Cooperativity and Frustration in Protein-Mediated Parallel Actin Bundles

We examine the mechanism of bundling of cytoskeletal actin filaments by two representative bundling proteins, fascin and espin. Small-angle X-ray studies show that increased binding from linkers drives a systematic \textit{overtwist} of actin filaments from their native state, which occurs in a linker-dependent fashion. Fascin bundles actin into a continuous spectrum of intermediate twist states, while espin only allows for untwisted actin filaments and fully-overtwisted bundles. Based on a coarse-grained, statistical model of protein binding, we show that the interplay between binding geometry and the intrinsic \textit{flexibility} of linkers mediates cooperative binding in the bundle. We attribute the respective continuous/discontinous bundling mechanisms of fascin/espin to differences in the stiffness of linker bonds themselves.Comment: 5 pages, 3 figures, figure file has been corrected in v

History of the software industry: the challenge

Martin Campbell-Kelly opened a new field in the history of computing in his groundbreaking From airline reservation to Sonic the Hedgehog; a history of the software industry. The book is discussed by Adrienne van den Bogaard and Frank Veraart and by Gerard Alberts, followed by a reply by the author. Van den Bogaard and Veraart join great appreciation for the three-sector division Campbell-Kelly developed to describe the history of the software industry, to a slight criticism of his ad hoc-argumentation in explaining why in each sector some enterprises survive and others do not. Lacking, in their view, is a discussion of the dynamics of software itself in the context of emerging practices and businesses. Alberts overcomes his prima facie unease with th

Waterloopkunde: een eeuw wiskunde en werkelijkheid

Onderzoekers van het Waterloopkundig Lab, de Deltadienst van Rijkswaterstaat, TNO en het Mathematisch Centrum bestudeerden in vredige competitie het dynamisch gedrag van de Haringvlietsluizen. De uiteenlopende tradities om dewiskunde in dienst te stellen van de waterbouwkunde, schaalmodellen, analogons, wiskundige modellen en rekenwerk, kwamen in een zogenaamde klapclub samen. De beslissing bleef uit. Korte tijd later raakten al deze inspanningen op de achtergrond door de revolutie in de richting van een heel nieuw type rekenmodellen

Insights into the mode of action of a putative zinc transporter CzrB in thermus thermophilus

peer-reviewedThis paper was obtained through PEER (Publishing and the Ecology of European Research) http://www.peerproject.euThe crystal structures of the cytoplasmic domain of the putative zinc transporter CzrB in the apoand zinc-bound forms reported herein are consistent with the protein functioning in vivo as a homodimer. NMR, X-ray scattering and size exclusion chromatography provide support for dimer formation. Full-length variants of CzrB in the apo and zinc-loaded states were generated by homology modelling with the Zn2+ / H+ antiporter YiiP. The model suggests a way in which zinc binding to the cytoplasmic fragment creates a docking site to which a metallochaperone can bind for delivery and transport of its zinc cargo. Since the cytoplasmic domain may exist in the cell as an independent, soluble protein a proposal is advanced that it functions as a metallochaperone and that it regulates the zinc-transporting activity of the full-length protein. The latter requires that zinc binding becomes uncoupled from the creation of a metallochaperone-docking site on CzrB

Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC

Pooled resequencing of 122 ulcerative colitis genes in a large Dutch cohort suggests population-Specific associations of rare variants in MUC2

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted resequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a populationspecific contribution of rare variants to UC

Memories of a Dying Industry: Sense and Identity in a British Paper Mill

Frogmore paper mill is a kind of time machine that allows historians of technology and the senses to study mechanized paper-making as it was done one hundred years ago. Before the introduction of instrumentation and automatic process control paper-making depended profoundly on the embodied skills of the workers. This paper will focus on the sensory knowledge and skills required for monitoring and controlling old machinery. Investigating skills-in-use will help to unravel the close link between sensing and acting to keep a continuous production process stable and running. Paper-makers would shift intuitively between different senses and sensory modes of monitoring and diagnosing sensory tell-tales to balance the production process. The importance of sensory knowledge and embodied skills also shaped paper-makers’ self-perception and professional ethos. The paper will examine the impact of new process control technology on the crucial role of sensory skills for the paper-makers’ individual and collective identities

Biodistribution, clearance, and long‐term fate of clinically relevant nanomaterials

Realization of the immense potential of nanomaterials for biomedical applications will require a thorough understanding of how they interact with cells, tissues, and organs. There is evidence that, depending on their physicochemical properties and subsequent interactions, nanomaterials are indeed taken up by cells. However, the subsequent release and/or intracellular degradation of the materials, transfer to other cells, and/or translocation across tissue barriers are still poorly understood. The involvement of these cellular clearance mechanisms strongly influences the long-term fate of used nanomaterials, especially if one also considers repeated exposure. Several nanomaterials, such as liposomes and iron oxide, gold, or silica nanoparticles, are already approved by the American Food and Drug Administration for clinical trials; however, there is still a huge gap of knowledge concerning their fate in the body. Herein, clinically relevant nanomaterials, their possible modes of exposure, as well as the biological barriers they must overcome to be effective are reviewed. Furthermore, the biodistribution and kinetics of nanomaterials and their modes of clearance are discussed, knowledge of the long-term fates of a selection of nanomaterials is summarized, and the critical points that must be considered for future research are addressed