One-pot chemoenzymatic synthesis of trolline and tetrahydroisoquinoline analogues

Chemoenzymatic reaction cascades can provide access to chiral compounds from low-cost starting materials in one pot. Here we describe one-pot asymmetric routes to tetrahydroisoquinoline alkaloids (THIAs) using the Pictet-Spenglerase norcoclaurine synthase (NCS) followed by a cyclisation, to give alkaloids with two new heterocyclic rings. These reactions operated with a high atom economy to generate THIAs in high yields

Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines

The Pictet-Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1′-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1′-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1′-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo

Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases

The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been shown to perform stereoselective Pictet–Spengler reactions between dopamine and several carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V gives a range of (1 S)-aryl-THIQs in high yields (48–99%) and e.e.s (79–95%). A co-crystallised structure of the M97V variant with an active site reaction intermediate analogue is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of (1 S)-THIQs

Structural Evidence for the Dopamine-First Mechanism of Norcoclaurine Synthase

Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocatalyst for the formation of chiral isoquinolines. Here we present new high-resolution X-ray crystallography data describing Thalictrum flavum NCS bound to a mechanism-inspired ligand. The structure supports two key features of the NCS "dopamine-first" mechanism: the binding of dopamine catechol to Lys-122 and the position of the carbonyl substrate binding site at the active site entrance. The catalytically vital residue Glu-110 occupies a previously unobserved ligand-bound conformation that may be catalytically significant. The potential roles of inhibitory binding and alternative amino acid conformations in the mechanism have also been revealed. This work significantly advances our understanding of the NCS mechanism and will aid future efforts to engineer the substrate scope and catalytic properties of this useful biocatalyst

Цифровизация технологических процессов в растениеводстве России

Currently, the influence of program documents on digital agriculture development is rather great in our country. Within the framework of the European Association of Agricultural Mechanical Engineering, a relevant definition of agriculture 4.0 has been elaborated and introduced.Research purpose: offering general recommendations on the digitalization of agriculture in RussiaMaterials and methods. The authors make use of the normative approach: the core of digital agriculture is compared with the current state of the agricultural sector in Russia.Results and discussion. The analysis has found that digital agriculture (agriculture 4.0 and 5.0) is based on developed mechanized technologies (agriculture 2.0), precision agriculture technologies (agriculture 3.0), the use of such digital technologies and technical means as the Internet of things, artificial intelligence, and robotics. The success of introducing digital agriculture depends on the success of all the three levels of the system. However, the problem of the lack of agricultural machinery indicates insufficient development of mechanized technologies;  poor implementation of precision agriculture technologies means the lack of experience of using these technologies by the majority of farms in our country; an insufficient number of leading Russian IT companies (such as Amazon, Apple, Google, IBM, Intel, Microsoft etc.) weakens the country’s capacity in making a breakthrough in the development of the Internet of things, artificial intelligence, and robotics.Conclusions. The authors have identified the need to form scientific approaches to the digitization of technological operations used in the cultivation of agricultural crops and classified precision agriculture technologies. They have underlined that the digitization of agricultural production in Russia must be carried out along with intensified mechanization (energy saturation); also, to introduce technologies of precision agriculture and digital agriculture, it is necessary to organize state-funded centers for training farmers in the use of these technologies. Finally, it is necessary to take measures to strengthen the development of the IT sphere, as well as formulate an integral approach to the problem of digitalization.Влияние информационных технологий на развитие экономики настолько велико, что его часто именуют четвертой промышленной революцией. В рамках Европейской ассоциации сельскохозяйственного машиностроения разработали аналогичное понятие – сельское хозяйство 4.0, что означает переход от точного сельского хозяйства к цифровому.Цель исследования Разработать общие рекомендации по цифровизации сельского хозяйства в России.Материалы и методы Использовали нормативный подход: сопоставление исследуемой сущности цифрового сельского хозяйства и текущего положения дел в отрасли.Результаты и обсуждение Установили, что цифровое сельское хозяйство (сельское хозяйство 4.0 и 5.0) базируется на развитых механизированных технологиях (сельское хозяйство 2.0), технологиях точного сельского хозяйства (сельское хозяйство 3.0) с использованием таких цифровых технологий и технических средств, как интернет вещей, искусственный интеллект, роботы. Уточнили, что прогресс внедрения цифрового сельского хозяйства зависит от успешности функционирования всех трех уровней системы. Заключили, что недостаточное количество сельхозтехники свидетельствует о слабом развитии механизированных технологий; замедленное внедрение точного сельского хозяйства означает отсутствие опыта работы с данными технологиями в большинстве сельхозпредприятий. Дефицит ведущих российских компаний в сфере IT (аналогичных Amazon, Apple, Google, IBM, Intel, Microsoft и другим) ослабляет потенциальные возможности прорыва нашей страны в создании и развитии интернета вещей, искусственного интеллекта, роботов.Выводы Выявили необходимость формирования научных подходов цифровизации технологических операций возделывания сельскохозяйственных культур. Представили классификацию технологий точного сельского хозяйства. Подчеркнули, что цифровизацию аграрного производства необходимо проводить на фоне роста механизации (энергонасыщенности); для внедрения технологий точного и цифрового сельского хозяйства следует организовать финансируемые государством центры обучения фермеров применению данных технологий. Требуется разработать меры по усилению развития сферы IT, сформировать интегральный подход к проблеме цифровизации

A Clustering Approach for Autism based Autistic Trait Classification

Machine learning (ML) techniques can be utilized by physicians, clinicians, as well as other users, to discover Autism Spectrum Disorder (ASD) symptoms based on historical cases and controls to enhance autism screening efficiency and accuracy. The aim of this study is to improve the performance of detecting ASD traits by reducing data dimensionality and eliminating redundancy in the autism dataset. To achieve this, a new semi-supervised ML framework approach called Clustering-based Autistic Trait Classification (CATC) is proposed that uses a clustering technique and validation of the classifiers is done by classification techniques. The proposed method identifies potential autism cases based on their similarity traits as opposed to a scoring function used by many ASD screening tools. Empirical results on different datasets involving children, adolescents, and adults were verified and compared to other common machine learning classification techniques. The results showed that CATC offers classifiers with higher predictive accuracy, sensitivity, and specificity rates than those of other intelligent classification approaches such as Artificial Neural Network (ANN), Random Forest, and Random Trees, and Rule Induction. These classifiers are useful as they are exploited by diagnosticians and other stakeholders involved in ASD screening

Enzymatic and Chemoenzymatic Three-Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines

Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step-efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3-hydroxybenzaldehyde and pyruvate), and involves a carboligation step, a subsequent transamination, and finally a Pictet–Spengler reaction with a carbonyl cosubstrate. Appropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)-metaraminol. Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo- and biocatalysts for optimal results

The ILE462VAL polymorphism of the cytochrome P450 CYP1A1 gene among Tundra Nenets in Yamalo-Nenets Autonomous Okrug, Nganasans in the Taimyr Peninsula and Russians in Siberia

The work concerns a polymorphism of the cytochrome Р450 CYP1A1 gene, the CYP1A1*2C variant (Ile462Val, rs1048943). This substitution results in a two- fold increase in enzyme activity, which leads to accumulation of active intermediates and increases the risk of DNA mutations and chemically induced carcinogenesis. It has been demonstrated that the 462Val allele may be a risk factor in some oncological and other multifactorial diseases. This study was performed on Tundra Nenets in Yamalo-Nenets Autonomous Okrug (N = 271), Nganasans in the Taimyr Peninsula (N = 186) and Russians in North Siberia (N = 267). The cohorts did not include descendants of mixed marriages. Genotyping was performed using Real-Time PCR with competitive TaqMan allele-specific probes. The frequency of the 462Val allele in the Tundra Nenets cohort was 23.8 % (95 % CI 20.4–27.6 %), which corresponds to the frequency range found in East Asian populations and is higher than the values typical of European populations. The 462Val allele frequency in the Russian cohort was 5.8 % (95 % CI 4.1–8.1 %), which corresponds to the frequency range of European populations. The 462Val allele frequency in the Nganasans cohort was 39.0 % (95 % CI 34.2–44.0 %), which is higher than the frequencies found in European, Asian and African populations. Frequencies of the  462Val variant close to that in Nganasans have been observed in Greenland Inuits, native Americans as a whole and the Southern Chinese. A high-frequency occurrence of the 462Val allele among Tundra Nenets and Nganasans may be indicative of a populationwide risk of diseases influenced by this genetic polymorphism, especially when traditional mainstays are gone or previously unknown ecotoxicants appear in the areas

Технические системы цифрового контроля качества обработки почвы

The production of tillage equipment is focused on the growing use of soil-protective and resource-saving farming and the use of the precision agriculture in tillage principles. The differentiated tillage concept arose, and occupied an intermediate position between traditional and anti-erosion (shallow) types of tillage. The authors conducted an analysis of technical systems for tillage quality digital control taking into account the indicated trends. They indicated that there was a certain inconsistency in the soil cultivation systems names in the scientific literature. (Research purpose) To provide an analytical overview of the tillage digital quality control technical systems. (Materials and methods) The authors used manufacturers’ brochures of tillage equipment, patents and scientific works. (Results and discussion) The authors examined the commercial offers existing in the world market in the differentiated tillage and digital quality control systems spheres. They presented an analysis of similar solutions available in the world scientific literature. They studied the issues of controlling the angle of disks’ attack, the depth of tillage, the soil surface ridging, the average size of the soil lumps, the amount of crop residues, determining the soil properties in a non-contact way. They identified the fragmentation of scientific and industrial developments in the sphere of tillage quality control. They suggested combining them into one system to automate the process of differentiated tillage. (Conclusions) It was shown that tillage equipment is becoming more adaptable in terms of meeting the specific requirements of the farmer for tillage. The authors identified promising areas for the future development of tillage machines: the inclusion of different subsystems of tillage quality digital control in the same system and the automation of differentiated tillage.Производство почвообрабатывающей техники ориентировано на растущее применение почвозащитного и ресурсосберегающего земледелия и использование принципов точного сельского хозяйства в почвообработке. Возникло понятие дифференцированной обработки почвы, которая занимает промежуточное положение между традиционной и противоэрозийной (неглубокой) обработками. Провели анализ технических систем цифрового контроля качества обработки почвы с учетом указанных тенденций. Показали, что в научной литературе существует определенная несогласованность в наименованиях систем обработки почвы. (Цель исследования) Представить аналитический обзор технических систем цифрового контроля качества обработки почвы. (Материалы и методы) Использовали проспекты компаний-производителей почвообрабатывающей техники, патенты и научные работы. (Результаты и обсуждение) Рассмотрели существующие на мировом рынке коммерческие предложения в сфере дифференцированной обработки почвы и системы цифрового контроля качества. Представили анализ аналогичных решений, имеющихся в мировой научной литературе. Изучили вопросы контроля угла атаки дисков, глубины обработки почвы, гребнистости поверхности почвы, средних размеров комков почвы, количества пожнивных остатков, определения свойств почвы бесконтактным способом. Выявили разрозненность научных и производственных разработок в сфере контроля качества обработки почвы. Предложили объединить их в одну систему, чтобы автоматизировать процесс дифференцированной почвообработки. (Выводы) Показали, что почвообрабатывающая техника становится все более адаптируемой в плане выполнения специфических требований фермера к обработке почвы. Определили перспективные направления для будущего развития почвообрабатывающих машин: включение в одну систему разных подсистем цифрового контроля качества обработки почвы и автоматизация дифференцированной почвообработки