The genetic basis of heart development is remarkably conserved from Drosophila to mammals, and insights from flies have greatly informed our understanding of vertebrate heart development. Recent ...evidence suggests that many aspects of heart function are also conserved and the genes involved in heart development also play roles in adult heart function. We have developed a Drosophila heart preparation and movement analysis algorithm that allows quantification of functional parameters. Our methodology combines high-speed optical recording of beating hearts with a robust, semi-automated analysis to accurately detect and quantify, on a beat-to-beat basis, not only heart rate but also diastolic and systolic intervals, systolic and diastolic diameters, percent fractional shortening, contraction wave velocity, and cardiac arrhythmicity. Here, we present a detailed analysis of hearts from adult Drosophila, 2-3-day-old zebrafish larva, and 8-day-old mouse embryos, indicating that our methodology is potentially applicable to an array of biological models. We detect progressive age-related changes in fly hearts as well as subtle but distinct cardiac deficits in
heterozygote mutant zebrafish. Our methodology for quantifying cardiac function in these genetically tractable model systems should provide valuable insights into the genetics of heart function.
Aim: Aim of the study is to investigate the frequency of and predictors for rehospitalization within the first 2 years of life among preterm infants.
Methods: All children born before 32 weeks of ...gestation in Northern Tyrol between January 2003 and July 2008 were prospectively enrolled. Data on rehospitalizations were obtained from hospital admission records. The association between candidate risk factors and readmission was analysed by means of logistic regression analysis.
Results: In the first and second years of life, 151 and 93 of 377 children (40.1% and 24.7%), respectively, were readmitted to one of the hospitals in Northern Tyrol. The most common causes of rehospitalization were respiratory disorders, accounting for 42.1% and 47.4% of total readmissions in the first and second years of life. Chronic lung disease (CLD), male sex and smoking in pregnancy were risk conditions relevant to readmission in the first year of life, but only CLD in the second year.
Conclusion: Infants born before 32 weeks of gestation have a high risk of rehospitalization with respiratory illness significantly contributing to postdischarge morbidity. Neonatal intensive care should aim to further improve respiratory health in preterm infants, and adequate follow‐up services must be offered.
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line ...pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood–transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant-independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1 -mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases.
The Russia–Ukraine conflict is also being fought in the maritime dimension. Regarding methods of warfare, of particular note has been the possible existence of a Russian naval blockade in the Sea of ...Azov and off the coast of Odessa in the Black Sea. The blockade played a significant role in the emergence of the grain crisis, and has been opined to be the main reason why vessels were not able to safely sail out of the Black Sea and deliver grain to areas in other parts of the world that were in much need thereof. This paper explores whether Russia imposed a blockade in a legal sense based on the law of naval warfare—allowing belligerent rights to be exercised—or whether the Russian activities should in fact be regarded as another form of maritime control or dominance over certain maritime areas during an international armed conflict.
The concept of corporate social responsibility (CSR) can be understood as a part of the intellectual capital (IC) of organizations, as a set of tacit knowledge of CSR holders transferred into the ...form of explicit knowledge recorded in the documents of organizations. The aim of this study, in terms of lifelong learning, is to determine whether CSR is a part of the IC, whether the knowledge of the CSR concept is of a tacit or explicit nature and to what extent the potential of such knowledge is used by small and medium-sized organizations (SMEs). The presented data are a selection taken from 3 studies carried out by the authors in 2014-2019. The study was conducted in the Olomouc region, SMEs were the respondents, and the content of the study referred to CSR. The data show that a tacit form of knowledge of the CSR concept prevails.
Population profiles of industrialized countries show dramatic increases in cardiovascular disease with age, but the molecular and genetic basis of disease progression has been difficult to study ...because of the lack of suitable model systems. Our studies of Drosophila show a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in the expression of the Drosophila homolog of human KCNQ1-encoded K⁺ channel α subunits. In humans, this channel is involved in myocardial repolarization, and alterations in the function of this channel are associated with an increased risk for Torsades des Pointes arrhythmias and sudden death. Hearts from young KCNQ1 mutant fruit flies exhibit prolonged contractions and fibrillations reminiscent of Torsades des Pointes arrhythmias, and they exhibit severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in WT flies. The fibrillations observed in mutant flies correlate with delayed relaxation of the myocardium, as revealed by increases in the duration of phasic contractions, extracellular field potentials, and in the baseline diastolic tension. These results suggest that K⁺ currents, mediated by a KCNQ channel, contribute to the repolarization reserve of fly hearts, ensuring normal excitation-contraction coupling and rhythmical contraction. That arrhythmias in both WT and KCNQ1 mutants become worse as flies age suggests that additional factors are also involved.
LYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We ...describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re‐distribution from target expressing cells resulted in a long terminal half‐life and a long‐lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well‐tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose‐limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil‐driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.
Abstract
Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar ...rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure-function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose-response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar.
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