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Pupil dilation is assumed to be a slow and indirect reflection of latent cognitive events. Deconvolution approaches promise a more precise study of these events, assuming that they all trigger a delayed pupil response.However, conventional deconvolution approaches neglect the possibility that between-event timings and the shape of the pupil responses differ between subjects, trials, and cognitive events. Accounting for this variability however is crucial to 1) achieve precise recovery of latent events and 2) to investigate how trial-level predictors influence cognitive processes.We present a new method that performs trial-level deconvolution by combining generalized additive mixed models with Hidden semi-Markov models. We tested this method on synthetic data and subsequently applied it to data from a lexical decision experiment (N=24) and recovered six processing events. Investigating the trial-level durations of the recovered events revealed that early visual and late decision-related processing were influenced differently by frequency and word-type.

Abstract Background Extensive glioblastoma infiltration justifies a 15-mm margin around the gross tumor volume (GTV) to define the radiotherapy clinical target volume (CTV). Amide proton transfer (APT)-weighted imaging could enable visualization of tumor infiltration, allowing more accurate GTV delineation. We quantified the impact of integrating APT-weighted imaging into GTV delineation of glioblastoma and compared two APT-weighted quantification methods—magnetization transfer ratio asymmetry (MTRasym) and Lorentzian difference (LD) analysis—for target delineation. Methods Nine glioblastoma patients underwent an extended imaging protocol prior to radiotherapy, yielding APT-weighted MTRasym and LD maps. From both maps, biological tumor volumes were generated (BTVMTRasym and BTVLD) and added to the conventional GTV to generate biological GTVs (GTVbio,MTRasym and GTVbio,LD). Wilcoxon signed-rank tests were performed for comparisons. Results The GTVbio,MTRasym and GTVbio,LD were significantly larger than the conventional GTV (p ≤ 0.022), with a median volume increase of 9.3% and 2.1%, respectively. The GTVbio,MTRasym and GTVbio,LD were significantly smaller than the CTV (p = 0.004), with a median volume reduction of 72.1% and 70.9%, respectively. There was no significant volume difference between the BTVMTRasym and BTVLD (p = 0.074). In three patients, BTVMTRasym delineation was affected by elevated signals at the brain periphery due to residual motion artifacts; this elevation was absent on the APT-weighted LD maps. Conclusion Larger biological GTVs compared to the conventional GTV highlight the potential of APT-weighted imaging for radiotherapy target delineation of glioblastoma. APT-weighted LD mapping may be advantageous for target delineation as it may be more robust against motion artifacts. Relevance statement The introduction of APT-weighted imaging may, ultimately, enhance visualization of tumor infiltration and eliminate the need for the substantial 15-mm safety margin for target delineation of glioblastoma. This could reduce the risk of radiation toxicity while still effectively irradiating the tumor. Trial registration NCT05970757 (ClinicalTrials.gov). Key Points Integration of APT-weighted imaging into target delineation for radiotherapy is feasible. The integration of APT-weighted imaging yields larger GTVs in glioblastoma. APT-weighted LD mapping may be more robust against motion artifacts than APT-weighted MTRasym. Graphical Abstract

Arguably New Zealand's best loved picturebook author/illustrator, Gavin Bishop invariably challenges populist power structures in his fiction and non-fiction. As such, his books are ideal vehicles for teaching children about such broad topics as race relations, colonisation, migration, class conflicts, gender relationships, environmental issues and spiritual beliefs. The fact that Bishop often addresses several of these simultaneously, and draws on found texts to do so, paves the way for the teacher to encourage the child to read not only the lines and images but between and beyond these in order to construct a fuller meaning. This article will discuss Bishop's (2018a) picturebook, "Cook's Cook: The Cook Who Cooked for Captain Cook," which qualifies as "faction", a genre that mixes fact and fiction, with Bishop reproducing historical events and characters whilst investing them with an imaginative dimension. Most obviously, the selected book portrays migration, including the colonisation of New Zealand and the Pacific, and its longer-term effects. Hence, it focuses on the subjugation of the indigenous people, culture, flora and fauna to those that are imported, as well as the domination of the working class by the upper class. However, Bishop is too skilful an author/artist to suggest that everything is black and white. Rather, through paralleling and fusing the aforementioned foci, and in the ways in which the print and pictures work separately, together, sometimes against each other, and in interaction with fore texts, he suggests that dichotomies are mixed. The article will examine those portrayed as minions and masters (whether human or non-human), their conflicts and conflations, and Bishop's use of verbal and visual techniques and fore texts to challenge dominant power structures. It will also argue that, while emphasising dichotomies, Bishop, the master storyteller and artist, creates structures that ensure his picturebook is balanced and whole and that, rather than treating the reader as a minion, allow him or her to become a master of meaning making.

The Rescorla-Wagner model has seen widespread success in modelling not only its original target of animal learning, but also several areas of human learning. However, despite its success, a number of studies with humans have found effects that are not predicted by the model, thus inspiring proposals for modifications to the model. One such proposal, by Van Hamme and Wasserman (1994, VHW), is that humans not only learn from present cues to all (present and absent) outcomes, as in the original model, but also learn from the absence of cues. They set out to test this hypothesis with a causal rating experiment. However, behaviour in learning studies may depend on the task. We propose that error-driven learning should be considered to be a form of implicit learning and that the results of VHW’s contingency judgement task might stem from explicit strategies involving logic and reasoning. The present study investigates this question by a) running simulations with both the original and modified versions of the model; b) replicating the VHW experiment (Experiment 1); and c) extending the experiment with new stimuli and by including unseen stimuli following the learning phases (Experiment 2). Simulations show that the VHW modified model predicts that cues learnt at the beginning will be unlearnt when absent over the following blocks, so that they become negative predictors over time. In contrast, the original RW predicts that the absent cues remain steady (positive) predictors over the blocks. Results showed no significant difference in cue assignment between training and test, in line with the original RW model. Moreover, predictive cues in the training phase showed significantly higher ratings than a new cue introduced in the test phase, at least in some cases, also partially supporting the original RW. We propose that in the development of human learning theory, attention should be paid to whether the behaviour (or other learning data) to be modelled results from implicit learning or involves higher level cognitive processes. We suggest that the RW may best capture implicit error-driven learning.

Current research on data in policy has primarily focused on street-level bureaucrats, neglecting the changes in the work of policy advisors. This research fills this gap by presenting an explorative theoretical understanding of the integration of data, local knowledge and professional expertise in the work of policy advisors. The theoretical perspective we develop builds upon Vickers’s (1995, The Art of Judgment: A Study of Policy Making, Centenary Edition, SAGE) judgments in policymaking. Empirically, we present a case study of a Dutch law enforcement network for preventing and reducing organized crime. Based on interviews, observations, and documents collected in a 13-month ethnographic fieldwork period, we study how policy advisors within this network make their judgments. In contrast with the idea of data as a rationalizing force, our study reveals that how data sources are selected and analyzed for judgments is very much shaped by the existing local and expert knowledge of policy advisors. The weight given to data is highly situational: we found that policy advisors welcome data in scoping the policy issue, but for judgments more closely connected to actual policy interventions, data are given limited value.

Abstract Background Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. Methods Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15–24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. Discussion Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. Trial registration ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

BackgroundThe Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. With limited antiviral drugs and vaccines available, vector control is the primary approach to prevent mosquito-borne diseases. A reliable and accurate DNA sequence of the Ae. albopictus genome is essential to develop new approaches that involve genetic manipulation of mosquitoes.ResultsWe use long-read sequencing methods and modern scaffolding techniques (PacBio, 10X, and Hi-C) to produce AalbF2, a dramatically improved assembly of the Ae. albopictus genome. AalbF2 reveals widespread viral insertions, novel microRNAs and piRNA clusters, the sex-determining locus, and new immunity genes, and enables genome-wide studies of geographically diverse Ae. albopictus populations and analyses of the developmental and stage-dependent network of expression data. Additionally, we build the first physical map for this species with 75% of the assembled genome anchored to the chromosomes.ConclusionThe AalbF2 genome assembly represents the most up-to-date collective knowledge of the Ae. albopictus genome. These resources represent a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures.

Mosquitoes are vectors for emerging and re-emerging infectious viral diseases of humans, livestock and other animals. In addition to these arthropod-borne (arbo)viruses, mosquitoes are host to an array of insect-specific viruses, collectively referred to as the mosquito virome. Mapping the mosquito virome and understanding if and how its composition modulates arbovirus transmission is critical to understand arboviral disease emergence and outbreak dynamics. In recent years, next-generation sequencing as well as PCR and culture-based methods have been extensively used to identify mosquito-associated viruses, providing insights into virus ecology and evolution. Until now, the large amount of mosquito virome data, specifically those acquired by metagenomic sequencing, has not been comprehensively integrated. We have constructed a searchable database of insect-specific viruses associated with vector mosquitoes from 175 studies, published between October 2000 and February 2022. We identify the most frequently detected and widespread viruses of the Culex, Aedes and Anopheles mosquito genera and report their global distribution. In addition, we highlight the challenges of extracting and integrating published virome data and we propose that a standardized reporting format will facilitate data interpretation and re-use by other scientists. We expect our comprehensive database, summarizing mosquito virome data collected over 20 years, to be a useful resource for future studies.

Using a novel adaptation of the visual world eye-trackingparadigm we investigated children’s and adults’ onlineprocessing of reference in a naturalistic language context.Participants listened to a 5-minute long storybook whilewearing eye-tracking glasses. The gaze data were analyzedrelative to the onset of referring expressions (i.e., full nounphrases (NPs) and pronouns) that were mentionedthroughout the story. We found that following the mentionof a referring expression there was an increase in theproportion of looks to the intended referent for both childrenand adults. However, this effect was only found early on inthe story. As the story progressed, the likelihood thatparticipants directed their eye gaze towards the intendedreferent decreased. We also found differences in the eye gazepatterns between NPs and pronouns, as well as betweenchildren and adults. Overall these findings demonstrate thatthe mapping between linguistic input and corresponding eyemovements is heavily influenced by discourse context.

Summary: The piRNA pathway in mosquitoes differs substantially from other model organisms, with an expanded PIWI gene family and functions in antiviral defense. Here, we define core piRNA clusters as genomic loci that show ubiquitous piRNA expression in both somatic and germline tissues. These core piRNA clusters are enriched for non-retroviral endogenous viral elements (nrEVEs) in antisense orientation and depend on key biogenesis factors, Veneno, Tejas, Yb, and Shutdown. Combined transcriptome and chromatin state analyses identify transcriptional readthrough as a conserved mechanism for cluster-derived piRNA biogenesis in the vector mosquitoes Aedes aegypti, Aedes albopictus, Culex quinquefasciatus, and Anopheles gambiae. Comparative analyses between the two Aedes species suggest that piRNA clusters function as traps for nrEVEs, allowing adaptation to environmental challenges such as virus infection. Our systematic transcriptome and chromatin state analyses lay the foundation for studies of gene regulation, genome evolution, and piRNA function in these important vector species.

Abstract Knowledge about contagiousness is key to accurate management of hospitalized COVID-19 patients. Epidemiological studies suggest that in addition to transmission through droplets, aerogenic SARS-CoV-2 transmission contributes to the spread of infection. However, the presence of virus in exhaled air has not yet been sufficiently demonstrated. In pandemic situations low tech disposable and user-friendly bedside devices are required, while commercially available samplers are unsuitable for application in patients with respiratory distress. We included 49 hospitalized COVID-19 patients and used a disposable modular breath sampler to measure SARS-CoV-2 RNA load in exhaled air samples and compared these to SARS-CoV-2 RNA load of combined nasopharyngeal throat swabs and saliva. Exhaled air sampling using the modular breath sampler has proven feasible in a clinical COVID-19 setting and demonstrated viral detection in 25% of the patients.

When encountering letter strings, we rapidly determine whether they are words. The speed of such lexical decisions (LDs) is affected by word frequency. Apart from influencing late, decision-related, processing stages, frequency has also been shown to affect very early stages, and even the processing of nonwords. We developed a detailed account of the different frequency effects involved in LDs by (1) dividing LDs into processing stages using a combination of hidden semi-Markov models and multivariate pattern analysis applied to EEG data and (2) using generalized additive mixed models to investigate how the effect of continuous word and nonword frequency differs between these stages. We discovered six stages shared between word types, with the fifth stage consisting of two substages for pseudowords only. In the earliest stages, visual processing was completed faster for frequent words, but took longer for word-like nonwords. Later stages involved an orthographic familiarity assessment followed by an elaborate decision process, both affected differently by frequency. We therefore conclude that frequency indeed affects all processes involved in LDs and that the magnitude and direction of these effects differ both by process and word type. [ABSTRACT FROM AUTHOR]

BackgroundThe immunopathogenesis of dengue virus (DENV) infection remains incompletely understood. To increase our understanding of inflammatory response in non-severe dengue, we assessed longitudinal changes in the inflammatory proteome in patients with an acute DENV infection.MethodsUsing a multiplex proximity extension assay (PEA), we measured relative levels of 368 inflammatory markers in plasma samples from hospitalized patients with non-severe DENV infection in the acute (n = 43) and convalescence (n = 35) phase of the infection and samples of healthy controls (n = 10).ResultsWe identified 203 upregulated and 39 downregulated proteins in acute versus convalescent plasma samples. The upregulated proteins had a strong representation of interferon (IFN) and IFN-inducible effector proteins, cytokines (e.g. IL-10, IL-33) and cytokine receptors, chemokines, pro-apoptotic proteins (e.g. granzymes) and endothelial markers. A number of differentially expressed proteins (DEPs) have not been reported in previous studies. Functional network analysis highlighted a central role for IFNγ, IL-10, IL-33 and chemokines. We identified different novel associations between inflammatory proteins and circulating concentrations of the endothelial glycocalyx disruption surrogate marker syndecan-1. Conclusion: This unbiased proteome analysis provides a comprehensive insight in the inflammatory response in DENV infection and its association with glycocalyx disruption.

During real-time language processing, people rely on linguistic and non-linguistic biases to anticipate upcoming linguistic input. One of these linguistic biases is known as the implicit causality bias, wherein language users anticipate that certain entities will be rementioned in the discourse based on the entity's particular role in an expressed causal event. For example, when language users encounter a sentence like “Elizabeth congratulated Tina…” during real-time language processing, they seemingly anticipate that the discourse will continue about Tina, the object referent, rather than Elizabeth, the subject referent. However, it is often unclear how these reference biases are acquired and how exactly they get used during real-time language processing. In order to investigate these questions, we developed a reference learning model within the PRIMs cognitive architecture that simulated the process of predicting upcoming discourse referents and their linguistic forms. Crucially, across the linguistic input the model was presented with, there were asymmetries with respect to how the discourse continued. By utilizing the learning mechanisms of the PRIMs architecture, the model was able to optimize its predictions, ultimately leading to biased model behavior. More specifically, following subject-biased implicit causality verbs the model was more likely to predict that the discourse would continue about the subject referent, whereas following object-biased implicit causality verbs the model was more likely to predict that the discourse would continue about the object referent. In a similar fashion, the model was more likely to predict that subject referent continuations would be in the form of a pronoun, whereas object referent continuations would be in the form of a proper name. These learned biases were also shown to generalize to novel contexts in which either the verb or the subject and object referents were new. The results of the present study demonstrate that seemingly complex linguistic behavior can be explained by cognitively plausible domain-general learning mechanisms. This study has implications for psycholinguistic accounts of predictive language processing and language learning, as well as for theories of implicit causality and reference processing.

Efficient virus replication in Aedes vector mosquitoes is essential for the transmission of arboviral diseases such as dengue virus (DENV) in human populations. Like in vertebrates, virus-host protein-protein interactions are essential for viral replication and immune evasion in the mosquito vector. Here, 79 mosquito host proteins interacting with DENV non-structural proteins NS1 and NS5 were identified by label-free mass spectrometry, followed by a functional screening. We confirmed interactions with host factors previously observed in mammals, such as the oligosaccharyltransferase complex, and we identified protein-protein interactions that seem to be specific for mosquitoes. Among the interactors, the double-stranded RNA (dsRNA) binding protein Loquacious (Loqs), an RNA interference (RNAi) cofactor, was found to be essential for efficient replication of DENV and Zika virus (ZIKV) in mosquito cells. Loqs did not affect viral RNA stability or translation of a DENV replicon and its proviral activity was independent of its RNAi regulatory activity. Interestingly, Loqs colocalized with DENV dsRNA replication intermediates in infected cells and directly interacted with high affinity with DENV RNA in the 3' untranslated region in vitro (KD = 48-62 nM). Our study provides an interactome for DENV NS1 and NS5 and identifies Loqs as a key proviral host factor in mosquitoes. We propose that DENV hijacks a factor of the RNAi mechanism for replication of its own RNA.

Summary: We describe a protocol for single-cell RNA sequencing of SARS-CoV-2-infected human induced pluripotent stem cell (iPSC)-derived kidney organoids. After inoculation of kidney organoids with virus, we use mechanical and enzymatic disruption to obtain single cell suspensions. Next, we process the organoid-derived cells into sequencing-ready SARS-CoV-2-targeted libraries. Subsequent sequencing analysis reveals changes in kidney cells after virus infection. The protocol was designed for kidney organoids cultured in a 6-well transwell format but can be adapted to organoids with different organ backgrounds.For complete details on the use and execution of this protocol, please refer to Jansen et al. (2022). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

ImportanceThe causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.ObjectiveTo conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.Data sourcesGenomewide association studies (GWAS) published up to January 15, 2015.Study selectionGWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.Data extraction and synthesisSummary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.Main outcomes and measuresOdds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.ResultsSummary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).Conclusions and relevanceIt is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

In a production by typing task, with extraneous factors (e.g., length) controlled, measures such as latency to initialkeystroke as well as mean inter keystroke interval typically vary systematically according to the word’s lexical properties.Conventionally, lexical effects in production tasks get interpreted as evidence of cascaded processing between central andperipheral levels. We compare mean and distribution of keystroke latencies within the same stem as it undergoes affixation insets such as DEPRESS, DEPRESSION, DEPRESSIVE. Novel is the comparison of stems that differ with respect to number ofaffixes like SUPER, SUPERIOR, SUPERIORITY. Results provide new insights into the ways in which morphological structurecan influence purportedly peripheral motor processing.

Changes in whole blood DNA methylation levels at several CpG sites have been associated with circulating blood lipids, specifically high-density lipoprotein and triglycerides. This study performs a discovery and validation epigenome-wide association study (EWAS) for circulating lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular diseases. Whole-blood DNA methylation profiles were assessed in a cohort of 1020 elderly individuals using the Illumina EPIC array and independent validation in 359 elderly males using the Illumina 450 k array. Plasma Lp(a) was measured using an apolipoprotein(a)-size-independent ELISA. Epigenome-wide rank regression analysis identified and validated a single CpG site, cg17028067 located in intron 1 of the LPA gene, that was significantly associated with plasma Lp(a) levels after correction for multiple testing. Genotyping of the site identified a relatively uncommon SNP (rs76735376, MAF

Abstract Background The Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. With limited antiviral drugs and vaccines available, vector control is the primary approach to prevent mosquito-borne diseases. A reliable and accurate DNA sequence of the Ae. albopictus genome is essential to develop new approaches that involve genetic manipulation of mosquitoes. Results We use long-read sequencing methods and modern scaffolding techniques (PacBio, 10X, and Hi-C) to produce AalbF2, a dramatically improved assembly of the Ae. albopictus genome. AalbF2 reveals widespread viral insertions, novel microRNAs and piRNA clusters, the sex-determining locus, and new immunity genes, and enables genome-wide studies of geographically diverse Ae. albopictus populations and analyses of the developmental and stage-dependent network of expression data. Additionally, we build the first physical map for this species with 75% of the assembled genome anchored to the chromosomes. Conclusion The AalbF2 genome assembly represents the most up-to-date collective knowledge of the Ae. albopictus genome. These resources represent a foundation to improve understanding of the adaptation potential and the epidemiological relevance of this species and foster the development of innovative control measures.

BackgroundEndothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet to be elucidated whether heparanase activity plays a major role in dengue-associated plasma leakage. Moreover, the major source of heparanase secretion and activation in dengue remains elusive. Since a relatively high amount of heparanase is stored in platelets, we postulate that heparanase released by activated platelets contributes to the increased plasma heparanase activity during dengue virus infection.MethodsHeparanase activity (plasma and urine), and heparan sulfate and syndecan-1 (plasma levels) were measured in dengue patients with thrombocytopenia in acute phase (n=30), during course of disease (n=10) and in convalescent phase (n=25). Associations with clinical parameters and plasma leakage markers were explored. Platelets from healthy donors were stimulated with dengue non-structural protein-1, DENV2 virus and thrombin to evaluate heparanase release and activity ex vivo.ResultsHeparanase activity was elevated in acute dengue and normalized during convalescence. Similarly, glycocalyx components, such as heparan sulfate and syndecan-1, were increased in acute dengue and restored during convalescence. Increased heparanase activity correlated with the endothelial dysfunction markers heparan sulfate and syndecan-1, as well as clinical markers of plasma leakage such as ascites, hematocrit concentration and gall-bladder wall thickening. Notably, platelet number inversely correlated with heparanase activity. Ex vivo incubation of platelets with thrombin and live DENV2 virus, but not dengue virus-2-derived non-structural protein 1 induced heparanase release from platelets.ConclusionTaken together, our findings suggest that the increase of heparanase activity in dengue patients is associated with endothelial glycocalyx degradation and plasma leakage. Furthermore, thrombin or DENV2 activated platelets may be considered as a potential source of heparanase.