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Abstract Proteasomes are highly conserved multienzyme complexes responsible for proteolytic degradation of the short-lived, regulatory, misfolded, and damaged proteins. They play an important role in the processes of brain plasticity, and decrease in their function is accompanied by the development of neurodegenerative pathology. Studies performed in different laboratories both on cultured mammalian and human cells and on preparations of the rat and rabbit brain cortex revealed a large number of proteasome-associated proteins. Since the identified proteins belong to certain metabolic pathways, multiple enrichment of the proteasome fraction with these proteins indicates their important role in proteasome functioning. Extrapolation of the experimental data, obtained on various biological objects, to the human brain suggests that the proteasome-associated proteins account for at least 28% of the human brain proteome. The proteasome interactome of the brain contains a large number of proteins involved in the assembly of these supramolecular complexes, regulation of their functioning, and intracellular localization, which could be changed under different conditions (for example, during oxidative stress) or in different phases of the cell cycle. In the context of molecular functions of the Gene Ontology (GO) Pathways, the proteins of the proteasome interactome mediate cross-talk between components of more than 30 metabolic pathways annotated in terms of GO. The main result of these interactions is binding of adenine and guanine nucleotides, crucial for realization of the nucleotide-dependent functions of the 26S and 20S proteasomes. Since the development of neurodegenerative pathology is often associated with regioselective decrease in the functional activity of proteasomes, a positive therapeutic effect would be obviously provided by the factors increasing proteasomal activity. In any case, pharmacological regulation of the brain proteasomes seems to be realized through the changes in composition and/or activity of the proteins associated with proteasomes (deubiquitinase, PKA, CaMKIIα, etc.).

The neurotoxins rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (МPTP) are used for modeling Parkinson's disease in animals (PD). They induce the mitochondrial respiratory chain dysfunction, which leads to the dopaminergic (DA) neuron degeneration. The advantage of the rotenone model consists in ability of rotenone to cause neurodegeneration showing symptoms and molecular biological characteristics similar to those of PD. Isatin (indoldione-2,3) is an endogenous regulator found in tissues and biological fluids of humans and animals. It exhibits a broad range of biological activity mediated by numerous isatin-binding proteins. In this work we have investigated behavioral reactions and profiles of brain isatin-binding proteins of rats with Parkinson's syndrome (PS) in comparison with the corresponding parameters of MPTP-induced Parkinsonism in mice. Systemic injection of rotenone caused severe PS comparable with the effect of MPTP injection. It was accompanied by significant body weight loss, death, oligokinesia, muscular rigidity, and postural instability of animals. In spite of the same pathogenic basis of PS caused by rotenone and MPTP, the molecular mechanisms of their action differ. In the case of rotenone-induced PS, the pool of isatin-binding proteins common of the control rats and the rats with PS (146) significantly exceeded the pool of the common proteins of control mice and mice with PS induced by MPTP, whether right after neurotoxin injection (27), or (all the more) in a week after the MPTP injection (14). The comparison of isatin-binding proteins specific of the animals with MPTP-induced PS and with the rotenone-induced PS (as compared with the control animals) revealed total absence of proteins common of these two models of PD. It is to be noted that both neurotoxins particularly affected the proteins participating in the signal transmission and enzyme activity regulation. The changes of the profile of isatin-binding proteins in response to the injection of rotenone suggest that the neuroprotector isatin could also influence positively in the case of the rotenone model of PD.

Background Heterogeneity exists in reported outcomes and outcome measurement instruments [OMI] from observational studies. A core outcome set [COS] for observational and real-world evidence [RWE] in inflammatory bowel disease [IBD] will facilitate pooling large datasets. This systematic review describes and classifies clinical and patient-reported outcomes, for COS development. Methods The systematic review of MEDLINE, EMBASE, and CINAHL databases identified observational studies published between 2000 and 2021 using the population exposure outcome [PEO] framework. Studies meeting eligibility criteria were included. After titles and abstracts screening, full-text articles were extracted by two independent reviewers. Primary and secondary outcomes with corresponding OMI were extracted and categorised in accordance with OMERACT Filter 2.1 framework. The frequency of outcomes and OMIs are described. Results From 5854 studies, 315 were included: 129 [41%] Crohn’s disease [CD], 60 [19%] ulcerative colitis [UC], and 126 [40%] inflammatory bowel disease [IBD] studies with 600 552 participants. Totals of 1632 outcomes and 1929 OMI were extracted mainly from medical therapy [181; 72%], surgical [34; 11%], and endoscopic [6; 2%] studies. Clinical and medical therapy-related safety were frequent outcome domains recorded in 194 and 100 studies. Medical therapy-related adverse events [n = 74] and need for surgery [n = 71] were the commonest outcomes. The most frequently reported OMI were patient or event numbers [n = 914], Harvey-Bradshaw Index [n = 45], and Montreal classification [n = 42]. Conclusions There is substantial variability in outcomes reporting and OMI types. Categorised outcomes and OMI from this review will inform a Delphi consensus on a COS for future RWE in IBD. Data collection standardisation may enhance the quality of RWE applied to decision-making.

Background and Aims The utility of real-world data is dependent on the quality and homogeneity of reporting. We aimed to develop a core outcome set for real-world studies in adult patients with inflammatory bowel disease [IBD]. Methods Candidate outcomes and outcome measures were identified and categorised in a systematic review. An international panel including patients, dietitians, epidemiologists, gastroenterologists, nurses, pathologists, radiologists, and surgeons participated in a modified Delphi consensus process. A consensus meeting was held to ratify the final core outcome set. Results A total of 26 panellists from 13 countries participated in the consensus process. A total of 271 items [130 outcomes, 141 outcome measures] in nine study domains were included in the first-round survey. Panellists agreed that real-world studies on disease activity should report clinical, endoscopic, and biomarker disease activity. A disease-specific clinical index [Harvey–Bradshaw Index, Partial Mayo Score, Simple Clinical Colitis Activity Index] should be used, rather than physician global assessment. In ulcerative colitis [UC], either the UC Endoscopic Index of Severity or the Mayo Endoscopic Score can be used, but there was no consensus on an endoscopic index for Crohn’s disease, nor was there consensus on the use of the presence of ulcers. There was consensus on using faecal calprotectin and C-reactive protein. There was no consensus on the use of histology in real-world studies. Conclusions A core outcome set for real-world studies in IBD has been developed based on international multidisciplinary consensus. Its adoption will facilitate synthesis in the generation of real-world evidence.

Objective. To characterize the fungal pathogenic complex of the root zone of cultivated soybean plants grown on sod-medium podzolic soil, to identify the most harmful pathogens of root diseases. Methods. Phytopathogenic micromycetes were isolated from affected soybean plants. For this, segments of plant material (roots, seeds, leaf blade) (3–5 mm) were thoroughly washed for 15 min under running water, their surface was sterilized with 96 % ethyl alcohol for 1 min, washed twice with sterile water and placed in Petri dishes on 4 % wort agar with 250 ppm streptomycin and placed in a thermostat (26 °C). At Day 4, isolates were obtained on wort agar and grown for 14 days at 26 °C. Confirmation of the pathogenicity of the selected isolates was carried out in a sterile vegetative experiment on Strive variety soybean plants. To do this, 1 dm3 glasses were filled with a substrate containing 50 g of consolidated vermiculite and 200 g of water and sterilized for 1 hour at 1.5 atm. Healthy soybean seeds were pre-selected, thoroughly washed under running water and sprouted in a humid chamber for 2 days so that the seedlings had a root length of 1–2 cm and carefully washed in sterile tap water. Ten soybean sprouts were placed in each glass and 3 mL of an aqueous spore-mycelial mixture of selected isolates (experiment) or 3 mL of sterile water (control) were added. At Day 14, the plants were removed, thoroughly and carefully washed, the number of affected plants was counted (% prevalence) and the dry matter of roots and shoots was measured. Results. A total of 16 strains of fungi, the causative agents of root diseases, were isolated in pure culture from roots, seeds and leaf plates of affected soybean plants. The isolated pathogens belonged to the genera Fusarium Link:Fr, Alternaria (Fr.) Keissler, Verticillium Nees. The phytopathogenic effect of fungi of the genus Verticillium isolated from the washed roots of soybean plants was insignificant. Fusarium was represented by F. oxysporum, F. solani, F. moniliforme var. lactis, F. gibbosum, among which F. gibbosum exerted the greatest phytopathogenic effect. The isolated F. gibbosum C4 affects seedlings first. The roots of the affected plants develop poorly, the plants are easily pulled out and lag behind in growth and development. Among the selected Alternaria strains, A. consortiale C8 which was characterized by rapid growth, turned out to be the most harmful. A. consortiale C8 first affects seedlings, then appears on other parts of plants: roots, stems, leaves. On soybean leaves, the first sign of alternaria leaf spots is dark brown spots of various sizes and shapes, the leaves wither and die. Affected plants lag behind in growth. Infection of soybean plants by phytopathogenic fungi leads to a decrease in the content of dry matter both in the roots and in the aboveground mass of the plants. In the case of F. gibbosum C4 infection, the content of dry matter in the roots decreased by 27 %, in the aboveground mass of plants — by 19 %. Infection with A. consortiale C8 led to a decrease in dry matter by 29 % and 27 %, respectively. Conclusion. The fungal pathogenic complex in soybean crops consisted of representatives of the Objective. To characterize the fungal pathogenic complex of the root zone of cultivated soybean plants grown on sod-medium podzolic soil, to identify the most harmful pathogens of root diseases. Methods. Phytopathogenic micromycetes were isolated from affected soybean plants. For this, segments of plant material (roots, seeds, leaf blade) (3–5 mm) were thoroughly washed for 15 min under running water, their surface was sterilized with 96 % ethyl alcohol for 1 min, washed twice with sterile water and placed in Petri dishes on 4 % wort agar with 250 ppm streptomycin and placed in a thermostat (26 °C). At Day 4, isolates were obtained on wort agar and grown for 14 days at 26 °C. Confirmation of the pathogenicity of the selected isolates was carried out in a sterile vegetative experiment on Strive variety soybean plants. To do this, 1 dm3 glasses were filled with a substrate containing 50 g of consolidated vermiculite and 200 g of water and sterilized for 1 hour at 1.5 atm. Healthy soybean seeds were pre-selected, thoroughly washed under running water and sprouted in a humid chamber for 2 days so that the seedlings had a root length of 1–2 cm and carefully washed in sterile tap water. Ten soybean sprouts were placed in each glass and 3 mL of an aqueous spore-mycelial mixture of selected isolates (experiment) or 3 mL of sterile water (control) were added. At Day 14, the plants were removed, thoroughly and carefully washed, the number of affected plants was counted (% prevalence) and the dry matter of roots and shoots was measured. Results. A total of 16 strains of fungi, the causative agents of root diseases, were isolated in pure culture from roots, seeds and leaf plates of affected soybean plants. The isolated pathogens belonged to the genera Fusarium Link:Fr, Alternaria (Fr.) Keissler, Verticillium Nees. The phytopathogenic effect of fungi of the genus Verticillium isolated from the washed roots of soybean plants was insignificant. Fusarium was represented by F. oxysporum, F. solani, F. moniliforme var. lactis, F. gibbosum, among which F. gibbosum exerted the greatest phytopathogenic effect. The isolated F. gibbosum C4 affects seedlings first. The roots of the affected plants develop poorly, the plants are easily pulled out and lag behind in growth and development. Among the selected Alternaria strains, A. consortiale C8 which was characterized by rapid growth, turned out to be the most harmful. A. consortiale C8 first affects seedlings, then appears on other parts of plants: roots, stems, leaves. On soybean leaves, the first sign of alternaria leaf spots is dark brown spots of various sizes and shapes, the leaves wither and die. Affected plants lag behind in growth. Infection of soybean plants by phytopathogenic fungi leads to a decrease in the content of dry matter both in the roots and in the aboveground mass of the plants. In the case of F. gibbosum C4 infection, the content of dry matter in the roots decreased by 27 %, in the aboveground mass of plants — by 19 %. Infection with A. consortiale C8 led to a decrease in dry matter by 29 % and 27 %, respectively. Conclusion. The fungal pathogenic complex in soybean crops consisted of representatives of the

hese recommendations summarise the current evidence on the medical management of adult patients with UC. Gaps were iden-tified during the analysis of the data, which should be addressed by further research. Where evidence is lacking or is very weak and evidence-based recommendations cannot be given, ECCO provides alternative tools, such as Topical Reviews28,95,153–158 or Position Papers.159–161 It is important that clinicians use these guidelines within the framework of local regulations, and seek to understand and address the individual needs and expectations of every patient. We recognise that constraints on health care resources are an im-portant factor in determining whether recommendations can be implemented for patients in many countries. The recommendations outlined here should be used to inform treatment decisions and form part of an overall multidisciplinary treatment plan for patients with UC, which may also encompass psychological, nutritional, and other non-pharmacological interventions.

This is the second of a series of two articles reporting the European Crohn’s and Colitis Organisation [ECCO] evidence-based consensus on the management of adult patients with ulcerative colitis [UC]. The first article is focused on medical management, and the present article addresses medical treatment of acute severe ulcerative colitis [ASUC] and surgical management of medically refractory UC patients, including preoperative optimisation, surgical strategies, and technical issues. The article provides advice for a variety of common clinical and surgical conditions. Together, the articles represent an update of the evidence-based recommendations of the ECCO for UC.

Possible triggers and genetic markers involved in pathogenesis of amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) are currently unknown. This study aimed to analyze the association between polymorphisms in the genes involved in thyroid hormones biosynthesis and metabolism. Thirty-nine consecutive patients with confirmed type 2 amiodarone-induced thyrotoxicosis were enrolled; 39 patients on the same therapy for at least 6 months without thyroid pathology were included as a control group. A comparative study was carried out to determine the distribution and genotypes of polymorphic markers of the (Na)-iodide symporter (NIS) genes (rs7250346, C/G substitution), thyroid stimulating hormone receptor (TSHR) (rs1991517, C/G substitution), thyroid peroxidase (TPO) (rs 732609, A/C substitution), DUOX 1-1 (C/T substitution), DUOX 1-2 (G/T substitution), DUOX 1-3 (C/T substitution), glutathione peroxidase 3 (GPX3) (C/T substitution), glutathione peroxidase 4 (GPX4) (C/T substitution). Statistical analysis was performed using Prism (Version 9.0.0 (86)). This study showed that the risk of AIT2 is 3.18 times higher in the G/T of the DUOX1 gene carriers. This study is the first report of genetic markers associated with amiodarone-related adverse events conducted in humans. The obtained results indicate the necessity for a personalized approach to amiodarone administration.

Background Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. Methods Apolipoprotein E deficiency (ApoE−/−) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA–protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. Results The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. Conclusion These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

Background: The effectiveness of anti-TNF or ustekinumab (UST) as a second-line biologic after vedolizumab (VDZ) failure has not yet been described. Aims and Methods: In this retrospective multicenter cohort study, We aim to investigate the effectiveness of anti-TNF and UST as second-line therapy in patients with Crohn’s disease (CD) who failed VDZ as a first-line treatment. The primary outcome was clinical response at week 16–22. Secondary outcomes included the rates of clinical remission, steroid-free clinical remission, CRP normalization, and adverse events. Results: Fifty-nine patients who failed on VDZ as a first-line treatment for CD were included; 52.8% patients received anti-TNF and 47.2% UST as a second-line therapy. In initial period (Week 16–22), the clinical response and remission rate was similar between both groups: 61.2% vs. 68%, p = 0.8 and 48.3% vs. 56%, p = 0.8 on anti-TNF and UST therapy, respectively. Furthermore, in the maintenance period the rate was similar: 75% vs. 82.3%, p = 0.8 and 62.5% vs. 70.5%, p = 0.8, respectively. Of the patients, 12 out of the 59 stopped the therapy, without a significant difference between the two groups (p = 0.6). Conclusion: Second-line biological therapy after VDZ failure therapy was effective in >60% of the patients with CD. No differences in effectiveness were detected between the use of anti-TNF and UST as a second line.

Aim. Our work was aimed at investigating the specificities in the formation of the genetic structure of populations depending on the productivity direction of cattle, bred in Ukraine, using single locus DNA fragments, and studying the impact of the parental form on genetic polymorphism of modern intensive specialized breeds as a factor. Methods. The following methods were used in the work: veterinary methods (peripheral blood sampling); molecular-genetic meth- ods (the isolation and genotyping of DNA samples of dairy (83 animals), meat (192 animals) and aboriginal (43 ani- mals) cattle, bred in Ukraine, were performed by 10 microsatellite loci from the list, recommended by the International Society for Animal Genetics (ISAG); the complex of statistics methods was used for mathematic-statistical analysis, using modern software. Results. The analysis by 10 microsatellite loci demonstrated the specificities of genetic dif- ferentiation and the similarities between the investigated cattle populations, bred in Ukraine. Our results provide new information about the impact of artificial selection factors on single locus DNA fragments under the specialization of cattle breeds. The impact of the factor of ancestral form on the genetic structure was determined and confirmed by the same polymorphism spectra of the investigated DNA fragments in the maternal and derivative breeds. Another con- firmation was found in the differences, observed in animals of different productivity directions, which are a probable result of the breed-forming process, demonstrated by the results of the mathematic calculations of the data obtained. It was shown that microsatellite DNA loci are highly informative markers of genetic processes, occurring in domestic cattle populations. Conclusions. The specificities in the formation of the genetic structure of populations depending on the productivity direction of animals were determined. The impact of the parental form on genetic polymorphism of modern intensive specialized breeds was noted. It was found that among 10 microsatellite loci, used by us, there were loci in each group of animals, regarding which the hypothesis about their neutrality was reliably rejected accord- ing to the results of Ewens-Watterson test: for dairy cattle (INRA023, ETH3, ETH225, BM1824, BM2113, ETH10 and SPS115), for meat cattle (TGLA122 and ETH225), and for aboriginal cattle (TGLA126, INRA023 and TGLA227). We determined a high level of genetic diversity, remarkable for each investigated cattle population, bred in Ukraine, and general tendencies of differentiation in the selected populations depending on the targeted breeding work, on the level of polymorphism of microsatellite DNA loci (Friedman’s test: P < 0.01), and a similar genetic picture for a number of loci of investigated DNA fragments, which may be related to the history of creating these breeds.

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Herein, we aimed to highlight current “gaps” in the understanding of the potential interactions between the Anle138b isomer ligand, a promising agent for clinical research, and the intrinsically disordered alpha-synuclein protein. The presence of extensive unstructured areas in alpha-synuclein determines its existence in the cell of partner proteins, including the cyclophilin A chaperone, which prevents the aggregation of alpha-synuclein molecules that are destructive to cell life. Using flexible and cascaded molecular docking techniques, we aimed to expand our understanding of the molecular architecture of the protein complex between alpha-synuclein, cyclophilin A and the Anle138b isomer ligand. We demonstrated the possibility of intricate complex formation under cellular conditions and revealed that the main interactions that stabilize the complex are hydrophobic and involve hydrogen.

Background We evaluated whether integration of novel diets for donors and patients, in addition to faecal transplantation [FT], could increase FT remission rate in refractory ulcerative colitis [UC]. Methods This was a blinded, randomised, controlled trial in adults with active UC, defined by a simple clinical colitis activity index [SCCAI] of ≥5 and ≤11 and endoscopic Mayo score 2–3, refractory to medication. Group 1 received free diet and single donor standard FT by colonoscopy on Day 1and rectal enemas on Days 2 and 14 without dietary conditioning of the donor. Group 2 received FT as above but with dietary pre-conditioning of the donor for 14 days and a UC Exclusion Diet [UCED] for the patients. Group 3 received the UCED alone. The primary endpoint was Week 8 clinical steroid-free remission, defined as SCCAI Results Of 96 planned patients, 62 were enrolled. Remission Week 8 Group 1 was 2/17 [11.8%], Group 2 was 4/19 [21.1%], Group 3 was 6/15 [40%] [non-significant]. Endoscopic remission Group 1 was 2/17 [12%], Group 2 was 3/19 [16%], Group 3 was 4/15 [27%] [Group 1 vs 3 p = 0.38]. Mucosal healing [Mayo 0] was achieved only in Group 3 [3/15, 20%] vs 0/36 FT patients [p = 0.022]. Exacerbation of disease occurred in 3/17 [17.6%] of Group 1, 4/19 [21.1%] of Group 2, and 1/15 [6.7%] of Group 3 [Group 2 vs 3, p = 0.35]. Conclusions UCED alone appeared to achieve higher clinical remission and mucosal healing than single donor FT with or without diet. The study was stopped for futility by a safety monitoring board.

To evaluate the impact of anxiety disorders on adherence to anticoagulant therapy (ACT) in patients with atrial fibrillation (AF).179 outpatients (131 women, 48 men, mean age 69.96.2 years) with AF were examined. The research methods included a physical examination according to the standards of medical care in an outpatient facility, clinical and psychopathological examination using psychometric scales.Based on the assessment of adherence to ACT using the MoriskyGreen test, 2 groups of patients were identified: Group 1 patients with high adherence to ACT, Group 2 patients with partial/low adherence to ACT. In group 1, anxiety disorders were verified in 51.7% of cases, in group 2 54.3%. There were no statistically significant differences in the prevalence and severity of anxiety in the study groups. In accordance with the binary logistic regression model, the probability of high adherence to therapy is determined by higher (compared with the group of patients with partial/low adherence to therapy) scores in terms of mental health (p0.001), vital activity (p=0.02) and the total score of the SF-36 scale (p=0.08), as well as the extraversion parameter (p=0.02) of the NEO-FFI scale.In the present study, no significant association was found between anxiety symptoms and a decrease in adherence to ACT in patients with AF. However, the results obtained suggest a contribution to the adherence to therapy of personality characteristics.Цель. Оценить влияние тревожных расстройств на приверженность антикоагулянтной терапии (АКТ) у пациентов с фибрилляцией предсердий (ФП). Материалы и методы. Обследованы 179 амбулаторных пациентов (131 женщина, 48 мужчин, средний возраст 69,96,2 года) с ФП. Методы исследования включали в себя соматическое обследование согласно стандартам оказания медицинской помощи в амбулаторном учреждении и клинико-психопатологическое с применением психометрических шкал. Результаты. На основании оценки приверженности АКТ с помощью теста МорискиГрина выделены 2 группы пациентов: 1-я группа пациенты с высокой приверженностью АКТ, 2-я группа пациенты с частичной/низкой приверженностью АКТ. В 1-й группе тревожные расстройства верифицировались в 51,7% случаев, во 2-й группе 54,3%. Статистически значимых различий по распространенности и тяжести тревожных расстройств в исследуемых группах не выявлено. В соответствии с моделью бинарной логистической регрессии вероятность высокой приверженности терапии определяется более высокими (в сравнении с группой пациентов с частичной/низкой приверженностью терапии) баллами по показателям психическое здоровье (р0,001), жизненная активность (р=0,02) и общим баллом шкалы SF-36 (р=0,08), а также параметром экстраверсия (р=0,02) шкалы NEO-FFI. Заключение. В настоящем исследовании не выявлено достоверной связи между тревожной симптоматикой и снижением приверженности АКТ у пациентов с ФП. Однако полученные результаты позволяют предположить вклад в приверженность терапии отдельных личностных характеристик.

(1) Background: Predicting which patients with upper gastro-intestinal bleeding (UGIB) will receive intervention during urgent endoscopy can allow for better triaging and resource utilization but remains sub-optimal. Using machine learning modelling we aimed to devise an improved endoscopic intervention predicting tool. (2) Methods: A retrospective cohort study of adult patients diagnosed with UGIB between 2012–2018 who underwent esophagogastroduodenoscopy (EGD) during hospitalization. We assessed the correlation between various parameters with endoscopic intervention and examined the prediction performance of the Glasgow-Blatchford score (GBS) and the pre-endoscopic Rockall score for endoscopic intervention. We also trained and tested a new machine learning-based model for the prediction of endoscopic intervention. (3) Results: A total of 883 patients were included. Risk factors for endoscopic intervention included cirrhosis (9.0% vs. 3.8%, p = 0.01), syncope at presentation (19.3% vs. 5.4%, p < 0.01), early EGD (6.8 h vs. 17.0 h, p < 0.01), pre-endoscopic administration of tranexamic acid (TXA) (43.4% vs. 31.0%, p < 0.01) and erythromycin (17.2% vs. 5.6%, p < 0.01). Higher GBS (11 vs. 9, p < 0.01) and pre-endoscopy Rockall score (4.7 vs. 4.1, p < 0.01) were significantly associated with endoscopic intervention; however, the predictive performance of the scores was low (AUC of 0.54, and 0.56, respectively). A combined machine learning-developed model demonstrated improved predictive ability (AUC 0.68) using parameters not included in standard GBS. (4) Conclusions: The GBS and pre-endoscopic Rockall score performed poorly in endoscopic intervention prediction. An improved predictive tool has been proposed here. Further studies are needed to examine if predicting this important triaging decision can be further optimized.

This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines. ispartof: JOURNAL OF CROHNS & COLITIS vol:14 issue:2 pages:155-168 ispartof: location:England status: published

ECCO reviewed the available high-quality evidence on the medical management of CD and developed evidence-based recommendations on the medical treatment of adult patients with CD. These guidelines do not cover specific situations, such as postoperative management of adult patients with CD, which was already covered in the latest ECCO Guidelines on Crohn’s disease.

Conventional approaches for studying and molecular typing of tumors include PCR, blotting, omics, immunocytochemistry, and immunohistochemistry. The last two methods are the most used, as they enable detecting both tumor protein markers and their localizations within the cells. In this study, we have investigated a possibility of using RNA aptamers, in particular, 2′-F-pyrimidyl-RNA aptamer ME07 (48 nucleotides long), specific to the receptor of epidermal growth factor (EGFR, ErbB1, Her1), as an alternative to monoclonal antibodies for aptacytochemistry and aptahistochemistry for human glioblastoma multiforme (GBM). A specificity of binding of FAM-ME07 to the receptor on the tumor cells has been demonstrated by flow cytometry; an apparent dissociation constant for the complex of aptamer – EGFR on the cell has been determined; a number of EGFR molecules has been semi-quantitatively estimated for the tumor cell lines having different amount of EGFR: A431 (106 copies per cell), U87 (104 copies per cell), MCF7 (103 copies per cell), and ROZH, primary GBM cell culture derived from patient (104 copies per cell). According to fluorescence microscopy, FAM-ME07 interacts directly with the receptors on A431 cells, followed by its internalization into the cytoplasm and translocation to the nucleolus; this finding opens a possibility of ME07 application as an escort aptamer for a delivery of therapeutic agents into tumor cells. FAM-ME07 efficiently stains sections of GBM clinical specimens, which enables an identification of EGFR-positive clones within a heterogeneous tumor; and providing a potential for further studying animal models of GBM.

Mitochondrial dysfunction and ubiquitin-proteasome system (UPS) failure contribute significantly to the development of Parkinson's disease (PD). The proteasome subunit Rpn13 located on the regulatory (19S) subparticle play an important role in the delivery of proteins, subjected to degradation, to the proteolytic (20S) part of proteasome. We have previously found several brain mitochondrial proteins specifically bound to Rpn13 (Buneeva et al. (2020) Biochemistry (Moscow), Supplement Series B: Biomedical Chemistry, 14, 297-305). In this study we have investigated the effect of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroprotector isatin on the mitochondrial subproteome of Rpn13-binding proteins of the mouse brain. Administration of MPTP (30 mg/kg) to animals caused movement disorders typical of PD, while pretreatment with isatin (100 mg/kg, 30 min before MPTP) reduced their severity. At the same time, the injection of MPTP, isatin, or their combination (isatin + MPTP) had a significant impact on the total number and the composition of Rpn13-binding proteins. The injection of MPTP decreased the total number of Rpn13-binding proteins in comparison with control, and the injection of isatin prior to MPTP or without MPTP caused an essential increase in the number of Rpn13-binding proteins, mainly of the functional group of proteins participating in the protein metabolism regulation, gene expression, and differentiation. Selected biosensor validation confirmed the interaction of Rpn13 subunit of proteasome with some proteins (glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, histones H2A and H2B) revealed while proteomic profiling. The results obtained testify that under the conditions of experimental MPTP-induced parkinsonism the neuroprotective effect of isatin may be aimed at the interaction of mitochondria with the components of UPS.Mitokhondrial'naia disfunktsiia i sboĭ v rabote ubikvitin-proteasomnoĭ sistemy (UPS) vnosiat sushchestvennyĭ vklad v razvitie bolezni Parkinsona (BP). Sub"edinitsa proteasomy Rpn13, raspolozhennaia na reguliatornoĭ subchastitse (19S), igraet vazhnuiu rol' v dostavke belkov, podlezhashchikh degradatsii, v proteoliticheskuiu chast' (20S) proteasomy. Ranee nami obnaruzhen riad mitokhondrial'nykh belkov mozga, spetsificheski sviazyvaiushchikhsia s Rpn13 (Buneeva i dr., Biomeditsinskaia khimiia, 2020, 66(2), 138-144). V dannoĭ rabote izucheno vliianie neĭrotoksina 1-metil-4-fenil-1,2,3,6-tetragidropiridina (MFTP) i neĭroprotektora izatina na mitokhondrial'nyĭ subproteom Rpn13-sviazyvaiushchikh belkov mozga myshi. Vvedenie MFTP (30 mg/kg) zhivotnym vyzyvalo razvitie dvigatel'nykh narusheniĭ, svoĭstvennykh dlia BP, a predvaritel'noe vvedenie izatina (100 mg/kg) oslablialo ikh vyrazhennost'. Pri étom vvedenie MFTP, izatina ili ikh kombinatsii (izatin + MFTP) privodilo k izmeneniiu obshchego chisla i sostava Rpn13-sviazyvaiushchikh belkov. Vvedenie MFTP snizhalo obshchee chislo Rpn13-sviazyvaiushchikh belkov po sravneniiu s kontrolem, a vvedenie izatina pered vvedeniem MFTP ili bez MFTP privodilo k sushchestvennomu uvelicheniiu chisla Rpn13-sviazyvaiushchikh belkov preimushchestvenno iz funktsional'noĭ gruppy belkov, uchastvuiushchikh v reguliatsii metabolizma belkov, a takzhe ékspressii genov, kletochnogo deleniia i differentsirovki. Vyborochnaia biosensornaia validatsiia podtverdila vzaimodeĭstvie riada belkov (glitseral'degid-3-fosfatdegidrogenaza, piruvatkinaza, gistony N2A i N2V), vyiavlennykh v khode proteomnogo profilirovaniia, s sub"edinitseĭ proteasomy Rpn13. Poluchennye rezul'taty svidetel'stvuiut o tom, chto v usloviiakh éksperimental'nogo MFTP-indutsirovannogo parkinsonizma neĭroprotektornoe deĭstvie izatina mozhet byt' napravleno na vzaimodeĭstvie mitokhondriĭ s komponentami UPS.

Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.

Objective. To study the efficacy of the use of a new strain of Trichoderma viride IMB F-100076 with high antagonistic and cellulolytic activity, in particular its effect on the photosynthetic apparatus and the yield of corn plants. Methods. Study of the effect of T. viride IMB F-100076 on corn94 yield was performed under the conditions of a three-year small-plot field experiment on sodmedium-podzolic soil. The content of chlorophyll a and b in the plants of the experimental variants was determined by spectrophotometry. Methods of mathematical statistics were used in processing the obtained data. Results. Data from a three-year field experiment showed that the application of straw had a negative effect on the yield of corn, which averaged 7.72 t/ha that is 12.3 % less than in the variant without the application of straw (control). Application of the antagonist fungus T. viride IMB F-100076 to the soil simultaneously with straw allowed to obtain an average yield of 9.5 t/ha during three years of study, which is 23 % higher than in the variant with straw. In the control variant (without application of straw and fungal suspension), the yield averaged 8.8 t/ha, which is 14 % higher than in the variant with straw not treated with fungus. It was shown that the content of chlorophylls in corn leaves increases under the influence of T. viride IMB F-100076. For instance, the total content of chlorophyll a and b was 261.04 mg/100 g of leaves, which is 39.0 % higher than in the variant with straw not treatment with a suspension of the fungus, and 15.3 % higher than in the control variant. The obtained results highlight that the treatment of straw with the fungus T. viride IMB F-100076 had a positive effect on the formation of the photosynthetic apparatus of corn plants. Conclusion. Simultaneous application of wheat straw and T. viride IMB F-100076 micromycete, which is characterized by high antagonistic and cellulolytic activity, provides a significant increase in corn yield versus the variant with straw not treated with fungus. The content of chlorophylls a and b in the leaves increases.

Background Recently, the implementation of artificial intelligence-aided colonoscopy (AIAC) has resulted in improved performance of colorectal cancer (CRC) screening. The adenoma detection rate (ADR) is a key quality indicator in screening colonoscopies and achieving high ADRs is crucial for optimal prevention of CRC. Guidelines suggest that ADRs of 20% in women and 30% in males are indicative of adequate performance. Patients with inflammatory bowel disease (IBD) may be at increased risk for CRC based on disease extent and duration. However, ADR in patients with IBD can be generally lower than in average-risk patients, mainly due to an age gap and the presence of dysplasia associated lesions as opposed to sporadic adenomas. Indeed, there is no consensus for an accepted ADR target in these patients. In addition, the impact of AIAC on ADR in these patients has yet to be described. We aimed to explore the ADR of patients with IBD in a large-volume endoscopic center and evaluate the effect of AIAC on ADR. Methods This was a retrospective study conducted at a high-volume gastroenterology department where all endoscopy suites were equipped with an AIA device (GI Genius, Medtronic, Ireland) starting from July 1st 2021. Data was collected on all colonoscopies performed in the 11 months before the mentioned date and compared to a 15-month period afterwards. We excluded patients that performed colonoscopy due to evaluation of IBD severity, for known or suspected malignancy, therapeutic endoscopies, incomplete colonoscopies and colonoscopies with inadequate preparation. The primary outcome of the study was ADR. Results Our study included 996 colonoscopies (237 pre-AIAC, 759 AIAC). The groups were similar in age (median 43.8 years, interquartile ratio (IQR) 28.7-61.2 vs 44.5 years, IQR 30.7-59.1, p=0.76) and gender distribution (55.3% vs 54.3% males, p=0.82). In both groups, there were more Crohn’s disease (62.9% pre-AIAC, 57.2% AIAC, p=0.13) than ulcerative colitis patients. The ADR in the pre-AIAC group tended to be higher in comparison to AIAC (6.3% vs 4%, p=0.15); When limiting to experienced gastroenterologists only (≥ 5 years), ADR results were significant higher in the pre-AIAC group (7.6% vs 3.8%, p=0.035). In addition, total procedure time (considered the time from procedure start and end as recorded by the endoscopy nurse) was significantly shorter in the AIAC group (21 minutes, IQR 17-28 vs 25 minutes, IQR 19-37, p Conclusion In a large-volume tertiary center cohort, the introduction of AIAC to real-world colonoscopies did not improve ADR in patients with IBD, questioning the integration of AIAC in routine practice.

Background Colonoscopy plays an essential role in the prevention of colorectal cancer screening and the management of inflammatory bowel disease (IBD). For patients with IBD, colonoscopy is advocated for detection of complications, guiding clinical decisions, and cancer surveillance. In most cases, sedation is a fundamental constituent of the procedure, reducing peri-procedural discomfort and improving examination quality. We aimed to compare the dosing of sedative medications and the duration of procedure for IBD patients compared to non-IBD controls in a large-volume endoscopic center. Methods This was a propensity score–matched retrospective study that took place at a high-volume gastroenterology department between June 2020 and September 2021. Colonoscopy data of patients with established IBD including medications and duration of procedure was collected, compared to a 1:2 propensity-scored matched cohort of non-IBD patients. Patients with polyposis, past abdominal surgery, known or suspected malignancy, suspected IBD, incomplete colonoscopies and colonoscopies with inadequate preparation were excluded. The sedation protocol in our institution includes an induction of Midazolam 1-2 mg and Fentanyl of 0.025-0.05 mg administered five minutes prior to procedure. An initial dose of 10-30 mg Propofol is initiated as well, with subsequent increments of 10-20 mg every 1-2 minutes, depending on sedation depth. Results During the study period, 14502 patients including 996 patients with IBD underwent colonoscopy and 4933 patients were excluded in accordance with the exclusion criteria. Propensity score matching was conducted using four characteristics - patient age, gender, American Society of anaesthesiologists score determined by the endoscopist, and endoscopists’ experience. A total of 2289 patients were included in the final analysis (763 IBD patients, 1526 control patients). The groups were similar in administered Propofol sedation doses [IBD- median dose of 100 mg, interquartile ratio (IQR) 70-150 vs control, 100 mg, IQR 80-150, p=0.2). In addition, total procedure time (considered the time from procedure start and end as recorded by the endoscopy nurse) was significantly longer in the IBD group (23 median minutes, IQR 18-30 vs 20 median minutes, IQR 16-27, p Conclusion In a retrospective analysis from a large-scale tertiary center cohort, colonoscopies of patients with IBD were significantly longer despite comparable terminal intubation rates; IBD patients did not require more intensive sedation than controls.

Background Ankylosing spondylitis (AS), which occurs in about 10% of inflammatory bowel disease (IBD) patients, is more common in Crohn's disease and does not correlate with bowel activity. The occurrence of IBD in patients with AS is 5-10%. We aimed to investigate the patterns of treatment modifications following newly diagnosed AS in patients with IBD or a new IBD diagnosis in patients with AS. Methods This is a retrospective observational study that included patients with coexisting IBD and AS that were followed simultaneously by the gastroenterology and the rheumatology departments of the Sheba Medical Center. Patients with a follow-up duration of at least 3 months since the second diagnosis were included. Results The cohort consisted of 68 patients, 41 with a first diagnosis of IBD (fIBD-group) and 27 with a first diagnosis of AS (fAS-group). Patients in the fAS-group were younger (median age of 36 years, inter quartile range (IQR) 25-48 vs. 43 years IQR 35-56, p=0.043), had more Crohn's disease (92.6% vs. 68.3%, p=0.016), had a shorter interval up to the second diagnosis (median of 3 years, IQR 1-6 vs. 6 years, IQR 2-11.5, p=0.03), and had an increased rate of past/current biologic treatment (81% vs. 51%, p=0.019) compared with the fIBD-group. Therapy modifications rates were 78% in the fIBD-group and 96% in the fAS-group as presented in Figure 1. The most common modification for the fIBD-group was initiation of biologic therapy in 18/32 patients (Adalimumab 44%, Infliximab 33%, Golimumab 5.75%, Etanercept 5.75%, Certolizumab pegol 5.75%, Ustekinumab 5.75%). In the fAS-group, switching biologic agent to Adalimumab or Infliximab (42%) and ceasing NSAIDs (27%) were the most common. At 1-year follow-up there were no significant differences in clinical outcomes (treatment failure, surgery/hospitalization, clinical remission) between fIBD and fAS groups. However, patients in both groups with treatment modifications, had a trend for higher rate of IBD clinical remission than patients without (72% vs. 40%, p=0.066). No difference was found in AS clinical outcome. Conclusion Treatment modifications are common among newly coexisting IBD and AS patients, preferably biologic drug modifications. These modifications may contribute to IBD clinical remission.

Background Recent studies such as the GEM project have identified microbial, serological and metabolomic markers that may help predict inflammatory bowel disease (IBD) well in advance of diagnosis, with the ultimate goal of pre-disease prevention. In this population-based study, we used the epi-Israeli IBD Research Nucleus (IIRN) validated cohort to explore the utility of routine blood tests as markers for pre-diagnostic IBD prediction. Methods We included all blood tests from all IBD patients diagnosed from 2005-2020 insured in three of the four Israeli health maintenance organizations (HMOs), and individually matched each to two non-IBD controls. Test results were collected and collated by number of months pre-diagnosis, then reported over time until diagnosis. Means were compared using Welch's t-test with false discovery rate correction to account for multiple comparisons. Trends over time were analyzed to detect tests that showed divergence between cases and controls at least one year before diagnosis. Results Pre-diagnosis results from 142 different blood tests were collected for 7,630 Crohn’s disease (CD) patients and 6,026 ulcerative colitis (UC) patients (mean age 33.3±17.4 years for CD and 38 ± 17.9 years for UC). Median duration of pre-diagnosis data collection was 50 (IQR 11-96) months for CD and 48 (IQR11-96) months for UC. Of the 142 tests, 24 (17%) showed significant differences between CD and controls at least one year pre-diagnosis (Figure 1); these included not only inflammation-related tests such as ESR, hemoglobin and albumin, but also seemingly unrelated tests such as bilirubin, cholesterol and creatinine. In UC patients, no tests showed statistically significant differences at least one year pre-diagnosis. Conclusion We were able to detect changes in blood tests collected as part of routine care long before CD diagnosis, opening the possibility of detecting early signals of future CD in patients undergoing routine blood tests. These may be used for developing screening and prediction models for prevention strategies. This research was partially supported by the Israeli Council for Higher Education (CHE) via the Data Science Research Center, Ben-Gurion University of the Negev, Israel. The epi-IIRN project has been funded by an educational grant from the Leona M. and Harry B. Helmsley Charitable Trust.

Background Treating perianal Crohn’s disease (pCD) is challenging with at least 60% of the patients not responding or relapsing after a year of 1st line biological therapy. Effectiveness data on 2nd and 3rd line in pCD is still quite limited. The aim of this study was to describe the effectiveness of 2nd and 3rd line biological therapy in pCD. Methods A retrospective cohort study of patients with pCD from a large tertiary center registry. We included all patients with pCD that were treated with >1 biologic while anti-TNF was the first one used. Primary outcome was defined as clinical failure of 2nd or 3rd line treatment (as defined by the clinician) or radiological evidence for disease progression by MRI or transrectal ultrasonography (TRUS). Secondary outcomes were relapse of perianal fistula or abscess. Results Registry included 893 patients with pCD who are being followed up routinely in a dedicated IBD clinic; 643 patients received 1 biological were excluded. Final cohort included 245 patients treated with ≥2 biologics. In 2nd line, 40/245 patients (16%) treated with infliximab (IFX), 128/245 (52%) with adalimumab (ADA), 48/245 (20%) with vedolizumab (VDZ) and 32/245 (13%) with ustekinumab (UST). 7/32 patients (22%) treated with UST failed the treatment, compared to 32/40 (80%), 101/128 (79%) , 37/48 (77%) patients treated with IFX, ADA and VDZ, respectively [Hazard Ratio(HR) 0.27 (0.1-0.69)]. Median time of 2nd line treatment with UST, anti-TNFs and VDZb was 2.5 (IQR=1-3[uk1] ), 3 (IQR=1-5) and 3 (IQR=1-4) years, respectively. Higher response rate in 2nd line therapy was associated with longer response duration to 1st line [OR (1.11-1.55), p 99/245 patients (40%) required 3rd line treatment (VDZ - 52/99 , UST - 47/99 (48%)) patients). 8/47 patients (17%) under UST therapy experienced clinical failure, compared to 41/52 (78.8%) patients treated with VDZ [HR 0.32 (0.12-0.68)]. Median duration (years) of third line treatment with both UST and VDZ was 3 years (IQR=3-1). Figure A shows Kaplan-Meier survival analysis to 2nd line and 3rd line failure. Conclusion 2nd and 3rd line biological therapies may be efficacious in pCD patients. Ustekinumab appears to be effective as a 2nd or 3rd line treatment. Longer duration of treatment is associated with a higher likelihood of response to 2nd line treatment.

Background The fecal metabolome is comprised from derivatives of the gut microbiome, the host, the environment, and the diet. Thus, it is a central output and effector that is linked with Crohn disease (CD). We aimed to characterize metabolomics profiles that are associated with CD and link metabolites with gut microbial diversity and composition. Methods Fecal metabolomics was performed using liquid chromatography coupled Mass Spectrometer (LC/MS). Microbiome was defined by 16Sseq. Multivariate analyses in MaAsLin2 identified differentially abundant metabolites and these were used for pathways enrichment analyses using Metacyc (PMID: 31586394). Hierarchical All-against-All association (HAllA; PMID: 35758795) was used to identify significant relationships between fecal metabolites and microbial amplicon sequence variants (ASVs). Results The cohort included 294 samples from 85 subjects (mean age 36, 51% males). 250 samples were from CD patients (n=59) and 44 samples were from controls (n=26). 545 metabolites were included in our predefined library and were subsequently analyzed. Multivariate analyses identified 86 increased and 18 decreased metabolites in CD, after controlling for age and gender (FDR Conclusion CD patients have distinct fecal metabolic signature which is also correlated with disease activity. Furthermore, we identified significant interactions between specific fecal metabolites and gut microbial ASVs enriched with saliva bacteria that were previously linked with CD. More research is needed to elucidate the factors governing this newly discovered link.

Background Histological remission is an important target for Ulcerative Colitis (UC) treatment; however, scoring of histological images is time-consuming and prone to inter and intra-observer variability. Thus, a need exists for an accurate, reproducible, and reliable automated method. Previously, we demonstrated an Artificial Intelligence (AI) Tool using image processing and machine learning algorithms to measure histological disease activity using the Nancy index consistently and accurately.1 Here, we aim to enhance the capabilities of the AI Tool, by adding substantially more population-diversified training data while maintaining accuracy and robustness of results. Methods Eight global sites submitted 600 UC histological images. These were added to the 200 images previously used to train and validate the AI Tool. The 800-image dataset was divided into 2 groups: 90% used for training, 10% for testing. The novel AI algorithms were trained using state-of-the-art image processing and machine learning techniques based on deep learning and feature extraction. Cell and tissue regions of each training image were manually annotated, measured, and assigned a Nancy Index independently by 3 histopathologists, and used to further train the AI using over 43,000 characterisations. The AI Tool fully characterises histological images, identifying tissue types, cell types, cell numbers and locations, and automatically measures the Nancy Index for each image. Intra Class Correlation (ICC) and Confusion Matrix analyses were performed to evaluate the AI Tool and assess accuracy. Results The average ICC was 92.1% among the histopathologists and 91.1% between histopathologists and AI Tool, compared with 88.3% and 87.2% in the previous study.1 Confusion matrix analysis (Table 1) demonstrated the strongest correlation at the extremes of the Nancy Index, with 80% correlation between predicted and true labels for Nancy Scores of 0 or 4. When 2 adjacent scores were combined, correlations were stronger: 96% for a true Nancy score of 0 being predicted as 0 or 1, and 100% for a true Nancy score of 2 being predicted as 2 or 3. Conclusion By adding a larger number of images to the AI Tool training data, the robustness of the AI Tool was substantially improved while maintaining accuracy. The continued high correlation of AI Tool performance with the histopathologists reinforces the potential role for the AI Tool for IBD clinical applications. Fully characterising whole slides could standardise and validate an AI-driven scoring system for histology slides in IBD, eliminating the subjectivity of the human pathologist in assessment of disease activity. References: 1. Peyrin-Biroulet L, et al. J Crohn's and Colitis. 2022;16(Suppl 1):i105.

CD133 is an extensively studied marker of the most malignant tumor cell population, designated as cancer stem cells (CSCs). However, the function of this glycoprotein and its involvement in cell regulatory cascades are still poorly understood. Here we show a positive correlation between the level of CD133 plasma membrane expression and the proliferative activity of cells of the Caco-2, HT-29, and HUH7 cancer cell lines. Despite a substantial difference in the proliferative activities of cell populations with different levels of CD133 expression, transcriptomic and proteomic profiling revealed only minor distinctions between them. Nonetheless, a further in silico assessment of the differentially expressed transcripts and proteins revealed 16 proteins that could be involved in the regulation of CD133 expression; these were assigned ranks reflecting the apparent extent of their involvement. Among them, the TRIM28 transcription factor had the highest rank. The prominent role of TRIM28 in CD133 expression modulation was confirmed experimentally in the Caco2 cell line clones: the knockout, though not the knockdown, of the TRIM28 gene downregulated CD133. These results for the first time highlight an important role of the TRIM28 transcription factor in the regulation of CD133-associated cancer cell heterogeneity.

This study explored the mechanisms by which the stability of super-secondary structures of the 3β-corner type autonomously outside the protein globule are maintained in an aqueous environment. A molecular dynamic (MD) study determined the behavioral diversity of a large set of non-homologous 3β-corner structures of various origins. We focused on geometric parameters such as change in gyration radius, solvent-accessible area, major conformer lifetime and torsion angles, and the number of hydrogen bonds. Ultimately, a set of 3β-corners from 330 structures was characterized by a root mean square deviation (RMSD) of less than 5 Å, a change in the gyration radius of no more than 5%, and the preservation of amino acid residues positioned within the allowed regions on the Ramachandran map. The studied structures retained their topologies throughout the MD experiments. Thus, the 3β-corner structure was found to be rather stable per se in a water environment, i.e., without the rest of a protein molecule, and can act as the nucleus or “ready-made” building block in protein folding. The 3β-corner can also be considered as an independent object for study in field of structural biology.

Isatin (indole-2,3-dione) is an endogenous regulator exhibiting various effects mediated by numerous isatin-binding proteins localized in different compartments of cells of the brain and peripheral tissues. It attenuates manifestations of experimental parkinsonism induced by administration of the MPTP neurotoxin and reduces the movement disorders characteristic of this disease. The molecular mechanisms of the neuroprotective action of isatin include its direct interaction with proteasomes, intracellular supramolecular complexes responsible for the targeted elimination of proteins. Incubation of fractions of 26S and 20S rabbit brain proteasomes, containing the whole spectrum of proteasomal subunits, as well as a number of proteasome-associated proteins, with isatin (100 μM) had a significant impact on the profile of released proteins. In the case of 26S proteasomes containing, in addition to the core part (20S proteasome), 19S regulatory subparticles, incubation with isatin resulted in a more than threefold increase in the number of dissociated proteins. In the case of 20S proteasomes (containing only the 20S core particle), incubation with isatin resulted in a significant decrease in the number of dissociated proteins compared to the control. Our results indicate an important role of the regulatory 19S subunit components in the formation of the proteasome subproteome and the sensitivity of these supramolecular complexes to isatin.Izatin (indol-2,3-dion) — éndogennyĭ reguliator, okazyvaiushchiĭ raznoobraznye éffekty, kotorye oposreduiutsia mnogochislennymi izatinsviazyvaiushchimi belkami, lokalizovannymi v razlichnykh kompartmentakh kletok mozga i perifericheskikh tkaneĭ. On proiavliaet svoĭstva neĭroprotektora, kotoryĭ v modeli éksperimental'nogo parkinsonizma, indutsirovannogo vedeniem neĭrotoksina MFTP, snizhaet dvigatel'nye narusheniia, svoĭstvennye étomu zabolevaniiu. Molekuliarnye mekhanizmy neĭroprotektornogo deĭstviia izatina vkliuchaiut ego priamoe vzaimodeĭstvie s proteasomami — vnutrikletochnymi nadmolekuliarnymi kompleksami, otvetstvennymi za targetnuiu éliminatsiiu belkov. Pri inkubatsii s izatinom (100 mkM) fraktsiĭ 26S i 20S proteasom mozga krolika, soderzhashchikh ves' spektr sobstvenno proteasomnykh sub"edinits, a takzhe riad assotsiirovannykh s proteasomami belkov, obnaruzheny sushchestvennye razlichiia v kolichestve i sostave vysvobodivshikhsia belkov. V sluchae 26S proteasom, soderzhashchikh, pomimo korovoĭ chasti (20S proteasoma), 19S reguliatornye subchastitsy, inkubatsiia s izatinom privodila k bolee chem trekhkratnomu uvelicheniiu chisla dissotsiirovavshikh belkov. V sluchae 20S proteasom (soderzhashchikh tol'ko korovuiu chast') inkubatsiia s izatinom privodila k sushchestvennomu snizheniiu chisla dissotsiirovavshikh belkov po sravneniiu s kontrolem. Poluchennye rezul'taty svidetel'stvuiut o vazhnoĭ roli komponentov reguliatornoĭ 19S subchastitsy v formirovanii subproteoma proteasom i chuvstvitel'nosti étikh nadmolekuliarnykh kompleksov k izatinu.

Background Idiopathic thrombocytopaenic purpura [ITP] is an acquired haematological disorder with an incidence of 1–6 per 100 00/year. ITP and inflammatory bowel disease [IBD] comorbidity has been reported in the literature, but insights regarding the course, outcome and optimal management are limited by its rarity. The current study aimed to evaluate the clinical presentation and outcome of ITP in patients with IBD. Methods This multicentre retrospective case series was performed as part of the ECCO Collaborative Network of Exceptionally Rare case reports [CONFER] project. Cases of patients with ITP and IBD were collected by participating investigators. Clinical data were recorded in a standardized collection form. Results This report includes 32 patients with concurrent ITP and IBD: ten were females, and the median age was 32.0 years (interquartile range [IQR] 20.5–39.5). Fourteen patients had a diagnosis of Crohn’s disease [CD] and the other 18 ulcerative colitis [UC]. The diagnosis of IBD preceded the ITP in 26 patients (median time between diagnoses was 7.0 years [IQR, 1.5–9.5]). Among those patients, 17 were in clinical remission at ITP diagnosis. Thirteen patients were treated with mesalamine, four with oral corticosteroids, one with rectal corticosteroids, two with azathioprine and five with anti-tumour necrosis factor agents. The median platelet count was 35 000/microliter [IQR, 10 000–70 000]. Eight patients had rectal bleeding, 13 had skin purpura, three had epistaxis, six had mucosal petechiae and 13 were asymptomatic. Regarding ITP treatment, 19 were treated with corticosteroids, one with anti-RhD immunoglobulin, 12 with intravenous immunoglobulins [IVIGs], four with thrombopoietin, three with rituximab and six patients eventually required splenectomy. Ten patients needed no treatment directed to the ITP. Three patients required colectomy during long-term follow-up, due to IBD or cancer but not to massive bleeding as a complication of ITP. One of eight patients who presented with rectal bleeding required splenectomy, and none required urgent colectomy. Two patients died during the follow-up, one of them due to bleeding complications located in the upper gastrointestinal tract. Median follow-up time was 6.5 years [IQR, 3–10]. With long-term follow-up, all patients had platelet counts above 50 000/microliter, and 24 were in IBD clinical remission. Conclusion Most ITP cases in this series occurred after the IBD diagnosis and responded well to regular ITP treatment. The course of the ITP in the IBD patients followed an expected course, including response to medical therapy and low rates of splenectomy.

The study objective was to investigate soft tissue microcirculation in the area of a lower limb long bone fracture. We studied fractures of the lower limb long bones from 0 to 7 days of age in 17 males and 37 females. The mean age of patients was 57.33±2.53 years. Histological examination of soft tissues from the area of the lower limb long bone fracture and at the distance from the fracture was performed. Standard hematoxylin and eosin staining was used. The thickness and diameter of arterioles, venules, and capillaries were evaluated by morphometry of the sections made. The observed pattern reflects the response of the microcirculation of the soft tissues to the mechanical impact. The relative ratio of the artery diameter to the small-caliber vein diameter was 1.01±0.13, and the artery wall thickness to the vein wall thickness was 2.03±0.28, which can be considered a natural reaction of the microcirculation blood vessels to the mechanical impact in 1-1.5 weeks after the formed fracture of the lower limb long bone.Изучение сосудисто-капиллярного русла мягких тканей в области перелома длинных трубчатых костей нижней конечности. Изучили переломы длинных трубчатых костей нижней конечности давностью от 0 до 7 дней у 17 мужчин и 37 женщин. Средний возраст пострадавших составил 57,33±2,53 года. Провели гистологическое исследование мягких тканей из зоны перелома длинных трубчатых костей нижней конечности и на отдалении от перелома. Использовали стандартные методы окраски гематоксилином и эозином. При морфометрии полученных срезов оценивали толщину и диаметр артериол, венул, капилляров. Полученные данные отражают реакцию микроциркуляторного русла мягких тканей на механическое воздействие. Относительное соотношение диаметра артерии к вене малого калибра 1,01±0,13, толщины стенки артерии к толщине стенки вены 2,03±0,28 можно считать закономерной реакцией сосудов микроциркуляторного русла на механическое воздействие в сроки 1—1,5 нед после сформировавшегося перелома длинных трубчатых костей нижней конечности.

Episodes of acute ileitis or colitis have been associated with future development of inflammatory bowel diseases (IBD). Nevertheless, the rate of future IBD among patients diagnosed with signs or symptoms of acute bowel inflammation is unknown. We aimed to assess the risk of IBD development among patients presenting with signs or symptoms of ileitis or colitis. We searched for all patients that visited the emergency department (ED) and underwent abdominal computed tomography (CT) who were eventually diagnosed with IBD during gastroenterology follow-ups within 9 years from the index admission. Multivariable models identified possible predictors of patients to develop IBD. Overall, 488 patients visited the ED and underwent abdominal imaging with abnormal findings, and 23 patients (4.7%) were eventually diagnosed with IBD (19 Crohn’s, 4 ulcerative colitis). Patients with a future IBD diagnosis were significantly younger (28 vs. 56 years, p < 0.001) with higher rates of diarrhea as a presenting symptom (17.4% vs. 4.1%, p = 0.015) compared to non-IBD patients. On multivariable analysis, age (p < 0.001), colitis (p = 0.004) or enteritis (p < 0.001) on imaging and a diagnosis of diarrhea in the ED (p = 0.02) were associated with development of IBD. Although alarming to patients and families, ED admission with intestinal inflammatory symptoms leads to eventual diagnosis of IBD in

In the last 20 years, the treatment and management of patients with Crohn’s disease (CD) and ulcerative colitis (UC) have been revolutionized by the introduction of biological therapies and small molecules [...]

Aptamers are structured oligonucleotides that specifically bind their targets. Oligonucleotides can be assembled in large nanostructures via intermolecular duplexes or G-quadruplexes. Addition of aptamers can be used to create nanostructures that bind specifically certain targets. Here two types of self-assembling locks were used to create bimodular aptamer constructions. Well-known aptamer to thrombin was chosen as a model object. The assembly of duplex locks was more efficient at low concentrations. The functional activity of aptamer modules was nearly the same as in HD1. However, the affinity of bimodular aptamers with G-quadruplex locks to immobilized thrombin was 5-10 times higher.

Background and Aims This study aimed to compare real-world clinical effectiveness and safety of vedolizumab, an α4β7-integrin inhibitor, and anti-tumour necrosis factor-α [anti-TNFα] agents in biologic-naïve ulcerative colitis [UC] and Crohn’s disease [CD] patients. Methods This was a 24-month retrospective medical chart study in adult UC and CD patients treated with vedolizumab or anti-TNFα in Canada, Greece and the USA. Inverse probability weighting was used to account for differences between groups. Primary outcomes were cumulative rates of clinical effectiveness [clinical response, clinical remission, mucosal healing] and incidence rates of serious adverse events [SAEs] and serious infections [SIs]. Secondary outcomes included cumulative rates of treatment persistence [patients who did not discontinue index treatment during follow-up] and dose escalation and incidence rates of disease exacerbations and disease-related surgeries. Adjusted analyses were performed using inverse probability weighting. Results A total of 1095 patients [604 UC, 491 CD] were included. By 24 months, rates of clinical effectiveness were similar between groups, but incidence rates of SAEs (hazard ratio [HR] = 0.42 [0.28–0.62]) and SIs (HR = 0.40 [0.19–0.85]) were significantly lower in vedolizumab vs anti-TNFα patients. Rates of treatment persistence [p < 0.01] by 24 months were higher in vedolizumab patients with UC. Incidence rates of disease exacerbations were lower in vedolizumab patients with UC (HR = 0.58 [0.45–0.76]). Other outcomes did not significantly differ between groups. Conclusion In this real-world setting, first-line biologic therapy in biologic-naïve patients with UC and CD demonstrated that vedolizumab and anti-TNFα treatments were equally effective at controlling disease symptoms, but vedolizumab has a more favourable safety profile.

Among the Arctic seas, the largest volume of river runoff (~45% of the total river-water inflow into the Arctic Ocean) enters the Siberian Kara Sea. The viral communities of the Kara Sea are important for the functioning of the marine ecosystem. Studies of virus–prokaryote interactions on the Kara Sea shelf have been conducted only in spring and autumn. Here, we investigated the abundance of free viruses, viruses attached to prokaryotes, and pico-sized detrital particles; the morphology (shape and size) of the viruses, viral infection and virus-mediated mortality of prokaryotes in early summer, i.e., during a seasonal ice melting period and maximum inflow of river-water volumes with high concentrations of dissolved and suspended organic carbon. Seawater samples for microbial analyses were collected across the Kara Sea shelf zone on board the Norilskiy Nickel as a research platform from June 29 to July 15, 2018. Abundances of prokaryotes (range (0.6–25.3) × 105 cells mL−1) and free viruses (range (10–117) × 105 viruses mL−1) were correlated (r = 0.63, p = 0.005) with an average virus: prokaryote ratio of 23.9 ± 5.3. The abundance of free viruses and viral-mediated mortality of prokaryotes were significantly higher in early summer than in early spring and autumn. Free viruses with a capsid diameter of 16–304 nm were recorded in the examined water samples. Waters in the Kara Sea shelf contained high concentrations of suspended organic particles 0.25–4.0 µm in size (range (0.6–25.3) × 105 particles mL−1). The proportions of free viruses, viruses attached to prokaryotes, and viruses attached to pico-sized detrital particles were 89.8 ± 6.0%, 2.2 ± 0.6% and 8.0 ± 1.3%, respectively, of the total virioplankton abundance (on average (61.5 ± 6.2) × 105 viruses mL−1). Viruses smaller than 60 nm clearly dominated at all studied sites. The majority of free viruses were not tailed. We estimated that an average of 1.4% (range 0.4–3.5%) of the prokaryote community was visibly infected by viruses, suggesting that a significant proportion of prokaryotic secondary production, 11.4% on average (range 4.0–34.0%), was lost due to viral lysis. There was a negative correlation between the abundance of pico-sized detrital particles and the frequency of visibly infected prokaryotic cells: r = −0.67, p = 0.0008.

Affinity-based proteomic profiling is widely used for the identification of proteins involved in the formation of various interactomes. Since protein–protein interactions (PPIs) reflect the role of particular proteins in the cell, identification of interaction partners for a protein of interest can reveal its function. The latter is especially important for the characterization of multifunctional proteins, which can play different roles in the cell. Pyruvate kinase (PK), a classical glycolytic enzyme catalyzing the last step of glycolysis, exists in four isoforms: PKM1, PKM2, PKL, and PKR. The enzyme isoform expressed in actively dividing cells, PKM2, exhibits many moonlighting (noncanonical) functions. In contrast to PKM2, PKM1, predominantly expressed in adult differentiated tissues, lacks well-documented moonlighting functions. However, certain evidence exists that it can also perform some functions unrelated to glycolysis. In order to evaluate protein partners, bound to PKM1, in this study we have combined affinity-based separation of mouse brain proteins with mass spectrometry identification. The highly purified PKM1 and a 32-mer synthetic peptide (PK peptide), sharing high sequence homology with the interface contact region of all PK isoforms, were used as the affinity ligands. This proteomic profiling resulted in the identification of specific and common proteins bound to both affinity ligands. Quantitative affinity binding to the affinity ligands of selected identified proteins was validated using a surface plasmon resonance (SPR) biosensor. Bioinformatic analysis has shown that the identified proteins, bound to both full-length PKM1 and the PK peptide, form a protein network (interactome). Some of these interactions are relevant for the moonlighting functions of PKM1. The proteomic dataset is available via ProteomeXchange with the identifier PXD041321.

Crohn’s disease (CD) is a chronic inflammatory condition that affects the gastrointestinal tract. It is part of a spectrum of inflammatory Bowel Diseases (IBD). The disease is complex, characterized by significant inter and intra-individual heterogeneity, which contributes to a diverse and multifaceted portrayal of the disease. Consequently, applying specific and accurate treatment is challenging, and therapeutic success rates remain disappointing and insufficient. In recent years, significant advances in the therapeutic potential of CD have been made. Hope has been provided by these developments in the form of an expanding treatment toolkit. However, even with these beneficial adjustments, patients are frequently treated using an ineffective “one size fits all” treatment protocol, ultimately leading to a plateau in drug effectiveness and a decline in overall treatment success rates. Furthermore, with the advancement in the genome-wide association study, in combination with significant bioinformatic developments, the world of medicine has moved in the direction of personalized, tailored-treatment medicine, and this trend has not escaped the world of IBDs. Prediction models, novel biomarkers, and complex algorithms are emerging and inspiring optimism that CD patients will be treated with “precision medicine” in the near future, meaning that their treatments will be selected based on the patient’s various unique features. In this review, we will outline the current diagnostic and therapeutic limitations that lead to a glass ceiling effect and thus send us in pursuit of discovering novel biomarkers. We will illustrate the challenges and difficulties in discovering relevant and innovative biomarkers and implementing them into everyday clinical practice. We will also heighten the progress made in practicing personalized medicine for CD patients and shed light on future directions and horizons.

Based on the approaches of continual mechanics and computer simulation, a computational methodology for establishing the operational parameters of functionally graded parts depending on the dimensional characteristics of elliptical defects is proposed. For the first time, using spatially non-local models of mechanics and the FEniCS finite element package, a calculation scheme was constructed for determining the contact strength of a material depending on the ratio of the sizes of the main radii of an elliptical defect in a structure. On the example of locomotive wheel tyres, it is shown that the most dangerous for operation are elliptical “needle-shaped” hubs with a ratio of the radii of the main axes of more than 40. They can also be a source for the development of “crack-type defects” during the operation of products. The established connection between the change in the properties of railway wheels under the action of loads and the characteristics of stress concentrators indicates that the shape of the concentrator is a more dangerous factor than its volume, and allows you to determine ways to control the operational parameters of parts with the presence of stress concentrators by surface engineering methods.

The purpose – to substantiate empirically a differentiated approach to the regulation of pre-start condition of swimmers at the training stage, taking into account the temperament type and anxiety level. Methods and organization of the research. We used the following research methods: analysis of data in scientific publications; psychological testing; questionnaires; analysis of competitive performance; mathematical and statistical processing of the studied indicators. The study involved 40 swimmers at the training stage. The athletic experience of the tested subjects is 4 years; the level of sports qualification-II-III sports categories. Results and discussion. Anxiety level tests of young swimmers revealed that personal and situational anxiety of individuals with various temperament types corresponds to the average level of anxiety, except for the "adequate" temperament type, which corresponds to a low level of anxiety. The group of subjects with the "adequate" temperament type (10.8%) exhibited the most significant increase in athletic performance in the 800 m freestyle, while the increase of performance of the group of subjects with "calm" and "intensive" temperaments was 2.1% and 2.7% lower, respectively. The group with the “adequate” temperament type exhibited the most significant increase in athletic performance in the 200 m IM (10.2%). There are statistically significant differences in results between the "adequate" and "calm" groups (p0.05). At the same time, the authors found that individuals with "calm" and "adequate" temperament types have a greater reliability of the start reaction time. Conclusion. The research outcomes show the significance of particular consideration for temperament types and indicators of personal and situational anxiety in the process of regulation of pre-start condition of swimmers at the training stage. Particular attention should be given to the athletes with "calm" and "intensive" temperament types.

Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.

Background: Urinary tract infection (UTI) is the most common urologic complication among patients with inflammatory bowel disease (IBD). However, data regarding UTI outcomes in this population are scarce. We aimed to evaluate adverse outcomes of UTI among patients with IBD. Methods: This was a retrospective cohort study of consecutive adult patients who visited the emergency room (ER) at Sheba Medical Center due to a UTI between 2012 and 2018. Data included demographic and clinical variables. UTI cases were extracted using ICD-10 coding. Results: Of 21,808 (ER) visits with a UTI, 122 were IBD patients (Crohn’s disease—52, ulcerative colitis—70). Contrary to non-IBD subjects, patients with IBD had higher rates of hospitalization, acute kidney injury (AKI) and 30 day-recurrent hospitalization (59.3% vs. 68.9%, p = 0.032; 4.6% vs. 13.9%, p < 0.001; 7.3% vs. 15.6%, p = 0.001, respectively). Among patients with IBD, advanced age (p = 0.005) and recent hospitalization (p = 0.037) were associated with increased risk for hospitalization, while hydronephrosis (p = 0.005), recent hospitalization (p = 0.011) and AKI (p = 0.017) were associated with increased 30-day recurrent hospitalization. Neither immunosuppressants nor biologics were associated with UTI outcomes among patients with IBD. Conclusions: Patients with IBD treated for a UTI had higher rates of hospitalization, AKI and 30-day recurrent hospitalization than non-IBD patients. No association was observed between immunosuppressants or biologics and UTI outcomes.