in a previous paper, suggests that a red sequence may already be in place beyond z=2. In order to test this hypothesis, we study the rest-frame U-B color distribution of massive galaxies at 2<z<3. The sample is drawn from our near-infrared spectroscopic survey for massive galaxies. The color distribution shows a statistically significant (>3 sigma) red sequence, which hosts ~60% of the stellar mass at the high-mass end. The red-sequence galaxies have little or no ongoing star formation, as inferred from both emission-line diagnostics and stellar continuum shapes. Their strong Balmer breaks and their location in the rest-frame U-B, B-V plane indicate that they are in a post-starburst phase, with typical ages of ~0.5-1.0 Gyr. In order to study the evolution of the red sequence, we compare our sample with spectroscopic massive galaxy samples at 0.02<z<0.045 and 0.6<z<1.0. The rest-frame U-B color reddens by ~0.25 mag from z~2.3 to the present at a given mass. Over the same redshift interval, the number and stellar mass density on the high-mass end (>10^11 Msol) of the red sequence grow by factors of ~8 and ~6, respectively. We explore simple models to explain the observed evolution. Passive evolution models predict too strong d(U-B), and produce z~0 galaxies that are too red. More complicated models that include aging, galaxy transformations, and red mergers can explain both the number density and color evolution of the massive end of the red sequence between z~2.3 and the present.Comment: Accepted for publication in the Astrophysical Journa

Production of isotopically enriched high molecular weight hyaluronic acid and characterization by solid-state NMR

Hyaluronic acid (HA) is a naturally occurring polysaccharide that is abundant in the extracellular matrix (ECM) of all vertebrate cells. HA-based hydrogels have attracted great interest for biomedical applications due to their high viscoelasticity and biocompatibility. In both ECM and hydrogel applications, high molecular weight (HMW)-HA can absorb a large amount of water to yield matrices with a high level of structural integrity. To understand the molecular underpinnings of structural and functional properties of HA-containing hydrogels, few techniques are available. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for such studies, e.g. 13C NMR measurements can reveal the structural and dynamical features of (HMW) HA. However, a major obstacle to 13C NMR is the low natural abundance of 13C, necessitating the generation of HMW-HA that is enriched with 13C isotopes. Here we present a convenient method to obtain 13C- and 15N-enriched HMW-HA in good yield from Streptococcus equi subsp. zooepidemicus. The labeled HMW-HA has been characterized by solution and magic angle spinning (MAS) solid-state NMR spectroscopy, as well as other methods. These results will open new ways to study the structure and dynamics of HMW-HA-based hydrogels, and interactions of HMW-HA with proteins and other ECM components, using advanced NMR techniques. </p

Ultradeep Near-Infrared ISAAC Observations of the HDF-S: Observations, Reduction, Multicolor Catalog, and Photometric Redshifts

We present deep near-infrared (NIR) Js, H, and Ks-band ISAAC imaging of the WFPC2 field of the HDF-S. The 2.5'x 2.5' high Galactic latitude field was observed with the VLT under the best seeing conditions with integration times amounting to 33.6 hours in Js, 32.3 hours in H, and 35.6 hours in Ks. We reach total AB magnitudes for point sources of 26.8, 26.2, and 26.2 respectively (3 sigma), which make it the deepest ground-based NIR observations to date, and the deepest Ks-band data in any field. The effective seeing of the coadded images is ~0.45" in Js, ~0.48" in H, and ~0.46" in Ks. Using published WFPC2 optical data, we constructed a Ks-limited multicolor catalog containing 833 sources down to Ks,tot ~< 26 (AB), of which 624 have seven-band optical-to-NIR photometry. These data allow us to select normal galaxies from their rest-frame optical properties to high redshift (z ~< 4). The observations, data reduction and properties of the final images are discussed, and we address the detection and photometry procedures that were used in making the catalog. In addition, we present deep number counts, color distributions and photometric redshifts of the HDF-S galaxies. We find that our faint Ks-band number counts are flatter than published counts in other deep fields, which might reflect cosmic variations or different analysis techniques. Compared to the HDF-N, we find many galaxies with very red V-H colors at photometric redshifts 1.95 < z < 3.5. These galaxies are bright in Ks with infrared colors redder than Js-Ks > 2.3 (in Johnson magnitudes). Because they are extremely faint in the observed optical, they would be missed by ultraviolet-optical selection techniques, such as the U-dropout method.Comment: LaTeX, 24 pages, 15 figures, 3 tables. Accepted for publication in the Astronomical Journal. The paper with full resolution images and figures is available at http://www.strw.leidenuniv.nl/~fires/papers/2002Labbe.ps.gz . The reduced data and catalogs can be found at http://www.strw.leidenuniv.nl/~fires/data/hdfs

Reflecting on the Science of Climate Tipping Points to Inform and Assist Policy Making and Address the Risks they Pose to Society

There is a diverging perception of climate tipping points, abrupt changes and surprises in the scientific community and the public. While such dynamics have been observed in the past, e.g., frequent reductions of the Atlantic meridional overturning circulation during the last ice age, or ice sheet collapses, tipping points might also be a possibility in an anthropogenically perturbed climate. In this context, high impact—low likelihood events, both in the physical realm as well as in ecosystems, will be potentially dangerous. Here we argue that a formalized assessment of the state of science is needed in order to establish a consensus on this issue and to reconcile diverging views. This has been the approach taken by the Intergovernmental Panel on Climate Change (IPCC). Since 1990, the IPCC has consistently generated robust consensus on several complex issues, ranging from the detection and attribution of climate change, the global carbon budget and climate sensitivity, to the projection of extreme events and their impact. Here, we suggest that a scientific assessment on tipping points, conducted collaboratively by the IPCC and the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, would represent an ambitious yet necessary goal to be accomplished within the next decade

Lipid membrane-mediated attraction between curvature inducing objects

Biological and Soft Matter Physic

A Compact Early-type Galaxy at z = 0.6 Under a Magnifying Lens: Evidence For Inside-out Growth

We use Keck laser guide star adaptive optics imaging and exploit the magnifying effects of strong gravitational lensing (the effective resolution is FWHM ~ 200 pc) to investigate the sub-kpc scale of an intermediate-redshift (z = 0.63) massive early-type galaxy being lensed by a foreground early-type galaxy; we dub this class of strong gravitational lens systems EELs, e.g., early-type/early-type lenses. We find that the background source is massive (M* = 10^{10.9} M_sun) and compact (r_e = 1.1 kpc), and a two-component fit is required to model accurately the surface brightness distribution, including an extended low-surface-brightness component. This extended component may arise from the evolution of higher-redshift `red nuggets' or may already be in place at z ~ 2 but is unobservable due to cosmological surface brightness dimming.Comment: 5 pages, 4 figures; accepted to MNRA