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Background: Targeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation. Methods: RNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CAR-T cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin. Findings: RNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CAR-T cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin. Interpretation: The study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CAR-T cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel anti-myeloid strategy. Fund: This work was supported by Cancer Research UK, CCLG, Treating Children with Cancer, and the alumni and donors to the University of Birmingham. (c) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Loss-of-function of the glucose-6-phosphate transporter is caused by biallelic mutations in SLC37A4 and leads to glycogen storage disease Ib. Here we describe a second disease caused by a single dominant mutation in the same gene. The mutation abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter leads to a congenital disorder of glycosylation instead of glycogen storage disease.

This paper empirically models the dynamics of Brazilian government bond (BGB) yields based on monthly macroeconomic data, in the context of the evolution of the key macroeconomic variables in Brazil. The results show that the current short-term interest rate has a decisive influence on the long-term interest rate on BGBs, after controlling for various key macroeconomic variables, such as inflation and industrial production. These findings support John Maynard Keynes’s claim that the central bank’s actions influence the long-term interest rate on government bonds mainly through the current short-term interest rate. These findings have important policy implications for Brazil. This paper relates the findings of the estimated models to ongoing debates in fiscal and monetary policies.

Polymetallic nodules increase habitat heterogeneity in some abyssal benthic ecosystems by providing hard substrate. Besides their important role in structuring ecosystems, polymetallic nodules have high grades of valuable minerals and are a target of likely future exploitation, particularly in the Pacific Clarion-Clipperton Zone (CCZ). Mining activities will remove hard substrate and sediment and cause sediment plumes potentially affecting faunal communities over large areas. Long-lived megafaunal assemblages may be particularly vulnerable but data are lacking on the density, biodiversity and community structure in many areas of the CCZ. This study aims to provide megabenthic community baseline data from two physically similar areas (B6S02 and B4S03) located in the contract area of Global Sea Mineral Resources N.V. (GSR). Seafloor images, obtained by an autonomous underwater vehicle are used to characterise the large areas required for robust evaluation of sparse megafauna. Higher altitude images cover a larger area for the same effort but have reduced resolution compared to images obtained closer to the seafloor, leading to difficulties in detecting and identifying individuals. Our comparison of images obtained at different altitudes shows that images taken above 8m altitude underestimate the megafauna density by almost 50%, so images

Innovation systems are sometimes referred to as complex systems, something that is intuitively understood but poorly defined. A complex system dynamically evolves in non-linear ways giving it unique properties that distinguish it from other systems. In particular, a common signature of complex systems is scale-invariant emergent properties. A scale-invariant property can be identified because it is solely described by a power law function, f(x) = kx^α, where the exponent, α, is a measure of scale-invariance. The focus of this paper is to describe and illustrate that innovation systems have properties of a complex adaptive system. In particular scale-invariant emergent properties indicative of their complex nature that can be quantified and used to inform public policy. The global research system is an example of an innovation system. Peer-reviewed publications containing knowledge are a characteristic output. Citations or references to these articles are an indirect measure of the impact the knowledge has on the research community. Peer-reviewed papers indexed in Scopus and in the Web of Science were used as data sources to produce measures of sizes and impact. These measures are used to illustrate how scale-invariant properties can be identified and quantified. It is demonstrated that the distribution of impact has a reasonable likelihood of being scale-invariant with scaling exponents that tended toward a value of less than 3.0 with the passage of time and decreasing group sizes. Scale-invariant correlations are shown between the evolution of impact and size with time and between field impact and sizes at points in time. The recursive or self-similar nature of scale-invariance suggests that any smaller innovation system within the global research system is likely to be complex with scale-invariant properties too. This record was migrated from the OpenDepot repository service in June, 2017 before shutting down.

Optical imaging devices such as the Video Plankton Recorder (VPR) harness unique capabilities to perform in situ observations and observe planktonic organisms in their natural environmental context. However, applying this technology in shallow and turbid coastal waters comes with a number of challenges. Depending on the research goal, methodological choices need to be made regarding the appropriate towing procedure and instrument settings, like magnification or field of view. In addition, limitations can be expected related to the physical characteristics of the water column, more specifically regarding suspended matter concentration and turbidity. To inform VPR users on the possibilities and limitations of the device in shallow and turbid coastal waters, this paper evaluates a number of specific deployment procedures in the Belgian part of the North Sea (BPNS). For three different towing procedures the practical feasibility, characteristics and output are assessed and the assets and liabilities for each of the tow types are discussed. A Z-shaped and a clover-shaped tow type are seen as best fit for detailed characterization of the plankton community of a limited geographical area. A straight tow type is more suitable for plankton studies over a larger area, with the potential to capture local plankton abundance peaks and to determine the relation with the spatial variation of the environmental conditions. The capacity of the various VPR magnification settings to capture specific plankton taxa or size groups, was tested during four straight line transects with different magnifications. The highest magnification can be used for organisms from 0.3 to 0.7 mm while the low magnification allows to observe larger organisms within the size range of 1.0 to 3.8 mm. Finally, the boundary conditions for the deployment of the VPR related to the turbidity of the water column were defined and the implications for deployment within the study area were investigated. This study shows that high turbidity values over 6.2 NTU inhibit the collection of useable data, complicating the VPR's application in many coastal and transitional waters.

Fibrinogen, a protein involved in blood coagulation, is very susceptible to oxidation. Oxidation alters its function and usually makes it more thrombogenic. Bilirubin, an end-product of the haem degradation in vertebrates, is known for its antioxidant properties. The present paper describes interaction between fibrinogen and bilirubin, and the influence of bilirubin on the formation of fibrin and protection against oxidation. The binding constant of 4.5 × 104 M−1 was determined for the fibrinogen/bilirubin complex at 37 °C. There is no change in secondary and tertiary structure of fibrinogen or its thermal stability upon bilirubin binding. The binding site of fibrinogen is not stereospecific for bilirubin and is able to accommodate both bilirubin conformers. A change in absorption maximum of bilirubin occurs upon its interaction with fibrinogen, suggesting an alteration in the conformation of bilirubin to the more cyclic one. Bilirubin exerts antioxidant effect on fibrinogen, preventing its carbonylation and aggregation. The presence of bilirubin induces the formation of fibrin with thicker fibres, as assessed by the coagulation assay. Fibrinogen and bilirubin interact at physiological concentrations, bilirubin may act as an antioxidant for fibrinogen and may modulate an important event in haemostasis, which altogether suggests possible physiological relevance of this interaction. This is the peer-reviewed version of the following article: Gligorijević, Nikola; Minić, Simeon L.; Robajac, Dragana B.; Nikolić, Milan; Ćirković-Veličković, Tanja; Nedić, Olgica, 2019. Characterisation and the effects of bilirubin binding to human fibrinogen. International Journal of Biological Macromolecules. 128, 74-79. [https://doi.org/10.1016/j.ijbiomac.2019.01.124] Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/2937]

Despite several attempts to provide a definite pattern regarding the effects of personality traits on performance in higher education, the debate over the nature of the relationship is far from being conclusive. The use of different subject pools and sample sizes, as well as the use of identification strategies that either do not adequately account for selection bias or are unable to establish causality between measures of academic performance and noncognitive skills, are possible sources of heterogeneity. This paper investigates the impact of the Big Five traits, as measured before the beginning of the academic year, on the grade point average achieved in the first year after the enrolment, taking advantage of a unique and large dataset from a cohort of Italian students in all undergraduate programs containing detailed information on student and parental characteristics. Relying on a robust strategy to credibly satisfy the conditional independence assumption, we find that higher levels of conscientiousness and openness to experience positively affect student score.

Fluorescence Correlation Spectroscopy (FCS) is a promising tool to study interactions on a single molecule level. The diffusion of fluorescent molecules in and out of the excitation volume of a confocal microscope leads to the fluorescence fluctuations that give information on the average number of fluorescent molecules present in the excitation volume and their diffusion coefficients. In this context, we complexed mRNA into lipoplexes and polyplexes and explored the association/dissociation degree of complexes by using gel electrophoresis and FCS. FCS enabled us to measure the association and dissociation degree of mRNA-based complexes both in buffer and protein-rich biological fluids such as human serum and ascitic fluid, which is a clear advantage over gel electrophoresis that was only applicable in protein-free buffer solutions. Furthermore, following the complex stability in buffer and biological fluids by FCS assisted to understand how complex characteristics, such as charge ratio and strength of mRNA binding, correlated to the transfection efficiency. We found that linear polyethyleneimine prevented efficient translation of mRNA, most likely due to a too strong mRNA binding, whereas the lipid based carrier Lipofectamine® messengerMAX did succeed in efficient release and subsequent translation of mRNA in the cytoplasm of the cells. Overall, FCS is a reliable tool for the in depth characterization of mRNA complexes and can help us to find the critical balance keeping mRNA bound in complexes in the extracellular environment and efficient intracellular mRNA release leading to protein production. Statement of Significance The delivery of messenger RNA (mRNA) to cells is promising to treat a variety of diseases. Therefore, the mRNA is typically packed in small lipid particles or polymer particles that help the mRNA to reach the cytoplasm of the cells. These particles should bind and carry the mRNA in the extracellular environment (e.g. blood, peritoneal fluid, …), but should release the mRNA again in the intracellular environment. In this paper, we evaluated a method (Fluorescence Correlation Spectroscopy) that allows for the in depth characterization of mRNA complexes and can help us to find the critical balance keeping mRNA bound in complexes in the extracellular environment and efficient intracellular mRNA release leading to protein production.

Ice-free areas occupy less than 0.25% of the Antarctic surface, and mainly occur along coastlines, or as inland nunataks protruding from the extensive ice sheet. Their extreme environment and geographical isolation have contributed to the evolution of highly adapted, and largely endemic terrestrial biota. Physical habitat mapping is important to identify the main drivers of spatial variation in soil biodiversity, to predict its response to climate change and to help conservation planning. In this paper we retrieved remotely sensed Land Surface Temperature (LST) and Digital Surface Models (DSM) for the Sor Rondane Mountains in East Antarctica from respectively the Thermal InfraRed Sensor (TIRS) on Landsat 8 and the Pleiades constellation of high resolution optical imagers. Satellite data were combined with ground truth temperature and elevation measurements with the aim to assess the performance of these remotely sensed data. Over a 2 year period, satellite derived LST corresponded to in situ temperature with Mean Average Difference (MAD) of − 2.5 K, and Root Mean Squared Difference (RMSD) of 6.3 K. Lower biases were observed for periods when the data loggers were frozen or snow covered (MAD − 1.8K) compared to intervals where the devices were not frozen (MAD − 4 K), with larger scatter (RMSD 7 K) being observed during the latter. These larger MAD and RMSD are caused by the differential heating of the top of the gravel/rocks as observed by the satellite compared to their underside, where the loggers were installed, and are also impacted by the time step of the in situ logging (3 h) and the non–linear heating of the surface. In addition, for the different study sites different biases were observed as a result of the spatial resolution of the TIRS, depending on the composition, structure, geomorphology, and the surroundings of the logger position. Sites on a narrow rock outcrop (e.g. the Perlebandet and Utsteinen nunataks) show a negative bias due to the surrounding ice fields decreasing the satellite pixel average temperature compared to the in situ measured temperatures. For sites with a more extensive rock and gravel composition further away from the ice sheet (Dry and Yuboku Valleys), a positive bias was found as a result of the temperature differential between the exposed top and covered bottom of the rocks and gravel. The DSM derived from Pleiades (without bias correction) showed in general a bias of − 6 m (MAD) and scatter of 9 m (RMSD) when compared to the Reference Elevation Model of Antarctica and IceSAT-1 LIDAR data. Lowest errors were also found here for the extensive Dry and Yuboku Valley sites (respectively − 5 and 3 m MAD, 7 and 4 m RMSD). Correspondence with in situ logged GPS positions was slightly worse, with a positive bias of 12 m (MAD) and scatter of 15 m (RMSD) across the sites. An analysis on the basis of these LST and DSM datasets, show a clear separability of sites by their average temperature and solar exposition (in terms of slope and aspect) at the time of Landsat overpass. Due to the Landsat overpass times, the LST datasets are however strongly biased, and further work is needed for a better understanding of the light and temperature climate in the ice-free regions. This could for example be achieved by coupling the DSM to a solar irradiance and terrain shadowing model.

Spiral waves in the heart underlie dangerous cardiac arrhythmias such as fibrillation. Low-voltage defibrillation and cardioversion are modern methods to treat such pathologies. This type of electrotherapy is based on the phenomenon of superseding spiral waves by a high-frequency source of excitation. In this paper, we numerically simulated the superseding process in a thin layer of the cardiac muscle. We captured the case of a sole spiral wave with a stable core at the centre of a square. We used different cell-level models as well as a variety of electrode configurations and studied the induced drift of the spiral wave. Regimes of the external stimulation were classified based on whether they provide an effective and safe, that is without break-up, way to shift the spiral toward the boundary.

© The Author(s). 2019. Background: Environmental change has resulted in changes in forest growth in Europe during the last century. This has consequences for the products and services delivered by forest. Mixing tree species is often proposed as a strategy to deal with the consequences of climate change. Diversifying forests is believed to result in higher productivity and increased growth stability. Tree species diversity is therefore expected to affect long-term trends in tree radial growth. However, this has not yet been studied. In this paper we study the effect of diversity on the radial growth and its long-term trends for beech and oak trees growing along a gradient of tree species diversity in the loamy region of central Belgium (from monocultures to mixed forests patches up to three species). Results: We found that beech trees have a higher radial growth whereas oak trees have a lower one when growing in mixtures. The contrasting diversity-productivity relationship observed for beech and oak is in agreement with their ranking in shade tolerance, where oaks suffer increased competition in mixed oak patches. Overall, in monocultures and mixtures, an increasing radial growth trend of + 2% for the period 1927–2015 and 21% for the period 1899–2015 was found for beech and oak, respectively. Tree species diversity did not alter the shape of this detected long-term radial growth trend. Nevertheless, for oak a lower year-to-year variability in radial growth is found in mixtures indicating ahigherresilience. Conclusion: We conclude that diversity impacts the average radial growth and its variability (only in the case of oak) but not the shape of the long-term trend in radial growth of beech and oak trees growing in the loamy region of central Belgium. ispartof: FOREST ECOSYSTEMS vol:6 issue:1 status: published

Many polycation-based gene delivery vectors show high transfection in vitro, but their cationic nature generally leads to significant toxicity and poor in vivo performance which significantly hampers their clinical applicability. Unlike conventional polycation-based systems, decationized polyplexes are based on hydrophilic and neutral polymers. They are obtained by a 3-step process: charge-driven condensation followed by disulfide crosslinking stabilization and finally polyplex decationization. They consist of a disulfide-crosslinked poly(hydroxypropyl methacrylamide) (pHPMA) core stably entrapping plasmid DNA (pDNA), surrounded by a shell of poly(ethylene glycol) (PEG). In the present paper the applicability of decationized polyplexes for systemic administration was evaluated. Cy5-labeled decationized polyplexes were evaluated for stability in plasma by fluorescence single particle tracking (fSPT), which technique showed stable size distribution for 48 h unlike its cationic counterpart. Upon the incubation of the polymers used for the formation of polyplexes with HUVEC cells, MTT assay showed excellent cytocompatibility of the neutral polymers. The safety was further demonstrated by a remarkable low teratogenicity and mortality activity of the polymers in a zebrafish assay, in great contrast with their cationic counterpart. Near infrared (NIR) dye-labeled polyplexes were evaluated for biodistribution and tumor accumulation by noninvasive optical imaging when administered systemically in tumor bearing mice. Decationized polyplexes exhibited an increased circulation time and higher tumor accumulation, when compared to their cationic precursors. Histology of tumors sections showed that decationized polyplexes induced reporter transgene expression in vivo. In conclusion, decationized polyplexes are a platform for safer polymeric vectors with improved biodistribution properties when systemically administered.

Biofilms are matrix-enclosed communities of bacteria that show increased antibiotic resistance and the capability to evade the immune system. They can cause recalcitrant infections which cannot be cured with classical antibiotic therapy. Drug delivery by lipid or polymer nanoparticles is considered a promising strategy for overcoming biofilm resistance. These particles are able to improve the delivery of antibiotics to the bacterial cells, thereby increasing the efficacy of the treatment. In this review we give an overview of the types of polymer and lipid nanoparticles that have been developed for this purpose. The antimicrobial activity of nanoparticle encapsulated antibiotics compared to the activity of the free antibiotic is discussed in detail. In addition, targeting and triggered drug release strategies to further improve the antimicrobial activity are reviewed. Finally, ample attention is given to advanced microscopy methods that shed light on the behavior of nanoparticles inside biofilms, allowing further optimization of the nanoformulations. Lipid and polymer nanoparticles were found to increase the antimicrobial efficacy in many cases. Strategies such as the use of fusogenic liposomes, targeting of the nanoparticles and triggered release of the antimicrobial agent ensured the delivery of the antimicrobial agent in close proximity of the bacterial cells, maximizing the exposure of the biofilm to the antimicrobial agent. The majority of the discussed papers still present data on the in vitro anti-biofilm activity of nanoformulations, indicating that there is an urgent need for more in vivo studies in this field.

This paper explores the role of cheap excuses in product choice. If agents feel that they fulfill one ethical aspect, they may care less about other independent ethical facets within product choice. Choosing a product that fulfills one ethical aspect may then suffice for maintaining a high moral self-image in agents and render it easier to ignore other ethically relevant aspects they would otherwise care about more. The use of such cheap excuses could thus lead to a “static moral self-licensing” effect, and this would extend the logic of the well-known dynamic moral self-licensing. Our experimental study provides empirical evidence that the static counterpart of moral self-licensing exists. Furthermore, effects spill over to unrelated, ethically relevant contexts later in time. Thus, static moral self-licensing and dynamic moral self-licensing can exist next to each other. However, it is critical that agents do not feel that they fulfilled an ethical criterion out of sheer luck, that is, agents need some room so that they can attribute the ethical improvement at least partly to themselves. Outsiders, although monetarily incentivized for correct estimates, are completely oblivious to the effects of moral self-licensing, both static and dynamic.

Background When the Zika virus outbreak became a global health emergency in early 2016, the scientific community responded with an increased output of Zika-related research. This upsurge in research naturally made its way into academic journals along with editorials, news, and reports. However, it is not yet known how or whether these scholarly communications were distributed to the populations most affected by Zika. Methodology/Principal findings To understand how scientific outputs about Zika reached global and local audiences, we collected Tweets and Facebook posts that linked to Zika-related research in the first six months of 2016. Using a language detection algorithm, we found that up to 90% of Twitter and 76% of Facebook posts are in English. However, when none of the authors of the scholarly article are from English-speaking countries, posts on both social media are less likely to be in English. The effect is most pronounced on Facebook, where the likelihood of posting in English is between 11 and 16% lower when none of the authors are from English-speaking countries, as compared to when some or all are. Similarly, posts about papers written with a Brazilian author are 13% more likely to be in Portuguese on Facebook than when made on Twitter. Conclusions/Significance Our main conclusion is that scholarly communication on Twitter and Facebook of Zika-related research is dominated by English, despite Brazil being the epicenter of the Zika epidemic. This result suggests that scholarly findings about the Zika virus are unlikely to be distributed directly to relevant populations through these popular online mediums. Nevertheless, there are differences between platforms. Compared to Twitter, scholarly communication on Facebook is more likely to be in the language of an author’s country. The Zika outbreak provides a useful case-study for understanding how scientific outputs are communicated to relevant populations. Our results suggest that Facebook is a more effective channel than Twitter, if communication is desired to be in the native language of the affected country. Further research should explore how local media—such as governmental websites, newspapers and magazines, as well as television and radio—disseminate scholarly publication.

Previous studies suggest a significant role of language in the court room, yet none has identified a definitive correlation between vocal characteristics and court outcomes. This paper demonstrates that voice-based snap judgments based solely on the introductory sentence of lawyers arguing in front of the Supreme Court of the United States predict outcomes in the Court. In this study, participants rated the opening statement of male advocates arguing before the Supreme Court between 1998 and 2012 in terms of masculinity, attractiveness, confidence, intelligence, trustworthiness, and aggressiveness. We found significant correlation between vocal characteristics and court outcomes and the correlation is specific to perceived masculinity even when judgment of masculinity is based only on less than three seconds of exposure to a lawyer’s speech sample. Specifically, male advocates are more likely to win when they are perceived as less masculine. No other personality dimension predicts court outcomes. While this study does not aim to establish any causal connections, our findings suggest that vocal characteristics may be relevant in even as solemn a setting as the Supreme Court of the United States.