Architectural plasticity of human BRCA2-RAD51 complexes in DNA break repair

The tumor suppressor BRCA2 is a large multifunctional protein mutated in 50-60% of familial breast cancers. BRCA2 interacts with many partners and includes multiple regions with potentially disordered structure. In homology directed DNA repair BRCA2 delivers RAD51 to DNA resulting in removal of RPA and assembly of a RAD51 nucleoprotein filame

HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair

The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required for meiotic HR during mouse spermatogenesis, in non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP compromises HR by triggering the removal of BRCA2 from the ICL site and thereby preventing the loading of RAD51. This establishes ectopic expression of a wild-type meiotic protein in the absence of any other protein-coding mutations as a new mechanism that can lead to an FA-like cellular phenotype. Naturally occurring elevated production of HSF2BP in tumors may be a source of cancer-promoting genomic instability and also a targetable vulnerability

Validation of Syndromic Surveillance for Respiratory Pathogen Activity

The studied respiratory syndromes are suitable for syndromic surveillance because they reflect respiratory pathogen activity pattern

Planar sensors for dielectric and magnetic materials measurement: A quantitative sensitivity comparison

Planar transmission lines are frequently used to characterize the RF properties of materials. However, the question arises which geometry should be chosen for optimal measurement sensitivity to the material under test. Thus far, this question appears to go unanswered. In this paper, the suitability of the three most popular planar geometries is compared for material characterization. To this end, the impact of a material under test on the apparent properties (i.e. the equivalent homogeneous cross-sections) is examined. This is done for the complex permittivity and the complex permeability, using conformal mapping methods, full-wave simulations and measurements. It is shown that the coplanar waveguide (without conductor backing) is the most suitable structure of the three, since it is the most sensitive to changes in the properties of the material under test

Backbone and side-chain C-13 and N-15 signal assignments of the alpha-spectrin SH3 domain by magic angle spinning solid-state NMR at 17.6 Tesla

Solid state NMR/Biophysical Organic Chemistr

Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures

AbstractNicotinic acetylcholine receptors are prototypes for the pharmaceutically important family of pentameric ligand-gated ion channels. Here we present atomic resolution structures of nicotine and carbamylcholine binding to AChBP, a water-soluble homolog of the ligand binding domain of nicotinic receptors and their family members, GABAA, GABAC, 5HT3 serotonin, and glycine receptors. Ligand binding is driven by enthalpy and is accompanied by conformational changes in the ligand binding site. Residues in the binding site contract around the ligand, with the largest movement in the C loop. As expected, the binding is characterized by substantial aromatic and hydrophobic contributions, but additionally there are close contacts between protein oxygens and positively charged groups in the ligands. The higher affinity of nicotine is due to a main chain hydrogen bond with the B loop and a closer packing of the aromatic groups. These structures will be useful tools for the development of new drugs involving nicotinic acetylcholine receptor-associated diseases

Verandercanvas: Een praktisch boek voor iedereen die doordacht wil werken aan organisatieverandering

In vrijwel alle organisaties vinden veranderingen plaats. Variërend van ingrijpende veranderingen zoals een reorganisatie tot relatief kleine aanpassingen in bijvoorbeeld samenwerkingsafspraken tussen teams. Het doel van dergelijke veranderingen is altijd om de organisatie en haar medewerkers beter te laten functioneren, zodat de organisatiedoelstellingen worden gerealiseerd. Maar succesvol veranderen gaat niet vanzelf. Het VeranderCanvas helpt om doordacht te werken aan organisatieverandering. Doordacht veranderen begint met een noodzaak of ambitie én een beeld van de resultaten die de verandering op moet leveren. Vervolgens wordt op gestructureerde wijze gewerkt aan het bereiken van die resultaten. Het stellen van een diagnose is voor doordacht veranderen cruciaal: ‘Waar staat de organisatie ten aanzien van de verandering?’. Pas als die vraag is beantwoord, kan worden bepaald aan welke onderwerpen moet worden gewerkt om de verandering succesvol te realiseren. Het zwaartepunt van het VeranderCanvas ligt daarom ook op deze cruciale fase in verandering, de diagnose. Op praktische wijze, ondersteund met aansprekende voorbeelden, worden alle facetten van het werken aan verandering systematisch doorlopen en wordt op basis van de diagnose inzichtelijk gemaakt welke onderdelen aandacht behoeven bij het ontwerpen en implementeren van de verandering. ‘Het VeranderCanvas neemt je mee in de dynamische wereld van verandermanagement en helpt je bij het doordacht werken aan verandering’ Het boek staat onder redactie van Anne-Bregje Huijsmans, Lisa van Rossum, Sjoerd Segijn, Kim Grinwis en Wouter ten Have; zij zijn allen werkzaam als adviseur bij TEN HAVE Change Management. Met dit boek en de ontwikkeling van het VeranderCanvas willen zij bijdragen aan de toegankelijkheid en toepasbaarheid van de kennis en inzichten uit het vak verandermanagement

Risk factors for osteoporosis in Caucasian patients with moderate chronic obstructive pulmonary disease: A case control study

The prevalence of osteoporosis is high in chronic obstructive pulmonary disease (COPD) patients. The gold standard for the diagnosis of osteoporosis is bone mineral density (BMD) measurements as assessed by dual energy absorptiometry (DXA) scanning as well as vertebral fractures as assessed by instant vertebral assessment (IVA). The aim of this study was to compare COPD GOLD II patients (that is, patients with moderate COPD, stage II, according to the GOLD classification) with osteoporosis (cases) to COPD GOLD II patients without osteoporosis (controls) to identify risk factors for osteoporosis. The diagnosis of osteoporosis was based on BMD and vertebral fractures. Cases (n=49) were matched for gender, age and forced expiratory volume in the first second to controls (n=49). We assessed pulmonary function, body composition, vitamin D, emphysema score (by high-resolution computer tomography), medical history and medication use in all patients. Variables that were significantly different between the cases and controls were included in a logistic regression analysis. COPD patients with osteoporosis had a significantly lower body mass index (BMI) and higher residual volume as the percentage of total lung capacity (RV%TLC) compared to COPD patients without osteoporosis. Decreasing BMI and increasing RV%TLC increased the odds ratio for osteoporosis. Overweight and obese BMI values were protective for osteoporosis. Screening for osteoporosis should be performed even in moderate COPD patients, especially in those with a low BMI and/or a high RV%TLC