Single-base substitutions in the CHM promoter as a cause of choroideremia

Although over 150 unique mutations affecting the coding sequence of CHM have been identified in patients with the X-linked chorioretinal disease choroideremia (CHM), no regulatory mutations have been reported, and indeed the promoter has not been defined. Here, we describe two independent families affected by CHM bearing a mutation outside the gene's coding region at position c.-98: C>A and C>T, which segregated with the disease. The male proband of family 1 was found to lack CHM mRNA and its gene product Rab escort protein 1, whereas whole-genome sequencing of an affected male in family 2 excluded the involvement of any other known retinal genes. Both mutations abrogated luciferase activity when inserted into a reporter construct, and by further employing the luciferase reporter system to assay sequences 5′ to the gene, we identified the CHM promoter as the region encompassing nucleotides c.-119 to c.-76. These findings suggest that the CHM promoter region should be examined in patients with CHM who lack coding sequence mutations, and reveals, for the first time, features of the gene's regulation

Upgrading legacy equipment to industry 4.0 through a cyber-physical interface

With the recent developments of Industry 4.0 technologies, maintenance can be improved significantly by making it “smart”, proactive and even self-aware. This paper introduces a new cutting-edge interfacing technology that enables smart active remote maintenance right on the machine in real-time while allowing integration of smart automated decision making and Industrial Internet of Things to upgrade existing legacy equipment through latest Industry 4.0 technology. This interfacing technology enables remote sensing and actuation access to legacy equipment for smart maintenance by entirely non-intrusive means, i.e. the original equipment does not have to be modified. The design was implemented in a real-world manufacturing environment

The open innovation research landscape: established perspectives and emerging themes across different levels of analysis

This paper provides an overview of the main perspectives and themes emerging in research on open innovation (OI). The paper is the result of a collaborative process among several OI scholars – having a common basis in the recurrent Professional Development Workshop on ‘Researching Open Innovation’ at the Annual Meeting of the Academy of Management. In this paper, we present opportunities for future research on OI, organised at different levels of analysis. We discuss some of the contingencies at these different levels, and argue that future research needs to study OI – originally an organisational-level phenomenon – across multiple levels of analysis. While our integrative framework allows comparing, contrasting and integrating various perspectives at different levels of analysis, further theorising will be needed to advance OI research. On this basis, we propose some new research categories as well as questions for future research – particularly those that span across research domains that have so far developed in isolation

Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins

We propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction. Negative stain and cryoEM data of several examples of BRIL-membrane protein chimera highlight the effectiveness of the sABs as universal fiducial marks. Taken together with a cryoEM structure of sAB bound human nicotinic acetylcholine receptor, this work demonstrates that these anti-BRIL sABs can greatly enhance the particle properties leading to improved cryoEM outcomes, especially for challenging membrane proteins

Synthetic antibodies against BRIL as universal fiducial marks for single−particle cryoEM structure determination of membrane proteins

We propose the concept of universal fiducials based on a set of pre-made semi-synthetic antibodies (sABs) generated by customized phage display selections against the fusion protein BRIL, an engineered variant of apocytochrome b562a. These sABs can bind to BRIL fused either into the loops or termini of different GPCRs, ion channels, receptors and transporters without disrupting their structure. A crystal structure of BRIL in complex with an affinity-matured sAB (BAG2) that bound to all systems tested delineates the footprint of interaction. Negative stain and cryoEM data of several examples of BRIL-membrane protein chimera highlight the effectiveness of the sABs as universal fiducial marks. Taken together with a cryoEM structure of sAB bound human nicotinic acetylcholine receptor, this work demonstrates that these anti-BRIL sABs can greatly enhance the particle properties leading to improved cryoEM outcomes, especially for challenging membrane proteins

Digital transformation, for better or worse: a critical multi-level research agenda

For better or worse, digital technologies are reshaping everything, from customer behaviors and expectations to organizational and manufacturing systems, business models, markets, and ultimately society. To understand this overarching transformation, this paper extends the previous literature which has focused mostly on the organizational level by developing a multi‐level research agenda for digital transformation (DT). In this regard, we propose an extended definition of DT as “a socioeconomic change across individuals, organizations, ecosystems, and societies that are shaped by the adoption and utilization of digital technologies.” We suggest four lenses to interpret the DT phenomenon: individuals (utilizing and adopting digital technologies), organizations (strategizing and coordinating both internal and external transformation), ecosystems (harnessing digital technologies in governance and co‐producing value propositions), and geopolitical frameworks (regulating the environments in which individuals and organizations are embedded). Based on these lenses, we build a multi‐level research agenda at the intersection between the bright and dark sides of DT and introduce the PIAI framework, which captures a process of perception, interpretation, and action that ultimately leads to possible impact. The PIAI framework identifies a critical research agenda consisting of a non‐exhaustive list of topics that can assist researchers to deepen their understanding of the DT phenomenon and provide guidance to managers and policymakers when making strategic decisions that seek to shape and guide the DT

Digital transformation, for better or worse: a critical multi-level research agenda

For better or worse, digital technologies are reshaping everything, from customer behaviors and expectations to organizational and manufacturing systems, business models, markets, and ultimately society. To understand this overarching transformation, this paper extends the previous literature which has focused mostly on the organizational level by developing a multi‐level research agenda for digital transformation (DT). In this regard, we propose an extended definition of DT as “a socioeconomic change across individuals, organizations, ecosystems, and societies that are shaped by the adoption and utilization of digital technologies.” We suggest four lenses to interpret the DT phenomenon: individuals (utilizing and adopting digital technologies), organizations (strategizing and coordinating both internal and external transformation), ecosystems (harnessing digital technologies in governance and co‐producing value propositions), and geopolitical frameworks (regulating the environments in which individuals and organizations are embedded). Based on these lenses, we build a multi‐level research agenda at the intersection between the bright and dark sides of DT and introduce the PIAI framework, which captures a process of perception, interpretation, and action that ultimately leads to possible impact. The PIAI framework identifies a critical research agenda consisting of a non‐exhaustive list of topics that can assist researchers to deepen their understanding of the DT phenomenon and provide guidance to managers and policymakers when making strategic decisions that seek to shape and guide the DT.</jats:p

Reversal of stress fibre formation by Nitric Oxide mediated RhoA inhibition leads to reduction in the height of preformed thrombi

Evidence has emerged to suggest that thrombi are dynamic structures with distinct areas of differing platelet activation and inhibition. We hypothesised that Nitric oxide (NO), a platelet inhibitor, can modulate the actin cytoskeleton reversing platelet spreading, and therefore reduce the capability of thrombi to withstand a high shear environment. Our data demonstrates that GSNO, DEANONOate, and a PKG-activating cGMP analogue reversed stress fibre formation and increased actin nodule formation in adherent platelets. This effect is sGC dependent and independent of ADP and thromboxanes. Stress fibre formation is a RhoA dependent process and NO induced RhoA inhibition, however, it did not phosphorylate RhoA at ser188 in spread platelets. Interestingly NO and PGI2 synergise to reverse stress fibre formation at physiologically relevant concentrations. Analysis of high shear conditions indicated that platelets activated on fibrinogen, induced stress fibre formation, which was reversed by GSNO treatment. Furthermore, preformed thrombi on collagen post perfused with GSNO had a 30% reduction in thrombus height in comparison to the control. This study demonstrates that NO can reverse key platelet functions after their initial activation and identifies a novel mechanism for controlling excessive thrombosis

The Open Innovation in Science research field: a collaborative conceptualisation approach

Openness and collaboration in scientific research are attracting increasing attention from scholars and practitioners alike. However, a common understanding of these phenomena is hindered by disciplinary boundaries and disconnected research streams. We link dispersed knowledge on Open Innovation, Open Science, and related concepts such as Responsible Research and Innovation by proposing a unifying Open Innovation in Science (OIS) Research Framework. This framework captures the antecedents, contingencies, and consequences of open and collaborative practices along the entire process of generating and disseminating scientific insights and translating them into innovation. Moreover, it elucidates individual-, team-, organisation-, field-, and society‐level factors shaping OIS practices. To conceptualise the framework, we employed a collaborative approach involving 47 scholars from multiple disciplines, highlighting both tensions and commonalities between existing approaches. The OIS Research Framework thus serves as a basis for future research, informs policy discussions, and provides guidance to scientists and practitioners