A Pipeline for Classifying Deleterious Coding Mutations in Agricultural Plants

The impact of deleterious variation on both plant fitness and crop productivity is not completely understood and is a hot topic of debates. The deleterious mutations in plants have been solely predicted using sequence conservation methods rather than function-based classifiers due to lack of well-annotated mutational datasets in these organisms. Here, we developed a machine learning classifier based on a dataset of deleterious and neutral mutations in Arabidopsis thaliana by extracting 18 informative features that discriminate deleterious mutations from neutral, including 9 novel features not used in previous studies. We examined linear SVM, Gaussian SVM, and Random Forest classifiers, with the latter performing best. Random Forest classifiers exhibited a markedly higher accuracy than the popular PolyPhen-2 tool in the Arabidopsis dataset. Additionally, we tested whether the Random Forest, trained on the Arabidopsis dataset, accurately predicts deleterious mutations in Orýza sativa and Pisum sativum and observed satisfactory levels of performance accuracy (87% and 93%, respectively) higher than obtained by the PolyPhen-2. Application of Transfer learning in classifiers did not improve their performance. To additionally test the performance of the Random Forest classifier across different angiosperm species, we applied it to annotate deleterious mutations in Cicer arietinum and validated them using population frequency data. Overall, we devised a classifier with the potential to improve the annotation of putative functional mutations in QTL and GWAS hit regions, as well as for the evolutionary analysis of proliferation of deleterious mutations during plant domestication; thus optimizing breeding improvement and development of new cultivars

Ацеклофенак в лечении патологии опорно-двигательного аппарата

The paper highlights data on the mechanisms of action and efficacy of aceclofenac in chronic inflammatory diseases of the joint and spine (rheumatoid arthritis, spondyloarthritis) and osteoarthritis (OA). It shows the comparable efficacy of aceclofenac and nonselective nonsteroidal anti-inflammatory drugs in different rheumatic diseases. Randomized controlled trials and meta-analyses have revealed the high gastrointestinal safety of aceclofenac, which is comparable with that of celecoxib, including the low risk of gastrointestinal bleeding. Since aceclofenac has no negative effect on the articular cartilage and has a good tolerability, it may be given to persons of any age, including long-term use, which does not affect the safety of treatment.В статье освещены данные о механизмах действия и эффективности ацеклофенака при хронических воспалительных заболеваниях суставов и позвоночника (ревматоидном артрите, спондилоартритах) и остеоартрите. Показана сопоставимая эффективность ацеклофенака и неселективных нестероидных противовоспалительных препаратов при различных ревматических заболеваниях. На основании результатов рандомизированных контролируемых исследований и метаанализов отмечена высокая безопасность ацеклофенака в отношении желудочно-кишечного тракта, сопоставимая с таковой целекоксиба, в том числе низкий риск развития желудочно-кишечного кровотечения. Поскольку ацеклофенак не оказывает негативного влияния на суставной хрящ и отличается хорошей переносимостью, его можно применять у лиц любого возраста, в том числе длительно, что не отражается на безопасности лечения

Возможности применения лефлуномидапри ревматических заболеваниях

I.M. Sechenov First Moscow State Medical University The given data available in the literature offer new possibilities for the use of leflunomide in rheumatology. The conducted trials enable leflunomide to be considered as a promising agent in the treatment of inflammatory diseases of the joint and vertebral column. The encouraging results of preliminary studies of the efficacy of leflunomide in Crohn's disease, Wegener's granulomatosis, and systemic lupus erythematosus need to be confirmed in large-scale randomized controlled studies.Представленные данные литературы открывают новые возможности применения лефлуномида в ревматологии. Проведенные испытания позволяют рассматривать лефлуномид как перспективный препарат при воспалительных заболеваниях суставов и позвоночника. Обнадеживающие результаты предварительных исследований эффективности лефлуномида при болезни Крона, гранулематозе Вегенера и системной красной волчанке требуют подтверждения в масштабных рандомизированных контролируемых исследованиях

Topical diclofenac for the treatment of the musculoskeletal diseases

Treatment of diseases of the musculoskeletal system to date remains not only a serious medical, but also socio-economic problem. Chronic diseases of the joints and spine are one of the most common causes of disability in patients. The main clinical manifestations of most diseases of the musculoskeletal system are pain and inflammation, which requires adequate antiinflammatory therapy. The data on various mechanisms of action of non-steroidal anti-inflammatory drug (NSAID) diclofenac (Voltaren), as well as the results of clinical studies and meta-analyses confirming its effectiveness and good tolerability are presented. The data of experimental and clinical studies of the efficacy and safety of local forms of diclofenac-Voltaren Emulgel (diclofenac-diethylamine) –are presented. Provides information about the form of the Voltaren Emulgel 2% for 12 hours. It is shown that a wide range of analgesic and anti-inflammatory effects of diclofenac (Voltaren), and good tolerance can be used as symptomatic therapy in the treatment of diseases of the musculoskeletal system

Aceclofenac in the treatment of diseases of the locomotor apparatus

The paper highlights data on the mechanisms of action and efficacy of aceclofenac in chronic inflammatory diseases of the joint and spine (rheumatoid arthritis, spondyloarthritis) and osteoarthritis (OA). It shows the comparable efficacy of aceclofenac and nonselective nonsteroidal anti-inflammatory drugs in different rheumatic diseases. Randomized controlled trials and meta-analyses have revealed the high gastrointestinal safety of aceclofenac, which is comparable with that of celecoxib, including the low risk of gastrointestinal bleeding. Since aceclofenac has no negative effect on the articular cartilage and has a good tolerability, it may be given to persons of any age, including long-term use, which does not affect the safety of treatment

Local forms of diclofenac in the treatment of acute and chronic pain

According to modern ideas, pain is a multidisciplinary problem with serious medical and socio-economic importance. The most common pain occurs in various structures of the musculoskeletal system. It is noted that the universal mechanism of acute and chronic pain is inflammation, which requires therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Data on the effectiveness and good tolerability of local NSAIDs are presented. The latest recommendations of the international Committee ESCEO 2019 on the management of patients with osteoarthritis (OA), which confirms the effectiveness and safety of local forms of NSAIDs, in connection with which, ESCEO recommends their use in elderly patients, in patients with comorbid conditions and at high risk of adverse reactions. It is also envisaged to use these drugs for the treatment of OA before the appointment of systemic NSAIDs. The results of randomized clinical trials (RCTS) and meta-analyses confirming clinical efficacy and safety in the treatment of acute and chronic pain by one of the representatives of local NSAIDs-diclofenac sodium gel are presented. Diclofenac sodium gel has been shown to be more effective than placebo in the treatment of acute and chronic pain. Good tolerability of the drug was observed in patients in different age groups, including patients older than 65 years, and in patients with comorbid conditions. The results obtained indicate the effectiveness and good tolerability of diclofenac sodium gel, including long-term, and allow the drug to be widely used as symptomatic therapy for the treatment of acute and chronic pain, including in elderly patients and patients with comorbid conditions

POSSIBILITIES OF USING LEFLUNOMIDE IN RHEUMATIC DISEASES

I.M. Sechenov First Moscow State Medical University The given data available in the literature offer new possibilities for the use of leflunomide in rheumatology. The conducted trials enable leflunomide to be considered as a promising agent in the treatment of inflammatory diseases of the joint and vertebral column. The encouraging results of preliminary studies of the efficacy of leflunomide in Crohn's disease, Wegener's granulomatosis, and systemic lupus erythematosus need to be confirmed in large-scale randomized controlled studies

Rheumatoid arthritis burden: medical and social problems

Ревматоидный артрит (РА) – системное воспалительное заболевание с преимущественным поражением суставов, обычно полиартикулярное. Заболевание может дебютировать с постепенно- го нарастания активности воспаления или остро, может иметь неуклонно прогрессирующее течение или протекать с периодическими обострениями, следующими за улучшением. Хронический характер течения РА обусловливает нарушение функциональных способностей больного, что в тяжелых случаях может привести пациента к необходимости передвижения на коляске или даже к невозможности покинуть постель. Несмотря на успехи терапии, в целом прогноз РА остается серьезным. В первую очередь это касается функциональной недостаточности (ФН) больных и снижению (утрате) их трудоспособности. По заключению T. Pincus и L.F Callahan [1] через 10 лет от начала болезни инвалидизируется 60% пациентов. В Швеции, по данным E.Fex и соавт.[2], через 8 лет от начала болезни не могли работать 37% больных. В Москве, по материалам О.М. Фоломеевой и соавт. [3], в 1999 г. стойкая нетрудоспособность при РА наступала в среднем через 8 лет от начала болезни, средний возраст выхода на инвалидность составил 48,5 года. РА ассоциируется также с повышением летальности, чаще всего по причине кардиоваскулярных заболеваний как следствия хронического воспаления, повышения риска развития лимфом, коррелирующим с тяжестью заболевания, а не с видом проводимой терапии, кроме того, осложнения терапии также могут влиять на продолжительность жизни больных. В настоящее время стало очевидным, что рано начатое лечение базисными противовоспалительными препаратами (БПВП) способно существенно улучшить функциональный и жизненный прогноз при РА. Однако проблема ранней диагностики РА до сих пор не решена, поскольку диагностические критерии РА не соответствуют цели как можно более ранней дифференциации раннего РА от других форм артритов [4] (рис.1). Это приводит к задержке с назначением БПВП и ухудшает функциональный прогноз при РА