Search

This article presents an analytical derivation of the volt-second error caused by converter nonlinearities such as dead time and the finite switching speeds of the emerging medium voltage silicon-carbide MOSFETs. The analytical model considers the transient behavior of the MOSFETs, the gate-driving circuitry, and the intrinsic parasitic capacitances of the MOSFETs and the power module. The importance of compensating converter nonlinearities has been revived with the utilization of wide bandgap semiconductor devices as the increased switching frequency penalizes the relative impact of dead time squared in motor drive applications. The first-order analytical model is validated with experimental and simulated results of switching events of a 10 kV silicon-carbide MOSFET power module. In addition, the analytical model is utilized to map out the individual contributions from each time period of the switching event.

The set of peptides processed and presented by major histocompatibility complex class II molecules defines the immunopeptidome, and its characterization holds keys to understanding essential properties of the immune system. High-throughput mass spectrometry (MS) techniques enable interrogation of the diversity and complexity of the immunopeptidome at an unprecedented scale. Here, we analyzed a large set of MS immunopeptidomics data from 40 donors, 221 samples, covering 30 unique HLA-DR molecules. We identified likely co-immunoprecipitated HLA-DR irrelevant contaminants using state-of-the-art prediction methods and unveiled novel light on the properties of HLA antigen processing and presentation. The ligandome (HLA binders) was enriched in 15-mer peptides, and the contaminome (nonbinders) in longer peptides. Classification of singletons and nested sets showed that the first were enriched in contaminants. Investigating the source protein location of ligands revealed that only contaminants shared a positional bias. Regarding subcellular localization, nested peptides were found to be predominantly of endolysosomal origin, whereas singletons shared an equal distribution between the cytosolic and endolysosomal origin. According to antigen-processing signatures, no significant differences were observed between the cytosolic and endolysosomal ligands. Further, the sensitivity of MS immunopeptidomics was investigated by analyzing overlap and saturation between biological MS replicas, concluding that at least 5 replicas are needed to identify 80% of the immunopeptidome. Moreover, the overlap in immunopeptidome between donors was found to be very low both in terms of peptides and source proteins, the latter indicating a critical HLA bias in the antigen sampling in the HLA antigen presentation. Finally, the complementarity between MS and in silico approaches for comprehensively sampling the immunopeptidome was demonstrated.Immunoinformatics analyses reveal novel insights to the properties of the HLA-DR immunopeptidome, suggesting singleton peptides to be a high source of HLA irrelevant contaminants.

We investigated associations between the number of pain sites (NPS) and role conflict with medically certified, pain-related sickness absence (SA) in employees of Norwegian enterprises (N = 5,654). Latent profile analyses identified exposure profiles based on 3 types of role conflict (work-role conflict, work-life conflict, and emotional dissonance). Multinomial logistic regressions estimated effects on absence (short-term absence of less than 56 days, long-term absence of more than 56 days) during 1 year after survey. Effects of the NPS on absence were compared across exposure profiles. Results suggested the NPS and all types of role conflict predicted absences separately. Mutually adjusted regressions revealed unique contributions of the NPS to the short-term and long-term absence (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.18, 1.30 and OR 1.51, 95% CI 1.37, 1.66) and of work-role conflict to the short-term absence (OR 1.18, 95% CI 1.03, 1.35). Latent profile analyses identified 4 exposure profiles (“1 unconflicted,” “2 dissonant, otherwise medium,” “3 conflicted, medium dissonance,” “4 conflicted and dissonant”). Profiles 3 and 4 exhibited elevated risk of SA, with the strongest baseline-adjusted effects for profile 4 (short-term absence OR 1.90, 95% CI 1.40, 2.57, long-term absence OR 1.95, 95% CI 1.15, 3.31). Effects of the NPS on short-term absence were stronger for profile 4 versus profile 1 (OR 1.38 vs 1.24, P < .001). Our findings suggest that addressing role conflicts may prevent pain-related absence, possibly also for individuals already experiencing pain.

We introduce a new command, summclust, that summarizes the cluster structure of the dataset for linear regression models with clustered disturbances. The key unit of observation for such a model is the cluster. We therefore propose cluster-level measures of leverage, partial leverage, and influence and show how to compute them quickly in most cases. The measures of leverage and partial leverage can be used as diagnostic tools to identify datasets and regression designs in which cluster–robust inference is likely to be challenging. The measures of influence can provide valuable information about how the results depend on the data in the various clusters. We also show how to calculate two jackknife variance matrix estimators efficiently as a by-product of our other computations. These estimators, which are already available in Stata, are generally more conservative than conventional variance matrix estimators. The summclustcommand computes all the quantities that we discuss.

OxLDL modulates innate and adaptive immunity, and extracellular vesicles (EVs) released from both non-immune and immune cells are proposed key players in atherosclerosis development. In the present study, we aimed to investigate EVs expressing markers related to adaptive immunity-driven inflammation and endothelial activation/dysfunction in hypercholesterolemic patients.

Recent developments within the field of medium voltage wide-bandgap semiconductor devices are drawing attention from both researchers and industries due to the demanding requirements for more efficient high-power energy conversion. The rapid development has entailed an increased awareness of the negative impact of the increased rate of change in voltage, dv/dt, and its derived issues caused by the inevitable parasitic capacitive couplings. This article is dedicated to present an overview of the parasitic capacitive couplings in high-power medium voltage power electronic converter systems, using an example reference system enabled by medium voltage SiC mosfets. The definitions of capacitive couplings are presented and the impacts raised by parasitic capacitive couplings are reviewed. In addition, the similarities of different capacitive couplings introduced by components in practical medium voltage systems are presented and summarized. Lastly, the challenges and future work with respect to parasitic capacitive couplings in medium voltage power electronics converter systems are shared from the authors' perspective.

Abstract:It has become a well-rehearsed truism that the growth of sub-Saharan African cities is the result of an amassing of persons, things and knowledge that takes place in the absence of centrally planned development initiatives and without any tightly orchestrated coordination of social life. Under such conditions, the argument goes, urbanites make do with whatever resources are available while increasingly chaotic cities expand beyond their social and material capacities. The question is, however, whether weak–and even absent–systems of urban management can be taken to signify a lack of coordination and planning of urban development. Might it not be, for instance, that cities organize and model themselves through means other than those afforded by formal urban planning schemes? Based on ethnographic data from Maputo, Mozambique, this article explores the shifting material forms of what are locally described as ‘bedroom drawer blueprints’ as an acutely potent type of urban modelling. Current and prospective house builders in Maputo exchange and share blueprints and physical and virtual models of houses that they plan to eventually build. Considered by residents as valuable social and material assets, such blueprints and models also offer an opportunity for experimenting with new forms of aesthetic organization of the city. Comparing the ongoing transactions and sharing of bedroom drawer blueprints with the increasing global circulation of middle-class architectural urban models, in this article I argue that it is the capacity of the former to move between different material forms and modalities that gives them their particular aesthetic potency and drive.Résumé:C’est désormais un truisme souvent répété que de dire que la croissance des villes africaines subsahariennes résulte d’un amassement de personnes, de choses et de connaissances qui survient en l’absence de programmes de développement à planification centralisée et sans coordination bien orchestrée de la vie sociale. Dans de telles conditions, selon l’argument, les urbains font avec les ressources disponibles tandis que les villes, de plus en plus chaotiques, se développent au-delà de leurs capacités sociales et matérielles. La question est de savoir, cependant, si la faiblesse, voire l’absence, de systèmes de gestion urbaine peut se traduire par un manque de coordination et de planification du développement urbain. Ne se pourrait-il pas, par exemple, que les villes s’organisent et s’inspirent à travers des moyens autres que ceux qu’offrent les programmes formels de développement urbain ? S’appuyant sur des données ethnographiques de Maputo (Mozambique), cet article explore les formes matérielles changeantes de ce que l’on appelle localement « bedroom drawer blueprints » [que l’on pourrait traduire par « plans de table de chevet »] comme type extrêmement puissant de modélisation urbaine. À Maputo, les entrepreneurs actuels et potentiels échangent et partagent des plans de construction et des modèles physiques et virtuels de maisons qu’ils projettent de construire un jour. Considérés par les résidents comme des biens sociaux et matériels de valeur, ces plans et modèles offrent également une occasion d’expérimenter de nouvelles formes d’organisation esthétique de la ville. Comparant les transactions en cours et le partage de plans à la circulation mondiale croissante de modèles urbains architecturaux des classes moyennes, l’auteur soutient dans cet article que la capacité de ces plans à passer d’une forme matérielle et d’une modalité à une autre est ce qui leur donne cette puissance esthétique particulière et ce dynamisme.Resumo:Tornou-se um truísmo bem ensaiado que o crescimento das cidades da África Subsaariana é o resultado de uma acumulação de pessoas, coisas e conhecimentos que ocorre na ausência de iniciativas de desenvolvimento centralizadas e sem qualquer coordenação estreitamente orquestrada da vida social. Em tais condições, o argumento vai, as cidades urbanas contentam-se com os recursos disponíveis, enquanto as cidades cada vez mais caóticas se expandem para além das suas capacidades sociais e materiais. A questão é, contudo, se os sistemas de gestão urbana, quer fracos - ou mesmo ausentes - podem ser levados a significar uma falta de coordenação e planeamento do desenvolvimento urbano. Não seria o caso, por exemplo, que as cidades se organizem e se modelizem por outros meios que não os proporcionados pelos esquemas formais de planeamento urbano? Com base em dados etnográficos de Maputo, Moçambique, este artigo explora as formas materiais variáveis do que é descrito localmente como “plantas de gavetas de quarto de dormir” como um tipo de modelação urbana extremamente potente. Os actuais e futuros construtores de casas em Maputo trocam e partilham plantas e modelos físicos e virtuais de casas que planeiam eventualmente construir. Considerados pelos residentes como bens sociais e materiais valiosos, tais plantas e modelos oferecem também uma oportunidade para experimentar novas formas de organização estética da cidade. Comparando as transacções em curso e a partilha de plantas de gavetas de quartos com a crescente circulação global de modelos urbanos arquitectónicos de classe média, neste artigo defendo que é a capacidade dos primeiros de se moverem entre diferentes formas e modalidades materiais que lhes confere a sua particular potência estética e dinamismo.

AbstractIt has become a well-rehearsed truism that the growth of sub-Saharan African cities is the result of an amassing of persons, things and knowledge that takes place in the absence of centrally planned development initiatives and without any tightly orchestrated coordination of social life. Under such conditions, the argument goes, urbanites make do with whatever resources are available while increasingly chaotic cities expand beyond their social and material capacities. The question is, however, whether weak – and even absent – systems of urban management can be taken to signify a lack of coordination and planning of urban development. Might it not be, for instance, that cities organize and model themselves through means other than those afforded by formal urban planning schemes? Based on ethnographic data from Maputo, Mozambique, this article explores the shifting material forms of what are locally described as ‘bedroom drawer blueprints’ as an acutely potent type of urban modelling. Current and prospective house builders in Maputo exchange and share blueprints and physical and virtual models of houses that they plan to eventually build. Considered by residents as valuable social and material assets, such blueprints and models also offer an opportunity for experimenting with new forms of aesthetic organization of the city. Comparing the ongoing transactions and sharing of bedroom drawer blueprints with the increasing global circulation of middle-class architectural urban models, in this article I argue that it is the capacity of the former to move between different material forms and modalities that gives them their particular aesthetic potency and drive.

Autonomous Underwater Vehicles (AUVs) are increasingly being used for offshore inspection tasks. This paper investigates how navigation using Simple Internal Model Control for Proportional-Integral-Derivative Control (SIMC-PID) operates in a realistic offshore environment with waves and ocean current acting as input disturbances while the available underwater sensors introduce time delays on the output signals. First, the time delays are determined by investigating available absolute positioning sensor systems. Then, a model of the AUV and the external disturbances is established. The model-based SIMC-PID controller is tuned and examined based on acceptable disturbance rejection while tolerating the dominant time delays. Two simulation case studies show that the heave controller, in both cases, struggles to stabilize in 0 to 8 meters depths, while the surge and sway controllers tolerate the Doppler Velocity Log case (DVL) acceptably. Short Baseline (SBL) shows unacceptable performance in 0 to 15 meters depths. It is concluded that the simplicity of the SIMC-PID controller is an advantage and, therefore, useful when time delays are relatively small, but more advanced techniques must be applied for larger delays such as those introduced by SBL systems.

Graphical Abstract

Many problems in biology require looking for a “needle in a haystack,” corresponding to a binary classification where there are a few positives within a much larger set of negatives, which is referred to as a class imbalance. The receiver operating characteristic (ROC) curve and the associated area under the curve (AUC) have been reported as ill-suited to evaluate prediction performance on imbalanced problems where there is more interest in performance on the positive minority class, while the precision-recall (PR) curve is preferable. We show via simulation and a real case study that this is a misinterpretation of the difference between the ROC and PR spaces, showing that the ROC curve is robust to class imbalance, while the PR curve is highly sensitive to class imbalance. Furthermore, we show that class imbalance cannot be easily disentangled from classifier performance measured via PR-AUC.

Activated T cells secrete interferon-γ, which triggers intracellular tryptophan shortage by upregulating the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme1–4. Here we show that despite tryptophan depletion, in-frame protein synthesis continues across tryptophan codons. We identified tryptophan-to-phenylalanine codon reassignment (W>F) as the major event facilitating this process, and pinpointed tryptophanyl-tRNA synthetase (WARS1) as its source. We call these W>F peptides ‘substitutants’ to distinguish them from genetically encoded mutants. Using large-scale proteomics analyses, we demonstrate W>F substitutants to be highly abundant in multiple cancer types. W>F substitutants were enriched in tumours relative to matching adjacent normal tissues, and were associated with increased IDO1 expression, oncogenic signalling and the tumour-immune microenvironment. Functionally, W>F substitutants can impair protein activity, but also expand the landscape of antigens presented at the cell surface to activate T cell responses. Thus, substitutants are generated by an alternative decoding mechanism with potential effects on gene function and tumour immunoreactivity.

As a response to the increased demand for more customized products at a lower cost and with shorter lead times, many of today’s manufacturing companies have embarked on the journey of modularization in either their product portfolio, their manufacturing setup or in both. However, transitioning towards a modular setup generates uncertainties on where and what to modularize, as well as on the consequence. Some of these questions can be answered and clarified through the use of data models, making it possible to create and test different architectural scenarios and thereby make decisions based on actual data rather than best guess and tacit knowledge. In order to get access to actual ERP data and be able to test and validate the method in a real life environment, this research is made in collaboration with a large manufacturing company using the design science methodology. The purpose of this research is to present an approach for creating a data model based on standard ERP data that will allow engineers and system architects to create strategic architectural scenarios and evaluate these in terms of expected savings, impact on manufacturing and other relevant parameters.

Reproductive hormones play a crucial role in the growth and maintenance of the mammalian skeleton. Indeed, the biological significance for this hormonal regulation of skeletal homeostasis is best illustrated by common clinical reproductive disorders, such as primary ovarian insufficiency, hypothalamic amenorrhea, congenital hypogonadotropic hypogonadism, and early menopause, which contribute to the clinical burden of low bone mineral density and increased risk for fragility fracture. Emerging evidence relating to traditional reproductive hormones and the recent discovery of newer reproductive neuropeptides and hormones has deepened our understanding of the interaction between bone and the reproductive system. In this review, we provide a contemporary summary of the literature examining the relationship between bone biology and reproductive signals that extend beyond estrogens and androgens, and include kisspeptin, gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, progesterone, inhibin, activin, and relaxin. A comprehensive and up-to-date review of the recent basic and clinical research advances is essential given the prevalence of clinical reproductive disorders, the emerging roles of upstream reproductive hormones in bone physiology, as well as the urgent need to develop novel safe and effective therapies for bone fragility in a rapidly aging population.Graphical Abstract

[Display omitted]

Based on ethnographic data from Maputo, Mozambique, this article explores middle-classness as an often-utopic aspiration articulated through particular forms of divides, that assert themselves by continuously deferring the stabilization of a supposedly growing middle-class population. As we argue, however, it is precisely by way of this deferral that new forms of urban citizenship are produced – that are available to the assumed members of the ‘middle-class’, as well as potentially to other residents enacting middle-classness as an urban ideal. After a brief review of how middle-class areas can be identified, the paper discusses the above argument through a comparison between two of the largest state-sponsored urban planning initiatives to be implemented in Mozambique in recent years. The first is in the Intaka Community on the northern periphery of Maputo, where residents re-configure the material aesthetics of the area in order to separate themselves from a collective that is based on supposed state-sanctioned middle-class values – but to which they do not want to remain attached. The second is in the KaTembe peninsula, where squatters have invaded the building site for the ‘New City’ and commenced building reed huts and laying foundations for cement-block houses in order to be resettled elsewhere. Strikingly, in both instances, middle-classness seems to be actualized by groups of urbanites that do not desire typical spatially envisioned middle-class status. However, the surprising effect is that this still articulates a particular conceptualization of middle-classness with a dominant utopian ideology for urban living.

Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon-? (IFN?) signalling, improves the response of patients with melanoma to checkpoint immunotherapy1,2. Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFN?3–5. However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma did not improve the efficacy of treatment compared to PD1 pathway blockade alone6,7, pointing to an incomplete understanding of the role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFN? treatment on mRNA translation. Notably, we observed accumulations of ribosomes downstream of tryptophan codons, along with their expected stalling at the tryptophan codon. This suggested that ribosomes bypass tryptophan codons in the absence of tryptophan. A detailed examination of these tryptophan-associated accumulations of ribosomes—which we term ‘W-bumps’—showed that they were characterized by ribosomal frameshifting events. Consistently, reporter assays combined with proteomic and immunopeptidomic analyses demonstrated the induction of ribosomal frameshifting, and the generation and presentation of aberrant trans-frame peptides at the cell surface after treatment with IFN?. Priming of naive T cells from healthy donors with aberrant peptides induced peptide-specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFN?, has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape.

Modular system architectures in both product and manufacturing domains are of high interest in both academia and industry, as having modular product platforms and reconfigurable manufacturing systems are a key enabler for companies to obtain the strategic flexibility needed to respond to rapidly shifting market and customer requirements. Previous research has focused extensively on modularizing products and manufacturing equipment. However, to fully reap the benefits of modularization, this cannot be treated solely as engineering efforts taking place in one domain or cross domains with co-platforming, but rather as a top management initiative. The purpose of this research is to review state-of-the-art literature on modularization/platforming looking across managerial levels and business domains, market, product, and manufacturing.

Workplace bullying is, by definition, a gradually escalating process, theorized to occur from psychosocial stressors when there is a lack of management intervention in escalating conflicts, and a lack of fair and robust conflict management procedures in the organization. Based on national probability survey data gathered in 2015–2016 from the official Norwegian employee-register, we investigated how a strong perceived climate for conflict management may buffer the escalation of workplace bullying over time. A total of 1197 respondents participated in the study at two measuring points. The average age at baseline was 45.20 years (SD = 9.98), and the sample consisted of 52.1% women and 47.9% men. Structural equation modelling in Mplus 7.4 was used to test the construct validity and the study’s hypothesis. As expected, the analyses showed that a strong conflict management climate buffered the escalation of workplace bullying. Exposure to bullying behaviour at T1 largely explained (47%) new and increased instances of bullying behaviour at T2, but only for those employees working in what they perceived as a weak conflict management climate. We conclude that a strong conflict management climate neutralizes the escalation and development of workplace bullying.

•A hydrodynamic model was set up for the fjord Kangerlussuaq.•The circulation was primarily oriented along the long axis of the fjord, characterised by fast [1.3 m/s] currents in the inner part of the fjord as opposed to slow currents [0.05 m/s] in the outer part.•The current regime in summertime is characterised by down-fjord currents in the upper 20 m due to the ice sheet runoff and up-fjord currents below.•The deep-lying water mass in the inner part of the fjord is nearly dynamically decoupled from the open ocean during summertime.•A sensitivity study of meltwater runoff shows that increasing the runoff considerably strengthens stratification in the upper 100 m of the water column.

Major histocompatibility complex II (MHC II) molecules play a vital role in the onset and control of cellular immunity. In a highly selective process, MHC II presents peptides derived from exogenous antigens on the surface of antigen-presenting cells for T cell scrutiny. Understanding the rules defining this presentation holds critical insights into the regulation and potential manipulation of the cellular immune system. Here, we apply the NNAlign_MA machine learning framework to analyze and integrate large-scale eluted MHC II ligand mass spectrometry (MS) data sets to advance prediction of CD4+ epitopes. NNAlign_MA allows integration of mixed data types, handling ligands with multiple potential allele annotations, encoding of ligand context, leveraging information between data sets, and has pan-specific power allowing accurate predictions outside the set of molecules included in the training data. Applying this framework, we identified accurate binding motifs of more than 50 MHC class II molecules described by MS data, particularly expanding coverage for DP and DQ beyond that obtained using current MS motif deconvolution techniques. Furthermore, in large-scale benchmarking, the final model termed NetMHCIIpan-4.0 demonstrated improved performance beyond current state-of-the-art predictors for ligand and CD4+ T cell epitope prediction. These results suggest that NNAlign_MA and NetMHCIIpan-4.0 are powerful tools for analysis of immunopeptidome MS data, prediction of T cell epitopes, and development of personalized immunotherapies.

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X‐chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome‐wide DNA‐methylation and RNA‐expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA‐methylation and RNA‐expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome‐wide DNA‐methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X‐chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.

Since the first description of Klinefelter syndrome (KS) was published in 1942 in The Journal of Clinical Endocrinology, large inter‐individual variability in the phenotypic presentation has been demonstrated. However, our understanding of the global impact of the additional X chromosome on the genome remains an enigma. Evidence from the existing literature of KS indicates that not just one single genetic mechanism can explain the phenotype and the variable expressivity, but several mechanisms may be at play concurrently. In this review, we describe different genetic mechanisms and recent advances in the understanding of the genome, epigenome, and transcriptome of KS and the link to the phenotype and clinical heterogeneity. Future studies are needed to unite clinical data, genomic data, and basic research attempting to understand the genetics behind KS. Unraveling the genetics of KS will be of clinical relevance as it may enable the use of polygenic risk scores to predict future disease susceptibility and enable clinical risk stratification of KS patients in the future.

The vesicular transport machinery regulates numerous essential functions in cells such as cell polarity, signaling pathways, and the transport of receptors and their cargoes. From a pharmaceutical perspective, vesicular transport offers avenues to facilitate the uptake of therapeutic agents into cells and across cellular barriers. In order to improve receptor-mediated transcytosis of biologics across the blood-brain barrier and into the diseased brain, a detailed understanding of intracellular transport mechanisms is essential. The vesicular transport machinery is a highly complex network and involves an array of protein complexes, cytosolic adaptor proteins, and the subcellular structures of the endo-lysosomal system. The endo-lysosomal system includes several types of vesicular entities such as early, late, and recycling endosomes, exosomes, ectosomes, retromer-coated vesicles, lysosomes, trans-endothelial channels, and tubules. While extensive research has been done on the trafficking system in many cell types, little is known about vesicular trafficking in brain endothelial cells. Consequently, assumptions on the transport system in endothelial cells are based on findings in polarised epithelial cells, although recent studies have highlighted differences in the endothelial system. This review highlights aspects of the vesicular trafficking machinery in brain endothelial cells, including recent findings, limitations, and opportunities for further studies.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZand TOB1, focal deletions in BRD4and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Here we present a blood–brain barrier (BBB) model that enables high-resolution imaging of nanoparticle (NP) interactions with endothelial cells and the capture of rare NP translocation events. The enabling technology is an ultrathin silicon nitride (SiN) membrane (0.5 μm pore size, 20% porosity, 400 nm thickness) integrated into a dual-chamber platform that facilitates imaging at low working distances (∼50 μm). The platform, the μSiM-BBB (microfluidic silicon membrane-BBB), features human brain endothelial cells and primary astrocytes grown on opposite sides of the membrane. The human brain endothelial cells form tight junctions on the ultrathin membranes and exhibit a significantly higher resistance to FITC-dextran diffusion than commercial membranes. The enhanced optical properties of the SiN membrane allow high-resolution live-cell imaging of three types of NPs, namely, 40 nm PS-COOH, 100 nm PS-COOH, and apolipoprotein E-conjugated 100 nm SiO2, interacting with the BBB. Despite the excellent barrier properties of the endothelial layer, we are able to document rare NP translocation events of NPs localized to lysosomal compartments of astrocytes on the “brain side” of the device. Although the translocation is always low, our data suggest that size and targeting ligand are important parameters for NP translocation across the BBB. As a platform that enables the detection of rare transmission across tight BBB layers, the μSiM-BBB is an important tool for the design of nanoparticle-based delivery of drugs to the central nervous system.

The set of peptides presented on a cell's surface by MHC molecules is poly-specific (it contains multiple sequence motifs matching the quantity of MHC molecules expressed). NNAlign_MA can exploit this type of data, by means of: (1) clustering peptides into individual specificities; (2) automatic annotation of clusters to an MHC molecule; and (3) training of a prediction model covering all MHCs present in the training set. NNAlign_MA expands MHC allelic coverage, thus improving T-cell epitope predictions.

ABSTRACTImmune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284).

Microvesicles (MVs) are a class of membrane particles shed by any cell in the body in physiological and pathological conditions. They are considered to be key players in intercellular communication, and with a molecular content reflecting the composition of the cell of origin, they have recently emerged as a promising source of biomarkers in a number of diseases.

The pathogenesis of Turner syndrome (TS) and the genotype–phenotype relationship has been thoroughly investigated during the last decade. It has become evident that the phenotype seen in TS does not only depend on simple gene dosage as a result of X chromosome monosomy. The origin of TS specific comorbidities such as infertility, cardiac malformations, bone dysgenesis, and autoimmune diseases may depend on a complex relationship between genes as well as transcriptional and epigenetic factors affecting gene expression across the genome. Furthermore, two individuals with TS with the exact same karyotype may exhibit completely different traits, suggesting that no conventional genotype–phenotype relationship exists. Here, we review the different genetic mechanisms behind differential gene expression, and highlight potential key‐genes essential to the comorbidities seen in TS and other X chromosome aneuploidy syndromes. KDM6A, important for germ cell development, has shown to be differentially expressed and methylated in Turner and Klinefelter syndrome across studies. Furthermore, TIMP1/TIMP3genes seem to affect the prevalence of bicuspid aortic valve. KDM5Ccould play a role in the neurocognitive development of Turner and Klinefelter syndrome. However, further research is needed to elucidate the genetic mechanism behind the phenotypic variability and the different phenotypic traits seen in TS.

The wild bootstrap was originally developed for regression models with heteroskedasticity of unknown form. Over the past 30 years, it has been extended to models estimated by instrumental variables and maximum likelihood and to ones where the error terms are (perhaps multiway) clustered. Like bootstrap methods in general, the wild bootstrap is especially useful when conventional inference methods are unreliable because large-sample assumptions do not hold. For example, there may be few clusters, few treated clusters, or weak instruments. The package boottestcan perform a wide variety of wild bootstrap tests, often at remarkable speed. It can also invert these tests to construct confidence sets. As a postestimation command, boottestworks after linear estimation commands, including regress, cnsreg, ivregress, ivreg2, areg, and reghdfe, as well as many estimation commands based on maximum likelihood. Although it is designed to perform the wild cluster bootstrap, boottestcan also perform the ordinary (nonclustered) version. Wrappers offer classical Wald, score/Lagrange multiplier, and Anderson–Rubin tests, optionally with (multiway) clustering. We review the main ideas of the wild cluster bootstrap, offer tips for use, explain why it is particularly amenable to computational optimization, state the syntax of boottest, artest, scoretest, and waldtest, and present several empirical examples.

•Overall treatment time for HNC treatment was reduced according to DAHANCA guidelines.•Sufficient accelerator capacity alone did not sufficiently minimize treatment time.•Surveillance of treatment calendars reduced breaches to 3% (6fx/wk) and 13% (5 fx/wk).•Radiobiological efficacy was increased by 1.3 Gy (6 fx/wk) and 2.0 Gy (5 fx/wk).•Surveillance of treatment calendars presented minimal financial costs.

Aspergillussection Nigricomprises filamentous fungi relevant to biomedicine, bioenergy, health, and biotechnology. To learn more about what genetically sets these species apart, as well as about potential applications in biotechnology and biomedicine, we sequenced 23 genomes de novo, forming a full genome compendium for the section (26 species), as well as 6 Aspergillus nigerisolates. This allowed us to quantify both inter- and intraspecies genomic variation. We further predicted 17,903 carbohydrate-active enzymes and 2,717 secondary metabolite gene clusters, which we condensed into 455 distinct families corresponding to compound classes, 49% of which are only found in single species. We performed metabolomics and genetic engineering to correlate genotypes to phenotypes, as demonstrated for the metabolite aurasperone, and by heterologous transfer of citrate production to Aspergillus nidulans. Experimental and computational analyses showed that both secondary metabolism and regulation are key factors that are significant in the delineation of Aspergillusspecies.

•System response to harmonic injection and voltage deviation under different grid stiffness.•The control design methodology for large scale electrolyzer system.•Accurate electrolyzer model for a real commercial product.