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\"Access to space technology has changed dramatically in the past 10 years. Traditionally, access to space capabilities required dedicated receivers and significant investment. With the advent of new information technologies that incorporate and disseminate the benefits of space directly to users, access to space technology is no longer so exclusive\"-- Provided by publisher.

Academic research plays a key role in identifying new drug targets, including understanding target biology and links between targets and disease states. To lead to new drugs, however, research must progress from purely academic exploration to the initiation of efforts to identify and test a drug candidate in clinical trials, which are typically conducted by the biopharma industry. This transition can be facilitated by a timely focus on target assessment aspects such as target-related safety issues, druggability and assayability, as well as the potential for target modulation to achieve differentiation from established therapies. Here, we present recommendations from the GOT-IT working group, which have been designed to support academic scientists and funders of translational research in identifying and prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical development programmes. Based on sets of guiding questions for different areas of target assessment, the GOT-IT framework is intended to stimulate academic scientists’ awareness of factors that make translational research more robust and efficient, and to facilitate academia–industry collaboration.Academic research has a key role in identifying new drug targets, but to lead to new drugs this research must progress to testing drug candidates in clinical trials, which are typically conducted by industry. This Perspective presents a framework to support academic scientists and funders in prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical trials.

\"This book presents recent advancements in positive psychology, specifically its application across broad areas of current interest. Chapters include submissions from various international authors in the field and cover discussion and presentation of relevant research, theories, and applications. The volume covers topics such as CBT, Psychotherapy, Coaching, Workplaces, Aging, Education, Leadership, Emotion, Interventions, Measurement, Technology, Design, Health, Relationships, Experiences, Communities. With the growing interest in the applications of positive psychology across diverse fields within psychology and beyond, this book will make a worthwhile contribution to the field. It will also fill the current need for a volume that highlights specifically the various recent advancements in positive psychology into diverse fields and as such will be of benefit to a wide range of professionals, including psychologists, educators, clinicians, therapists, and many others.\" -- Publisher's website.

The branched structure and stereoisomerism of carbohydrates make them difficult to analyse; here, ion mobility–mass spectrometry is used to distinguish unambiguously between synthetic trisaccharides that differ in connectivity or configuration. A new approach to carbohydrate analysis The branched structure and stereoisomerism of carbohydrates make them difficult to analyse, especially if they are synthetic. Peter Seeberger and colleagues demonstrate here that ion mobility–mass spectrometry (IM–MS), a method that separates molecules according to mass, charge, size, and shape, can unambiguously identify glycan regio- and stereoisomers. Six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration were analysed. The analysis is rapid and requires only small amounts of sample, suggesting that IM–MS will be an exceptionally effective tool for the analysis of complex carbohydrates. Carbohydrates are ubiquitous biological polymers that are important in a broad range of biological processes 1 , 2 , 3 . However, owing to their branched structures and the presence of stereogenic centres at each glycosidic linkage between monomers, carbohydrates are harder to characterize than are peptides and oligonucleotides 4 . Methods such as nuclear magnetic resonance spectroscopy can be used to characterize glycosidic linkages, but this technique requires milligram amounts of material and cannot detect small amounts of coexisting isomers 5 . Mass spectrometry, on the other hand, can provide information on carbohydrate composition and connectivity for even small amounts of sample, but it cannot be used to distinguish between stereoisomers 6 . Here, we demonstrate that ion mobility–mass spectrometry—a method that separates molecules according to their mass, charge, size, and shape—can unambiguously identify carbohydrate linkage-isomers and stereoisomers. We analysed six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration. Our data show that coexisting carbohydrate isomers can be identified, and relative concentrations of the minor isomer as low as 0.1 per cent can be detected. In addition, the analysis is rapid, and requires no derivatization and only small amounts of sample. These results indicate that ion mobility–mass spectrometry is an effective tool for the analysis of complex carbohydrates. This method could have an impact on the field of carbohydrate synthesis similar to that of the advent of high-performance liquid chromatography on the field of peptide assembly in the late 1970s.

The properties of clouds that may be observed by satellite instruments, such as optical thickness and cloud-top pressure, are only loosely related to the way clouds are represented in models of the atmosphere. One way to bridge this gap is through ‘‘instrument simulators,’’ diagnostic tools that map the model representation to synthetic observations so that differences can be interpreted as model error. But simulators may themselves be restricted by limited information or by internal assumptions. This paper considers the extent to which instrument simulators are able to capture essential differences between the Moderate Resolution Imaging Spectroradiometer (MODIS) and the International Satellite Cloud Climatology Project (ISCCP), two similar but independent estimates of cloud properties. The authors review the measurements and algorithms underlying these two cloud climatologies, introduce a MODIS simulator, and detail datasets developed for comparison with global models using ISCCP and MODIS simulators. In nature MODIS observes less midlevel cloudiness than ISCCP, consistent with the different methods used to determine cloud-top pressure; aspects of this difference are reproduced by the simulators. Differences in observed distributions of optical thickness, however, are not captured. The largest differences can be traced to different approaches to partly cloudy pixels, which MODIS excludes and ISCCP treats as homogeneous. These cover roughly 15% of the planet and account for most of the optically thinnest clouds. Instrument simulators cannot reproduce these differences because there is no way to synthesize partly cloudy pixels. Nonetheless, MODIS and ISCCP observations are consistent for all but the optically thinnest clouds, and models can be robustly evaluated using instrument simulators by integrating over the robust subset of observations.

Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.

The extent to which deficits in the perception and experience of fear contribute to psychopathic symptoms is an ongoing matter of debate. Traditional theories emphasize diminished threat processing as the core fear deficit in psychopathic individuals, whereas recent approaches, such as the fear enjoyment hypothesis (FEH), propose that anomalies in the subjective experience of fear are related to interpersonal-affective psychopathic traits. In order to test predictions of the FEH, we conducted an online experimental study to examine whether approach and avoidance tendencies in response to fear-eliciting stimuli are related to specific psychopathic traits (interpersonal-affective symptoms and boldness). We expected these traits to be associated with faster approach towards and slower avoidance of fear-evoking images in an approach-avoidance task (AAT). In a community-based sample of 211 individuals (69% female), self-reported interpersonal-affective traits predicted more positive appraisal ratings of and a faster approach towards fear-evoking stimuli in the AAT paradigm. The link between psychopathic traits and faster approach towards fear images could not be explained by traits related to impulsiveness or impaired inhibitory control. The present findings shed light on the subjective appraisal of fear-evoking situations by individuals with elevated psychopathic traits. Implications on etiological models of psychopathy are discussed.

Normothermic machine perfusion (NMP) has emerged as an innovative organ preservation technique. Developing an understanding for the donor organ immune cell composition and its dynamic changes during NMP is essential. We aimed for a comprehensive characterization of immune cell (sub)populations, cell trafficking and cytokine release during liver NMP. Single-cell transcriptome profiling of human donor livers prior to, during NMP and after transplantation shows an abundance of CXC chemokine receptor 1 + /2 + (CXCR1 + /CXCR2 + ) neutrophils, which significantly decreased during NMP. This is paralleled by a large efflux of passenger leukocytes with neutrophil predominance in the perfusate. During NMP, neutrophils shift from a pro-inflammatory state towards an aged/chronically activated/exhausted phenotype, while anti-inflammatory/tolerogenic monocytes/macrophages are increased. We herein describe the dynamics of the immune cell repertoire, phenotypic immune cell shifts and a dominance of neutrophils during liver NMP, which potentially contribute to the inflammatory response. Our findings may serve as resource to initiate future immune-interventional studies. Normothermic machine perfusion (NMP) is a method of keeping transplant organs maintained closer to physiological conditions. Here the authors analyse the immune cell dynamics during NMP in human donor livers using scRNA sequencing as a way of assessing the effects of NMP upon the immune status of the organ.

One of two papers showing that delta-like 4/Notch signalling limits angiogenic sprouting and branching by regulating tip cell formation. In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A 1 , 2 . VEGF-A is also essential for the induction of endothelial tip cells 2 , but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)–Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using γ-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4 , or endothelial-specific genetic deletion of Notch1 , all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4–Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene 3 , 4 , 5 , and indicates that modulators of Dll4 or Notch signalling, such as γ-secretase inhibitors developed for Alzheimer’s disease, might find usage as pharmacological regulators of angiogenesis.

The study presented here provides researchers with a revised list of affective German words, the Berlin Affective Word List Reloaded (BAWL-R). This work is an extension of the previously published BAWL (Võ, Jacobs, & Conrad, 2006), which has enabled researchers to investigate affective word processing with highly controlled stimulus material. The lack of arousal ratings, however, necessitated a revised version of the BAWL. We therefore present the BAWL-R, which is the first list that not only contains a large set of psycholinguistic indexes known to influence word processing, but also features ratings regarding emotional arousal, in addition to emotional valence and imageability. The BAWL-R is intended to help researchers create stimulus material for a wide range of experiments dealing with the affective processing of German verbal material.