Delivering the power of nanomedicine to patients today

The situation of the COVID-19 pandemic reminds us that we permanently need high-value flexible solutions to urgent clinical needs including simplified diagnostic technologies suitable for use in the field and for delivering targeted therapeutics. From our perspective nanotechnology is revealed as a vital resource for this, as a generic platform of technical solutions to tackle complex medical challenges. It is towards this perspective and focusing on nanomedicine that we take issue with Prof Park's recent editorial published in the Journal of Controlled Release. Prof. Park argued that in the last 15 years nanomedicine failed to deliver the promised innovative clinical solutions to the patients (Park, K. The beginning of the end of the nanomedicine hype. Journal of Controlled Release, 2019; 305, 221\u2013222 [1]. We, the ETPN (European Technology Platform on Nanomedicine) [2], respectfully disagree. In fact, the more than 50 formulations currently in the market, and the recent approval of 3 key nanomedicine products (e. g. Onpattro, Hensify and Vyxeos), have demonstrated that the nanomedicine field is concretely able to design products that overcome critical barriers in conventional medicine in a unique manner, but also to deliver within the cells new drug-free therapeutic effects by using pure physical modes of action, and therefore make a difference in patients lives. Furthermore, the >400 nanomedicine formulations currently in clinical trials are expecting to bring novel clinical solutions (e.g. platforms for nucleic acid delivery), alone or in combination with other key enabling technologies to the market, including biotechnologies, microfluidics, advanced materials, biomaterials, smart systems, photonics, robotics, textiles, Big Data and ICT (information & communication technologies) more generally. However, we agree with Prof. Park that \u201c it is time to examine the sources of difficulty in clinical translation of nanomedicine and move forward \u201c. But for reaching this goal, the investments to support clinical translation of promising nanomedicine formulations should increase, not decrease. As recently encouraged by EMA in its roadmap to 2025, we should create more unity through a common knowledge hub linking academia, industry, healthcare providers and hopefully policy makers to reduce the current fragmentation of the standardization and regulatory body landscape. We should also promote a strategy of cross-technology innovation, support nanomedicine development as a high value and low-cost solution to answer unmet medical needs and help the most promising innovative projects of the field to get better and faster to the clinic. This global vision is the one that the ETPN chose to encourage for the last fifteen years. All actions should be taken with a clear clinical view in mind, \u201c without any fanfare\u201d, to focus \u201con what matters in real life\u201d, which is the patient and his/her quality of life. This ETPN overview of achievements in nanomedicine serves to reinforce our drive towards further expanding and growing the maturity of nanomedicine for global healthcare, accelerating the pace of transformation of its great potential into tangible medical breakthroughs

Survival through networks: the 'grip' of the administrative links in the Russian post-Soviet context

© 2014 Taylor & Francis. Based on an analysis of the post-Soviet transformation experience of four defence sector organizations in a Russian region where the defence sector occupies a substantial part of the local economy, this article develops a typology of network relationships: Grooved Inter-relationship Patterns (Gr’ip) networks and Fluid Inter-relationship Patterns (Fl’ip) networks. This typology can be applied to a range of transition/emerging market and low system trust contexts. Gr’ip networks, in this case, represent the persisting legacy of the Soviet command-administrative system. Fl’ip networks are here an attempt by the defence companies to link into the civilian supply chains of a developing market economy. This article argues that Gr’ip networks had and still have a crucial role to play in Russian enterprises’ survival and development

From Lever to Club?: conditionality in the European Union during the financial crisis

How did the European Union come to develop so many instruments of conditionality during the Eurozone debt crisis, despite the well-documented limitations of such measures in other contexts? This article argues that major EU actors–Council, Commission, and Central Bank–were influenced by their own recent and positive experiences with conditionality, especially in the EU’s enlargement in the early 2000s and the early phase of the global financial crisis. However, despite the promise of conditional instruments in these two earlier episodes, further EU reliance on conditional policies has not brought the positive outcomes the main European institutions had hoped for. As EU institutions turned to harder and harder forms of conditionality in the Euro crisis, they relearned many of the familiar negative lessons of conditionality and ultimately had to concede that the apparent success of its conditionality tools in the two earlier phases was exceptional. The article documents the evolution of conditionality over these periods, showing how EU conditionality instruments changed over time, beginning as a ‘lever’ to assist the accession of candidate states in the enlargement period, and evolving into a ‘club’ used to impose macroeconomic discipline in the late 2000s. It shows why this approach to the Euro crisis failed and was ultimately downgraded as Eurozone policy shifted in favour of monetary measures in which conditionality played only a marginal role

Train schedule delays leading to overcrowding, injuries and fatalities

Abstract: Rail industry in South Africa is facing a dilemma in connection with trains overcrowding causing injuries and fatalities. This paper emphasized this topic analysis to reach the understanding of the problem to an eventual solution that will benefit both the train user and the operator. One of the priority insights look was at the annual train planned schedule versus the actual state of trains given to run. The overall objective of the paper’s study was to analyze the existing train schedule that is currently in use and whether addressing the needs of the commuter. The paper highlighted that the found-out train planned schedule are not always met due to technical issues. The paper also investigated the number of healthy trains versus the commuter demand per peak, because operationally fit trains are required to avoid service distraction that can lead to overcrowding of trains

Aggregating sequences that occur in many proteins constitute weak spots of bacterial proteostasis

Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichiacoli and Acinetobacterbaumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy

Strategic Sensemaking and Political Connections in Unstable Institutional Contexts

Emerging economies are often characterized by pervasive institutional changes and resultant institutional voids. In the absence of strong formal institutions, firms rely on informal institutions to fill these voids. This article argues that the process of sensemaking for firms in turbulent environments is continuous and dependent on cyclical adjustments connecting performance via a feedback loop to scanning and interpretation. Far from being a one-time occurrence, environmental sensemaking is a process operating in accord with continuous environmental changes. This study’s findings derive from an in-depth analysis of a Russian pharmaceutical firm and an Indian telecommunications firm, and demonstrate that entrepreneurs make sense and gain legitimacy through political connections. The study further finds that improvements in institutional environments reduce the salience of political networks, thereby creating a choice for firms to rely on formed market mechanisms or continue along the path of political connections that evolve to public–private partnerships

The anti-sigma factor RsrA responds to oxidative stress by reburying its hydrophobic core

Redox-regulated effector systems that counteract oxidative stress are essential for all forms of life. Here we uncover a new paradigm for sensing oxidative stress centred on the hydrophobic core of a sensor protein. RsrA is an archetypal zinc-binding anti-sigma factor that responds to disulfide stress in the cytoplasm of Actinobacteria. We show that RsrA utilizes its hydrophobic core to bind the sigma factor σ R preventing its association with RNA polymerase, and that zinc plays a central role in maintaining this high-affinity complex. Oxidation of RsrA is limited by the rate of zinc release, which weakens the RsrA-σ R complex by accelerating its dissociation. The subsequent trigger disulfide, formed between specific combinations of RsrA's three zinc-binding cysteines, precipitates structural collapse to a compact state where all σ R-binding residues are sequestered back into its hydrophobic core, releasing σ R to activate transcription of anti-oxidant genes

Family Firms and Firm Performance: Evidence from Japan

Corrigendum: Nature Structural and Molecular Biology 16 (12), 1331 (2009) doi:10.1038/nsmb1209-1331bInternational audienceThioredoxins (Trxs) are oxidoreductase enzymes, present in all organisms, that catalyze the reduction of disulfide bonds in proteins. By applying a calibrated force to a substrate disulfide, the chemical mechanisms of Trx catalysis can be examined in detail at the single-molecule level. Here we use single-molecule force-clamp spectroscopy to explore the chemical evolution of Trx catalysis by probing the chemistry of eight different Trx enzymes. All Trxs show a characteristic Michaelis-Menten mechanism that is detected when the disulfide bond is stretched at low forces, but at high forces, two different chemical behaviors distinguish bacterial-origin from eukaryotic-origin Trxs. Eukaryotic-origin Trxs reduce disulfide bonds through a single-electron transfer reaction (SET), whereas bacterial-origin Trxs show both nucleophilic substitution (SN2) and SET reactions. A computational analysis of Trx structures identifies the evolution of the binding groove as an important factor controlling the chemistry of Trx catalysis