Generation of Mutants from the 57B Region of Drosophila melanogaster

The 57B region of Drosophila melanogaster includes a cluster of the three homeobox genes orthopedia (otp), Drosophila Retinal homeobox (DRx), and homeobrain (hbn). In an attempt to isolate mu tants for these genes, we performed an EMS mutagenesis and isolated lethal mutants from the 57B region, among them mutants for otp, DRx, and hbn. With the help of two newly generated deletions from the 57B region, we mapped additional mutants to specific chromosomal intervals and identi fied several of these mutants from the 57B region molecularly. In addition, we generated mutants for CG15651 and RIC-3 by gene targeting and mutants for the genes CG9344, CG15649, CG15650, and ND-B14.7 using the CRISPR/Cas9 system. We determined the lethality period during develop ment for most isolated mutants. In total, we analysed alleles from nine different genes from the 57B region of Drosophila, which could now be used to further explore the functions of the corresponding genes in the future

Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial

Background: Myocardial fibrosis is characterized by excessive cross‐linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross‐linking and/or deposition. Methods and results: We investigated 381 HFpEF patients from the multicentre, randomized, placebo‐controlled Aldo‐DHF trial with measures of the E:e' ratio. The ratio of serum carboxy‐terminal telopeptide of collagen type I to serum matrix metalloproteinase‐1 (CITP:MMP‐1, an inverse index of myocardial collagen cross‐linking) and serum carboxy‐terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1‐year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP‐1 and PICP tertiles at baseline. While CITP:MMP‐1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP‐1 levels, this ratio was significantly reduced in the remaining spironolactone‐treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP‐1 levels but was reduced in the remaining spironolactone‐treated patients. Conclusions: A biochemical phenotype of high collagen cross‐linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross‐linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients

Incremental prognostic value of a novel metabolite-based biomarker score in congestive heart failure patients

Aims: The Cardiac Lipid Panel (CLP) is a newly discovered panel of metabolite-based biomarkers that has shown to improve the diagnostic value of N terminal pro B type natriuretic peptide (NT-proBNP). However, little is known about its usefulness in predicting outcomes. In this study, we developed a risk score for 4-year cardiovascular death in elderly chronic heart failure (CHF) patients using the CLP. Methods and results: From the Cardiac Insufficiency Bisoprolol Study in Elderly trial, we included 280 patients with CHF aged \u3e65 years. A targeted metabolomic analysis of the CLP biomarkers was performed on baseline serum samples. Cox regression was used to determine the association of the biomarkers with the outcome after accounting for established risk factors. A risk score ranging from 0 to 4 was calculated by counting the number of biomarkers above the cut-offs, using Youden index. During the mean (standard deviation) follow-up period of 50 (8) months, 35 (18%) subjects met the primary endpoint of cardiovascular death. The area under the receiver operating curve for the model based on clinical variables was 0.84, the second model with NT-proBNP was 0.86, and the final model with the CLP was 0.90. The categorical net reclassification index was 0.25 using three risk categories: 0–60% (low), 60–85% (intermediate), and \u3e85% (high). The continuous net reclassification index was 0.772, and the integrated discrimination index was 0.104. Conclusions: In patients with CHF, incorporating a panel of three metabolite-based biomarkers into a risk score improved the prognostic utility of NT-proBNP by predicting long-term cardiovascular death more precisely. This novel approach holds promise to improve clinical risk assessment in CHF patients

Incremental prognostic value of a novel metabolite‐based biomarker score in congestive heart failure patients

Aims: The Cardiac Lipid Panel (CLP) is a newly discovered panel of metabolite-based biomarkers that has shown to improve the diagnostic value of N terminal pro B type natriuretic peptide (NT-proBNP). However, little is known about its usefulness in predicting outcomes. In this study, we developed a risk score for 4-year cardiovascular death in elderly chronic heart failure (CHF) patients using the CLP. Methods and results: From the Cardiac Insufficiency Bisoprolol Study in Elderly trial, we included 280 patients with CHF aged >65 years. A targeted metabolomic analysis of the CLP biomarkers was performed on baseline serum samples. Cox regression was used to determine the association of the biomarkers with the outcome after accounting for established risk factors. A risk score ranging from 0 to 4 was calculated by counting the number of biomarkers above the cut-offs, using Youden index. During the mean (standard deviation) follow-up period of 50 (8) months, 35 (18%) subjects met the primary endpoint of cardiovascular death. The area under the receiver operating curve for the model based on clinical variables was 0.84, the second model with NT-proBNP was 0.86, and the final model with the CLP was 0.90. The categorical net reclassification index was 0.25 using three risk categories: 0-60% (low), 60-85% (intermediate), and >85% (high). The continuous net reclassification index was 0.772, and the integrated discrimination index was 0.104. Conclusions: In patients with CHF, incorporating a panel of three metabolite-based biomarkers into a risk score improved the prognostic utility of NT-proBNP by predicting long-term cardiovascular death more precisely. This novel approach holds promise to improve clinical risk assessment in CHF patients

Challenges and Opportunities in Data Visualization Education: A Call to Action

This paper is a call to action for research and discussion on data visualization education. As visualization evolves and spreads through our professional and personal lives, we need to understand how to support and empower a broad and diverse community of learners in visualization. Data Visualization is a diverse and dynamic discipline that combines knowledge from different fields, is tailored to suit diverse audiences and contexts, and frequently incorporates tacit knowledge. This complex nature leads to a series of interrelated challenges for data visualization education. Driven by a lack of consolidated knowledge, overview, and orientation for visualization education, the 21 authors of this paper-educators and researchers in data visualization-identify and describe 19 challenges informed by our collective practical experience. We organize these challenges around seven themes People, Goals & Assessment, Environment, Motivation, Methods, Materials, and Change. Across these themes, we formulate 43 research questions to address these challenges. As part of our call to action, we then conclude with 5 cross-cutting opportunities and respective action items: embrace DIVERSITY+INCLUSION, build COMMUNITIES, conduct RESEARCH, act AGILE, and relish RESPONSIBILITY. We aim to inspire researchers, educators and learners to drive visualization education forward and discuss why, how, who and where we educate, as we learn to use visualization to address challenges across many scales and many domains in a rapidly changing world: viseducationchallenges.github.io.Comment: Accepted for publication at VIS 2023 Conference, Melbourne, VI

Sex determination, sex chromosomes and karyotype evolution in insects

Insects harbor a tremendous diversity of sex determining mechanisms both within and between groups. For example, in some orders such as Hymenoptera, all members are haplodiploid, whereas Diptera contain species with homomorphic as well as male and female heterogametic sex chromosome systems or paternal genome elimination. We have established a large database on karyotypes and sex chromosomes in insects, containing information on over 13000 species covering 29 orders of insects. This database constitutes a unique starting point to report phylogenetic patterns on the distribution of sex determination mechanisms, sex chromosomes, and karyotypes among insects and allows us to test general theories on the evolutionary dynamics of karyotypes, sex chromosomes, and sex determination systems in a comparative framework. Phylogenetic analysis reveals that male heterogamety is the ancestral mode of sex determination in insects, and transitions to female heterogamety are extremely rare. Many insect orders harbor species with complex sex chromosomes, and gains and losses of the sex-limited chromosome are frequent in some groups. Haplodiploidy originated several times within insects, and parthenogenesis is rare but evolves frequently. Providing a single source to electronically access data previously distributed among more than 500 articles and books will not only accelerate analyses of the assembled data, but also provide a unique resource to guide research on which taxa are likely to be informative to address specific questions, for example, for genome sequencing projects or large-scale comparative studies

Repeat controlled human malaria infection of healthy UK adults with blood-stage plasmodium falciparum:Safety and parasite growth dynamics

In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasite immunity (manifest as reduced parasite growth in vivo) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics in vivo following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03906474, NCT02927145

Exogenous Ether Lipids Predominantly Target Mitochondria

Ether lipids are ubiquitous constituents of cellular membranes with no discrete cell biological function assigned yet. Using fluorescent polyene-ether lipids we analyzed their intracellular distribution in living cells by microscopy. Mitochondria and the endoplasmic reticulum accumulated high amounts of ether-phosphatidylcholine and ether-phosphatidylethanolamine. Both lipids were specifically labeled using the corresponding lyso-ether lipids, which we established as supreme precursors for lipid tagging. Polyfosine, a fluorescent analogue of the anti-neoplastic ether lipid edelfosine, accumulated to mitochondria and induced morphological changes and cellular apoptosis. These data indicate that edelfosine could exert its pro-apoptotic power by targeting and damaging mitochondria and thereby inducing cellular apoptosis. In general, this study implies an important role of mitochondria in ether lipid metabolism and intracellular ether lipid trafficking

A pan-European epidemiological study reveals honey bee colony survival depends on beekeeper education and disease control

Reports of honey bee population decline has spurred many national efforts to understand the extent of the problem and to identify causative or associated factors. However, our collective understanding of the factors has been hampered by a lack of joined up trans-national effort. Moreover, the impacts of beekeeper knowledge and beekeeping management practices have often been overlooked, despite honey bees being a managed pollinator. Here, we established a standardised active monitoring network for 5 798 apiaries over two consecutive years to quantify honey bee colony mortality across 17 European countries. Our data demonstrate that overwinter losses ranged between 2% and 32%, and that high summer losses were likely to follow high winter losses. Multivariate Poisson regression models revealed that hobbyist beekeepers with small apiaries and little experience in beekeeping had double the winter mortality rate when compared to professional beekeepers. Furthermore, honey bees kept by professional beekeepers never showed signs of disease, unlike apiaries from hobbyist beekeepers that had symptoms of bacterial infection and heavy Varroa infestation. Our data highlight beekeeper background and apicultural practices as major drivers of honey bee colony losses. The benefits of conducting trans-national monitoring schemes and improving beekeeper training are discussed