Improvement of Aglycone π-Stacking Yields Nanomolar to Sub-nanomolar FimH Antagonists

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti-adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium-affinity state in the absence and a high-affinity state in the presence of shear forces. Until recently, mostly the high-affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low-affinity state. In this communication, we demonstrate that fluorination of biphenyl α-d -mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub-nanomolar K_D values for the low- and high-affinity states, respectively. The face-to-face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as ¹H,¹⁵N-HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.     

Recent Developments and Practical Feasibility of Polymer‐Based Antifouling Coatings

While nature has optimized its antifouling strategies over millions of years, synthetic antifouling coatings have not yet reached technological maturity. For an antifouling coating to become technically feasible, it should fulfill many requirements: high effectiveness, long‐term stability, durability, ecofriendliness, large‐scale applicability, and more. It is therefore not surprising that the search for the perfect antifouling coating has been going on for decades. With the discovery of metal‐based antifouling paints in the 1970s, fouling was thought to be a problem of the past, yet its untargeted toxicity led to serious ecological concern, and its use became prohibited. As a response, research shifted focus toward a biocompatible alternative: polymer‐based antifouling coatings. This has resulted in numerous advanced and innovative antifouling strategies, including fouling‐resistant, fouling‐release, and fouling‐degrading coatings. Here, these novel and exciting discoveries are highlighted while simultaneously assessing their antifouling performance and practical feasibility.     

Taking on a wider view: public value interests of construction clients in a changing construction industry

For financial and strategic reasons, public and semi-public construction clients increasingly depend on private parties to carry out public service delivery. They subcontract operational responsibilities to private parties while remaining socio-politically responsible for ensuring public values. Public administration literature mainly addresses the importance of procedural and performance values in safeguarding public values. However, safeguarding the quality of the built environment also requires a focus on product values. In this study, we aim to increase the understanding of the meaning and significance of public values in the daily practice of public construction clients and identify the challenges they face in commissioning these seemingly opposing values. A set of semi-structured interviews with the public administrators of a variety of public and semi-public construction client organizations in the Netherlands shows that both internal and external factors influence the collaborative practices between clients and contractors. This causes a value shift from an emphasis on procedural values to managing performance and product values, indicating that clients need to take on a wider view on public values. Six main public value dilemmas were found that complicate the task of developing an open, transparent and sustainable long-term client–contractor relationship. The current contractual system, however, lacks the flexibility to facilitate this product-based value view in construction.     

Bioinspired pressure actuated adhesive system

We developed a dry synthetic adhesive system inspired by gecko feet adhesion that can switch reversibly from adhesion to non-adhesion with applied pressure as external stimulus. Micropatterned polydimethylsiloxane (PDMS) surfaces with pillars of 30 μm length and 10 μm diameter were fabricated using photolithography and moulding. Adhesion properties were determined with a flat probe as a function of preload. For low and moderate applied compressive preloads, measured adhesion was 7.5 times greater than on flat controls whereas for high applied preloads adhesion dropped to very low values. In situ imaging shows that the increased preload caused the pillars to deform by bending and/or buckling and to lose their adhesive contact. The elasticity of PDMS aids the pillar recovery to the upright position upon removal of preload enabling repeatability of the switch.     

What governs the transition to a sustainable hydrogen economy? Articulating the relationship between technologies and political institutions

There is a lack of integrated knowledge on the transition to a sustainable energy system. The paper focuses on the relationship between technologies and institutions in the field of hydrogen from the perspective of political theory. The paper unfolds four paradigms of governance: ‘Governance by policy networking’, Governance by government’, ‘Governance by corporate business’, and ‘Governance by challenge’, and looks into the major line of argument in support of these paradigms and into their possible bias with respect to hydrogen options. Each of these paradigms reveals an institutional bias in that it articulates specific opportunities for collaboration and competition in order to stimulate the transition to a sustainable hydrogen economy. The paper makes the observation that there is a compelling need to reframe fashionable discourse such as the necessary shift from government to governance or from government to market. Instead, specific questions with respect to the impact of guiding policy frameworks on innovation will highlight that neither ‘neutral’ nor ‘optimal’ frameworks for policy making exist, where competing hydrogen options are at stake. The identification of paradigms of governance maybe considered a methodological device for (participator) policy analysis.     

Creating trauma-informed systems: Child welfare, education, first responders, health care, juvenile justice.

Children and adolescents who are exposed to traumatic events are helped by numerous child-serving agencies, including health, mental health, education, child welfare, first responder, and criminal justice systems to assist them in their recovery. Service providers need to incorporate a trauma-informed perspective in their practices to enhance the quality of care for these children. This includes making sure that children and adolescents are screened for trauma exposure; that service providers use evidence-informed practices; that resources on trauma are available to providers, survivors, and their families; and that there is a continuity of care across service systems. This article reviews how traumatic stress impacts children and adolescents' daily functioning and how various service systems approach trauma services differently. It also provides recommendations for how to make each of these service systems more trauma informed and an appendix detailing resources in the National Child Traumatic Stress Network that have been produced to meet this objective. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A new bioadhesive for in vivo bone adhesion

A new bone adhesive was used to facilitate the union of bone fragments detached and repositioned on the tibia of dogs. The sites were X-rayed and histologically examined 1 and 6 weeks post-operatively. By 6 weeks, the bone fragments were found to be solidly attached in their original sites. Histological examination revealed no signs of inflammation, infection or any other adverse reactions, neither on the operated bone, nor in remote tissues of internal organs (spleen, lung, liver, kidney, and lymph nodes). The tested specimens exhibit, de novo bone growth into the adhesive, concomitant with clear signs of biodegradation of the adhesive. Additional in vivo experiments were carried out in white rats, whereby the adhesive was implanted subcutaneously and it became evident that the implanted material enabled new bone formation (ectopic), with no adverse effects within the immediate site as well as in the remote areas. Moreover, the biocompatible nature of the material revealed distinct signs of biodegradability.     

IV. Yeast sequencing reports. New open reading frames,one of which is similar to the nifV gene of Azotobacter vinelandii,Found on a 12·5 kbp fragment of chromosome IV of Saccharomyces cerevisiae

The nucleotide sequence of a 12·5 kbp segment of the left arm of chromosome IV is described. Five open reading frames (ORFs) longer than 100 amino acids were detected, all of which are completely confined to the 12·5 kbp region. Two ORFs (D1271 and D1286) correspond to previously sequenced genes (PPH22 and VMA1 or TFP1, respectively). ORF D1298 shows the characteristics of α-isopropylmalate and homocitrate synthase genes and is similar to the nifV gene of Azotobacter vinelandii. Two more ORFs have no apparent homologue in the data libraries. Conversely, two smaller ORFs of 25 and 85 amino acids encoding the ribosomal protein YL41A and an ATPase inhibitor, respectively, were detected. Although a substantial part of the 12·5 kbp fragment apparently lacks protein-coding characteristics, no other elements, such as tRNA genes or transposons, were found. The nucleotide sequence data reported in this paper will appear in the EMBL, GenBank and DDBJ Nucleotide Sequence Databases under the Accession Number X83276.     

Robust shape regression for supervised vessel segmentation and its application to coronary segmentation in CTA

This paper presents a vessel segmentation method which learns the geometry and appearance of vessels in medical images from annotated data and uses this knowledge to segment vessels in unseen images. Vessels are segmented in a coarse-to-fine fashion. First, the vessel boundaries are estimated with multivariate linear regression using image intensities sampled in a region of interest around an initialization curve. Subsequently, the position of the vessel boundary is refined with a robust nonlinear regression technique using intensity profiles sampled across the boundary of the rough segmentation and using information about plausible cross-sectional vessel shapes. The method was evaluated by quantitatively comparing segmentation results to manual annotations of 229 coronary arteries. On average the difference between the automatically obtained segmentations and manual contours was smaller than the inter-observer variability, which is an indicator that the method outperforms manual annotation. The method was also evaluated by using it for centerline refinement on 24 publicly available datasets of the Rotterdam Coronary Artery Evaluation Framework. Centerlines are extracted with an existing method and refined with the proposed method. This combination is currently ranked second out of 10 evaluated interactive centerline extraction methods. An additional qualitative expert evaluation in which 250 automatic segmentations were compared to manual segmentations showed that the automatically obtained contours were rated on average better than manual contours.     

Evaluation of registration methods on thoracic CT: the EMPIRE10 challenge

EMPIRE10 (Evaluation of Methods for Pulmonary Image REgistration 2010) is a public platform for fair and meaningful comparison of registration algorithms which are applied to a database of intrapatient thoracic CT image pairs. Evaluation of nonrigid registration techniques is a nontrivial task. This is compounded by the fact that researchers typically test only on their own data, which varies widely. For this reason, reliable assessment and comparison of different registration algorithms has been virtually impossible in the past. In this work we present the results of the launch phase of EMPIRE10, which comprised the comprehensive evaluation and comparison of 20 individual algorithms from leading academic and industrial research groups. All algorithms are applied to the same set of 30 thoracic CT pairs. Algorithm settings and parameters are chosen by researchers expert in the configuration of their own method and the evaluation is independent, using the same criteria for all participants. All results are published on the EMPIRE10 website (http://empire10.isi.uu.nl). The challenge remains ongoing and open to new participants. Full results from 24 algorithms have been published at the time of writing. This paper details the organization of the challenge, the data and evaluation methods and the outcome of the initial launch with 20 algorithms. The gain in knowledge and future work are discussed.