Mull it over: mutation testing based on LLVM

This paper describes Mull, an open-source tool for mutation testing based on the LLVM framework. Mull works with LLVM IR, a low-level intermediate representation, to perform mutations, and uses LLVM JIT for just-in-time compilation. This design choice enables the following two capabilities of Mull: language independence and fine-grained control over compilation and execution of a tested program and its mutations. Mull can work with code written in any programming language that supports compilation to LLVM IR, such as C, C++, Rust, or Swift. Direct manipulation of LLVM IR allows Mull to do less work to generate mutations: only modified fragments of IR code are recompiled, and this results in faster processing of mutated programs. To our knowledge, no existing mutation testing tool provides these capabilities for compiled programming languages. We describe the algorithm and implementation details of Mull, highlight current limitations of Mull, and present the results of our evaluation of Mull on real-world projects such as RODOS, OpenSSL, LLVM.Comment: 6 pages, 4 tables, ICSTW 2018, Mutation Worksho

Вакцинация от COVID-19 в системе национальной безопасности Российской Федерации: согласование частных и публичных интересов

The subject. Having a proven positive social and economic effect, vaccination remains one of the most important institutions in the system of public safety. The development of this institution requires a rational legal support, considering not only current epidemic process, but also potential threats of bioterrorism and the development of biological weapons. In this light, effective legal regulation of vaccination measures, determination of their desirable forms and scope of the population coverage, as well as cooperation between citizens and the State in ensuring epidemiological safety become a matter of paramount importance.The purpose. The authors propose to discuss two issues: the limits of the possibility of introducing the institution of mandatory vaccination and the issue of legal assistance for the population to participate in vaccination programs in order to achieve the maximum possible coverage.The methodology. The article employs a comprehensive approach which combines formal interpretation and comparative analysis of legal acts and courts decisions with the insights from sociology, behavioral sciences and discourse analysis. The article focuses on the international and national standards of regulation of the vaccination by the means of public and private law in order to achieve herd immunity.Our analysis of the vaccination institute place in the legal system demonstrates that this institution can be included in a row of disciplinary, coercive and binding institutions for citizens prescribing mandatory participation. However, its coercive potential is relatively small and is limited to certain segments of the society that are of strategic importance for ensuring the epidemiological safety. The article posits that such groups remain in the legal field of exceptions, whereas in general, the vaccination institute presumes that the mandatory component is prescribed primarily to the state, not the citizens. And therefore, the citizen's participation in vaccination has the character of an individual rational choice.Conclusions. Our analysis shows that the law on vaccination should be focused on the facilitating socially desirable individual choice rather than binding norm prescription. In this area, the main tasks of legal regulation are establishment of an adequate system of accounting and distribution of individual risks, as well as fair compensation for possible damages during vaccinations. The second main direction of legal development is overcoming information asymmetry in the situation of individual decision-making in order to reduce the shortage of reliable data and to ensure effective communication within an expert community, the state and the person. We propose that this development contributes to the transformation of a purely legal norm on vaccination into a social and cultural one and strengthens the cooperative strategies of citizens in the fight against vaccine-controlled diseases.Предметом исследования являются вопросы правового регулирования мероприятий по вакцинации от COVID-19 в контексте национальной безопасности Российской Федерации, а также взаимодействие граждан и государства в обеспечении эпидемиологической безопасности. Целью статьи является поиск наилучших практик по вопросам необходимости и определения пределов возможности внедрения правового института обязательной вакцинации и содействия правовыми методами участию населения в программах вакцинации с целью достижения максимально возможного охвата граждан Российской Федерации. Методологическую основу статьи составляет междисциплинарный комплексный подход, сочетающий формально-юридический метод и сравнительный анализ правовых актов и судебных решений с научными выводами из социологии, политологии, медицины, биоэтики. Статья посвящена международным и национальным стандартам регулирования вакцинации средствами публичного и частного права в целях достижения коллективного иммунитета. Выделены основные направления совершенствования правового регулирования вакцинации в России: установление адекватной системы учета и распределения индивидуальных рисков, а также справедливое возмещение возможного ущерба при вакцинации; преодоление информационной асимметрии в ситуации индивидуального принятия решений с целью снижения дефицита достоверных данных и обеспечения эффективной коммуникации внутри экспертного сообщества, государства и личности

The potential of neurofilaments analysis using dry-blood and plasma spots

The lack of biomarkers for an early diagnosis of neurodegenerative disorders (NDs) has hampered the development of therapeutics whose effect would be enhanced by a timely intervention. Neurofilaments light chain (Nf-L), an integral part of the axonal structure, has emerged as a robust fluid biomarker for fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). To facilitate large-scale studies into early-stage neurodegeneration, reduce costs of samples collection/processing and cold-chain storage, we describe the measurement of Nf-L in blood fractions obtained from dry blood spots (DBS) and dry plasma spots (DPS), two filter paper-based remote blood collection tools. To test the feasibility of using this approach, Nf-L analysis in DBS/DPS is compared to that in plasma obtained from the same blood sample, looking at Nf-L discriminatory power in the clinical stratification of ALS compared to healthy controls. With the best pre-analytical treatment for total protein recovery and using highly sensitive immunoassays, we report the detection of different Nf-L levels in DBS elute compared to reference plasma and DPS from the same blood samples. However, Nf-L measurement in DBS elutes provides a very good discrimination of ALS from healthy controls which is comparable to that obtained using plasma Nf-L assays. With the available immunodetection methods, we show that Nf-L measurement based on DPS microsampling is similar to that in plasma. The filter-paper biophysical characteristics and the interference of high haemoglobin concentration released by erythrocyte lysis is likely to perturb Nf-L detection in DBS elute. Further studies into DBS-based Nf-L detection and its analytical optimization are needed to make this method suitable for routine Nf-L blood analyses in neurodegeneration

The main and accessory olfactory systems interact in the control of mate recognition and sexual behavior

Peer reviewe

ZFP30 promotes adipogenesis through the KAP1-mediated activation of a retrotransposon-derived Pparg2 enhancer.

Krüppel-associated box zinc finger proteins (KZFPs) constitute the largest family of mammalian transcription factors, but most remain completely uncharacterized. While initially proposed to primarily repress transposable elements, recent reports have revealed that KFZPs contribute to a wide variety of other biological processes. Using murine and human in vitro and in vivo models, we demonstrate here that one poorly studied KZFP, ZFP30, promotes adipogenesis by directly targeting and activating a retrotransposon-derived Pparg2 enhancer. Through mechanistic studies, we further show that ZFP30 recruits the co-regulator KRAB-associated protein 1 (KAP1), which, surprisingly, acts as a ZFP30 co-activator in this adipogenic context. Our findings provide an understanding of both adipogenic and KZFP-KAP1 complex-mediated gene regulation, showing that the KZFP-KAP1 axis can also function in a non-repressive manner

Nutrient sensing modulates malaria parasite virulence

The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host, primarily for nutrient supply. Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signalling networks that enable cells to sense and adapt to varying environmental conditions. Canonical nutrient-sensing pathways are presumed to be absent from the causative agent of malaria, Plasmodium, thus raising the question of whether these parasites can sense and cope with fluctuations in host nutrient levels. Here we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status. KIN shares homology with SNF1/AMPKα, and yeast complementation studies suggest that it is part of a functionally conserved cellular energy-sensing pathway. Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence

Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain

Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14–20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain

Sex Differences in Social Interaction Behavior Following Social Defeat Stress in the Monogamous California Mouse (Peromyscus californicus)

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior

Prenatal Excess Glucocorticoid Exposure and Adult Affective Disorders:A Role for Serotonergic and Catecholamine Pathways

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal ‘programming’ of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety‐ and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways

"Eating addiction", rather than "food addiction", better captures addictive-like eating behavior

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved. This review has been compiled by scientists of the NeuroFAST consortium (The Integrated Neurobiology of Food Intake, Addiction and Stress; www.neurofast.eu), a research program that aims to reveal neurobiological and psychological mechanisms underlying habit-forming addictive processes related to the overconsumption of highly palatable food. The research leading to these results has received funding from the European Union's Seventh Framework programme for research, technological development and demonstration under grant agreement no. 245009.Peer reviewedPublisher PD