Ergo, SMIRK is safe: a safety case for a machine learning component in a pedestrian automatic emergency brake system.

Integration of machine learning (ML) components in critical applications introduces novel challenges for software certification and verification. New safety standards and technical guidelines are under development to support the safety of ML-based systems, e.g., ISO 21448 SOTIF for the automotive domain and the Assurance of Machine Learning for use in Autonomous Systems (AMLAS) framework. SOTIF and AMLAS provide high-level guidance but the details must be chiseled out for each specific case. We initiated a research project with the goal to demonstrate a complete safety case for an ML component in an open automotive system. This paper reports results from an industry-academia collaboration on safety assurance of SMIRK, an ML-based pedestrian automatic emergency braking demonstrator running in an industry-grade simulator. We demonstrate an application of AMLAS on SMIRK for a minimalistic operational design domain, i.e., we share a complete safety case for its integrated ML-based component. Finally, we report lessons learned and provide both SMIRK and the safety case under an open-source license for the research community to reuse.

Molecular mechanisms of ethanol biotransformation: enzymes of oxidative and nonoxidative metabolic pathways in human.

Ethanol, as a small-molecule organic compound exhibiting both hydrophilic and lipophilic properties, quickly pass through the biological barriers. Over 95% of absorbed ethanol undergoes biotransformation, the remaining amount is excreted unchanged, mainly with urine and exhaled air.The main route of ethyl alcohol metabolism is its oxidation to acetaldehyde, which is converted into acetic acid with the participation of cytosolic NAD+ - dependent alcohol (ADH) and aldehyde (ALDH) dehydrogenases. Oxidative biotransformation pathways of ethanol also include reactions catalyzed by the microsomal ethanol oxidizing system (MEOS), peroxisomal catalase and aldehyde (AOX) and xanthine (XOR) oxidases. The resulting acetic acid can be activated to acetyl-CoA by the acetyl-CoA synthetase (ACS).It is also possible, to a much smaller extent, non-oxidative routes of ethanol biotransformation including its esterification with fatty acids by ethyl fatty acid synthase (FAEES), re-esterification of phospholipids, especially phosphatidylcholines, with phospholipase D (PLD), coupling with sulfuric acid by alcohol sulfotransferase (SULT) and with glucuronic acid using UDP-glucuronyl transferase (UGT, syn. UDPGT).The intestinal microbiome plays a significant role in the ethanol biotransformation and in the initiation and progression of liver diseases stimulated by ethanol and its metabolite - acetaldehyde, or by lipopolysaccharide and ROS.

Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas.

A series of 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Compound 6 showed significant inhibition against Gram-positive cocci and had inhibitory effect on the S. aureus topoisomerase IV decatenation activity and S. aureus DNA gyrase supercoiling activity. Compounds were tested for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses, including HIV-1 and other several important human pathogens. Interestingly, derivative 8 showed potent activity against HIV-1 wild type and variants bearing clinically relevant mutations. Newly synthesized tryptamine derivatives showed also a wide spectrum activity, proving to be active against positive- and negative-sense RNA viruses.

Synthesis and Biological Activities of Ethyl 2-(2-pyridylacetate) Derivatives Containing Thiourea, 1,2,4-triazole, Thiadiazole and Oxadiazole Moieties.

Thirty six novel heterocyclic derivatives of ethyl 2-(2-pyridylacetate) were efficiently synthesized. The new compounds involve the linkage of a 2-pyridyl ring with thiosemicarbazide (compounds 1-7), 1,2,4-triazole (compounds 1a-7a), 1,3,4-thiadiazole (compounds 1b-7b), and 1,3,4-oxadiazole (compounds 1f-7f) moieties. The last group of compounds 1e-7e involves the connection of a 2-pyridyl ring with 1,2,4-triazole and thiourea. ¹H-NMR, 13C-NMR and MS methods were used to confirm the structures of the obtained derivatives. The molecular structures of 3, 3b, 7a and 7f were further confirmed by X-ray crystallography. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. In addition, the obtained compounds were tested for cytotoxicity and antiviral activity against HIV-1.

Effects of Age-of-Acquisition on Proficiency in Polish Sign Language: Insights to the Critical Period Hypothesis.

This study focuses on the relationship between the age of acquisition of Polish Sign Language (PJM) by deaf individuals and their receptive language skills at the phonological, morphological and syntactic levels. Sixty Deaf signers of PJM were recruited into three equal groups (n = 20): (1) a group exposed to PJM from birth from their deaf parents; (2) a group of childhood learners of PJM, who reported learning PJM between 4 and 8 years; (3) a group of adolescent learners of PJM, who reported learning PJM between 9 and 13 years. The PJM Perception and Comprehension Test was used to assess three aspects of language processing: phonological, morphological and syntactic. Participants were asked to decide whether a series of signs and sentences were acceptable in PJM. Results show that the age of PJM acquisition has a significant impact on performance on this task. The earlier deaf people acquire PJM, the more likely they were to distinguish signs and sentences considered permissible and impermissible in PJM by native signers. Native signers had significantly greater accuracy on the phonological, morphological, and syntactic items than either the Childhood or the Adolescent signers. Further, the Childhood signers had significantly greater accuracy than the Adolescent signers on all three parts of the test. Comparing performance on specific structures targeted within each part of the test revealed that multi-channel signs and negative suffixes posed the greatest challenge for Adolescent signers relative to the Native signers. The above results provide evidence from a less-commonly studied signed language that the age of onset of first language acquisition affects ultimate outcomes in language acquisition across all levels of grammatical structure. In addition, this research corroborates prior studies demonstrating that the critical period is independent of language modality. Contrary to a common public health assumption that early exposure to language is less vital to signed than to spoken language development, the results of this study demonstrate that early exposure to a signed language promotes sensitivity to phonological, morphological and syntactic patterns in language.

Cytochrome P450 polymorphism--molecular, metabolic, and pharmacogenetic aspects. IV. Application of long polymerase chain reaction for identification of CYP2D6 gene duplication.

In the human organism 58 cytochrome P450 (CYP) isoenzymes belonging to 18 families have been described. Isoenzyme CYP2D6 is an important human xenobiotic-metabolizing enzyme. CYP2D6 biotransforms a significant number of drugs, widely used in clinical practice, such as antidepressants, neuroleptics, antiarrhythmics, analgesics, antiemetics and anticancer agents. The occurrence of polymorphic variants of the enzyme results in different metabolic capacity ranging from poor to ultrarapid. Ultrarapid metabolizer phenotype explains lack of response and decreased levels of drugs which are metabolized by CYP2D6. Therefore, the identification of ultrarapid metabolizers as potential non-compliance cases requiring dose adjustment, has serious clinical importance. In this study we evaluate a long-PCR procedure for detecting CYP2D6 gene duplication.

Cytochrome P450 polymorphism--molecular, metabolic and pharmacogenetic aspects. I. Mechanisms of activity of cytochrome P450 monooxygenases.

Cytochrome P450, initially perceived as a type of cell pigment, was soon identified as a hemoprotein with an enzymatic activity characteristic for monooxygenases with an affinity for differentiated endo- or exogenous substrates, including drugs. So far in the human organism 58 CYP isoenzymes belonging to 18 families have been described. Most from the CYP monooxygenases superfamily turned out to be integral elements of hepatocytic reticular monooxygenase complexes which also contain NADPH-dependent cytochrome P450 reductase (CPR). Later investigations indicated the possibility of the participation in electron transport for reticular CYP isoenzymes, alternative NADH-dependent reticular system composed of cytochrome b5 reductase (CBR) and cytochrome b5. The demonstration of the activity of some CYP superfamily isoenzymes not only in hepatocytes but also in many other cells of the human organism, numerous plant and animal tissues and even in cells of fungi, protists and prokaryotes has contributed to the significantly increased understanding of the role of CYP in biological systems. In addition, some CYP isoenzymes were found to be characteristic for the inner mitochondrial membrane monooxygenase complexes which contain NADPH-dependent adrenodoxin reductase (AR) and adrenodoxin (Ad), which is identical with ferredoxin-1 (Fd-1) and hepatoredoxin (Hd).

Cytochrome P450 polymorphism--molecular, metabolic, and pharmacogenetic aspects. II. Participation of CYP isoenzymes in the metabolism of endogenous substances and drugs.

In the human organism 58 cytochrome P450 (CYP) isoenzymes belonging to 18 families have been described. These hemoproteins, with enzymatic activity characteristic for monooxygenases, show a broad affinity for chemically differentiated endo- or exogenous compounds, including drugs. CYP isoenzymes participate in metabolic pathways important for proper physiological functioning of the human organism, i.e.: cholesterol, bile acid and oxysterol biosynthesis; metabolism of fatty acids, prostaglandins, prostacyclins, leukotrienes, steroid hormones, ketone bodies, vitamines A and D. CYP isoenzymes participate in the metabolism of over 80% of drugs and other xenobiotic substances which can be present in the human organism. Differences in molecular structure and kinetics of conformational changes of particular isoenzymes of CYP superfamily monooxygenases on the one hand determine their affinity direction for chemically differentiated groups of compounds susceptible to oxidation, on the other hand determine the mechanism and position of the oxidative change of their molecules. Drugs and their metabolites and other endogenous and xenobiotic compounds may be acting not only as substrates, but also as competitive and non- competitive inhibitors, suicide inhibitors and inducers of CYP isoenzymes as well as repressors of CYP genes. These relationships are the metabolic basis of numerous multidirectional interactions between drugs, drug metabolites, food components, stimulants, environmental toxins and metabolites of these xenobiotics.

Cytochrome P450 polymorphism--molecular, metabolic, and pharmacogenetic aspects. III. Influence of CYP genetic polymorphism on population differentiation of drug metabolism phenotype.

In the human genome 684 alleles of CYP genes, and additionally 30 complete CYP pseudogenes, have been identified. So far 388 isoforms of 58 human CYP isoenzymes have been described at the phenotypic level. The molecular forms of many CYP isoenzymes responsible for drug biotransformation show a differentiated degree of specific catalytic activity - from increased, through normal and decreased to various extent, to trace or even absent. Depending on the homo- or heterozygous genotype, a broad palette of phenotypic forms may be present, differentiated in respect to biotransformation dynamics of specific drugs. The progress of molecular biology with particular consideration of genotyping and DNA microarray technologies has created a basis for the dynamic progress of pharmacogenetics, allowing fast and sensitive determination of the individual pharmacogenetic profile, encompassing a large set of CYP alleles extended by allelic variants of genes encoding other enzymes participating in drug metabolism. The possibility to evaluate the pharmacogenetic profile of patients together with the increasing knowledge about the mechanisms of inhibition, repression and also induction of enzymes participating in biotransformation of xenobiotics and endogenous compounds create increasing possibilities of elaborating optimal individualized pharmacotherapeutic strategies.

Alpha-Tocopherol Serum Levels Are Increased in Caucasian Women with Uterine Fibroids: A Pilot Study.

Uterine fibroids (UFs) are benign tumors of the reproductive tract, arising from smooth muscle cells of the uterus. Steroid hormones, estrogen, and progesterone are considered to be the most important links in the pathophysiology of UFs. Alpha-tocopherol (AT) is the most active form of vitamin E. What is important as far as UFs are concerned is that ATs contain structural determinants, which makes them possible ligands for estrogen receptors (ERs). We present a retrospective cohort study performed in a university teaching hospital. We included a total of 162 patients divided into 2 groups: with UFs and controls. The effects of age, body mass index (BMI), positive medical history, parity, and AT serum concentrations on the risk for the development of UFs were investigated. Mean AT serum concentrations were 11.66 ± 4.97 µg/ml and 7.83 ± 3.13 µg/ml (medians 10.56 µg/ml and 7.42 µg/ml) in patients with UFs confirmed on ultrasound and controls, respectively. The presented difference was statistically significant. Higher BMI, positive family history, and low parity were found to be major risk factors for UFs. In our study, we confirmed that elevated serum AT concentration might be an important risk factor for UFs in Caucasian women. Further research in this area is necessary.

RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy.

Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors' pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.

Constraints on Negative Prefixation in Polish Sign Language.

The aim of this article is to describe a negative prefix, NEG-, in Polish Sign Language (PJM) which appears to be indigenous to the language. This is of interest given the relative rarity of prefixes in sign languages. Prefixed PJM signs were analyzed on the basis of both a corpus of texts signed by 15 deaf PJM users who are either native or near-native signers, and material including a specified range of prefixed signs as demonstrated by native signers in dictionary form (i.e. signs produced in isolation, not as part of phrases or sentences). In order to define the morphological rules behind prefixation on both the phonological and morphological levels, native PJM users were consulted for their expertise. The research results can enrich models for describing processes of grammaticalization in the context of the visual-gestural modality that forms the basis for sign language structure.