Chemoinformatics-Driven Approaches for Kinase Drug Discovery

Given their importance for the majority of cell physiology processes, protein kinases are among the most extensively studied protein targets in drug discovery. Inappropriate regulation of their basal levels results in pathophysiological disorders. In this regard, small-molecule inhibitors of human kinome have been developed to treat these conditions effectively and improve the survival rates and life quality of patients. In recent years, kinase-related data has become increasingly available in the public domain. These large amounts of data provide a rich knowledge source for the computational studies of kinase drug discovery concepts. This thesis aims to systematically explore properties of kinase inhibitors on the basis of publicly available data. Hence, an established "selectivity versus promiscuity" conundrum of kinase inhibitors is evaluated, close structural analogs with diverging promiscuity levels are analyzed, and machine learning is employed to classify different kinase inhibitor binding modes. In the first study, kinase inhibitor selectivity trends are explored on the kinase pair level where kinase structural features and phylogenetic relationships are used to explain the obtained selectivity information. Next, selectivity of clinical kinase inhibitors is inspected on the basis of cell-based profiling campaign results to consolidate the previous findings. Further, clinical candidates are mapped to medicinal chemistry sources and promiscuity levels of different inhibitor subsets are estimated, including designated chemical probes. Additionally, chemical probe analysis is extended to expert-curated representatives to correlate the views established by scientific community and evaluate their potential for chemical biology applications. Then, large-scale promiscuity analysis of kinase inhibitor data combining several public repositories is performed to subsequently explore promiscuity cliffs (PCs) and PC pathways and study structure-promiscuity relationships. Furthermore, an automated extraction protocol prioritizing the most informative pathways is proposed with focus on those containing promiscuity hubs. In addition, the generated promiscuity data structures including cliffs, pathways, and hubs are discussed for their potential in experimental and computational follow-ups and subsequently made publicly available. Finally, machine learning methods are used to develop classification models of kinase inhibitors with distinct experimental binding modes and their potential for the development of novel therapeutics is assessed

Interpretable bilinear attention network with domain adaptation improves drug-target prediction

Predicting drug-target interaction is key for drug discovery. Recent deep learning-based methods show promising performance but two challenges remain: (i) how to explicitly model and learn local interactions between drugs and targets for better prediction and interpretation; (ii) how to generalize prediction performance on novel drug-target pairs from different distribution. In this work, we propose DrugBAN, a deep bilinear attention network (BAN) framework with domain adaptation to explicitly learn pair-wise local interactions between drugs and targets, and adapt on out-of-distribution data. DrugBAN works on drug molecular graphs and target protein sequences to perform prediction, with conditional domain adversarial learning to align learned interaction representations across different distributions for better generalization on novel drug-target pairs. Experiments on three benchmark datasets under both in-domain and cross-domain settings show that DrugBAN achieves the best overall performance against five state-of-the-art baselines. Moreover, visualizing the learned bilinear attention map provides interpretable insights from prediction results.Comment: 16 pages, 6 figure

EPIDEMIOLOGY AND PROGNOSTIC FACTORS IN PATIENTS WITH SUBDURAL HEMATOMA

SDH was first described in 1658 and in 1914 trauma was recognized as one of the causes. Acute SDH is more common in younger population while chronic is common in the elderly with the peak of incidence of 7.35/100000 per year in the age group 70-79 years. Trauma is one of the main causes of SDH although in 30-50% of patients direct trauma to the head can be omitted. Other predisposing factors include: anticoagulant therapy, epilepsy, and hypertension. The aim of the study was to determine risk factors and prognostic factors for the occurrence of SDH, also to show what age group  is most at risk for developing chronic and acute SDH. Identify the diagnostic steps in proving SDH and the best method of treatment. The study includes 267 patients treated in the period from 1.1.2019 to 31.12.2019 at the Clinic for Neurosurgery CCS. SDH was diagnosed by neurological examination and brain CT in all patients and all were treated conservatively or surgically. The analytical statistics were used parametric and non-parametric tests of difference. The study included 185 men and 82 women of middle age 68 ± 17.19 years. Most patients were between 6-8 decades. Multiple changes in  CT were observed in 63.3% of patients. Chronic SDH had 50.5% of patients and 45.6% had acute SDH. The most common symptoms were headache, psycho-organic syndrome, and hemiparesis. Patients with a GCS score of more than 8 had a better prognosis and outcome. Surgical treatment was the main course of treatment in our study. CT with / without contrast is the gold standard in detecting SDH. Men are at higher risk for the occurrence of SDH. Symptoms can occur later in the clinical presentation so we need to take caution when performing neurological examination. Factors that can lead us to suspect possible SDH are: age, gender, type of injury, clinical presentation, and time of occurrence

iTrust News Certificate: A Blockchain-Based Solution for News Verification and Reputation Management

The proliferation of fake news and misinformation in the digital era poses a significant challenge to news organizations and content creators. In this paper, we intro-duce the iTrust News Certificate, the architecture of an online blockchain-based solution designed to combat fake news, enhance news verification, and maintain reputation within the media ecosystem. Unlike previous attempts, iTrust News Certificate focuses on us-er-friendly features while ensuring transparency and reliability. By leveraging blockchain technology, iTrust News Certificate establishes a decentralized and immutable ledger for storing news-related metadata. This ledger ensures the integrity and traceability of news articles, making it extremely difficult for malicious actors to tamper with or propagate false information

COMPARATIVE ANALYSIS OF SURGICAL AND ENDOVASCULAR TREATMENT OF INTRACRANIAL ANEURYSMS

With a prevalence of about 2.3%, intracranial aneurysms represent the most common cause of spontaneous subarachnoid hemorrhage. Many studies compared currently most common therapeutic options-neurosurgical clipping and endovascular embolization, but so far no single solution in which therapeutic method should have an advantage has been found. The aim was to compare the outcome of treatment on discharge, among patients treated with clipping or embolization. The data of 62 patients treated at the Neurosurgery Clinic of the Clinical Center of Serbia, were obtained through discharge lists. The analysis included data on sex, age, Glasgow coma scale, aneurysm rupture, Hunt & Hess scale, localization, number of aneurysms, length of overall and postoperative stay as well as the existence of complications. The condition on discharge was assessed using the Glasgow outcome scale. In our study 37 subjects (59.7%) had a subarachnoid hemorrhage, while 25 (41.9%) patients were without bleeding. 30 patients underwent surgery, while 32 were treated by embolization. No significant relationship between the treatment modality and outcome on discharge was observed (p=0.115). Patients without bleeding had a significantly better outcome on discharge when treated by endovascular method (p<0.001), whereas in the group with a rupture no differences were found (p=0.35). Complications were significantly more common after surgery (p=0.026). No difference among the groups in the length of the total hospital stay was found (p=0.246), while a significantly longer postprocedural period was recorded following neurosurgical treatment (p=0.029). Groups treated with different modalities did not differ in the outcome on discharge. However, the percentage of complications was greater in the group of patients undergoing surgery, as well as the length of postoperative hospital stay. We believe that furthe detailed analyzes offering information on the condition of patients after a long period of follow-up iare required

Susceptibility of dried berries to infestation by Plodia interpunctella (Lepidoptera: Pyralidae) in correlation with total sugar content: Poster

By assessing the degree of resistance of stored products to infestation by insect pests and correlating it with physical, chemical and nutritional characteristics of products, we could gain a real insight in these pests feeding preferences, and consequently in their biology and ecology. The aim of this study was to assess the degree of resistance of five dried berry species (strawberry, raspberry, blackberry, black chokeberry and cranberry) to infestation caused by the major pest of dried berries, Plodia interpunctella. Susceptibility was rated based on the Index of susceptibility (IS) for insect development and the Susceptibility rating. Dried cranberries were absolutely resistant to infestation by P. interpunctella (IS = 0) - no larvae reached the adult stage. Four other dried berry species were also resistant (IS ranged 2.01 – 2.44). In other words, dried cranberries are very unsuitable food for P. interpunctella, while other four tested species were slightly more suitable. The content of total sugars in dried berries varied from 24.2% (black chokeberry) to 72.8% (strawberry), but important correlation between IS and total sugar content was not found. By analysing feeding preferences of P. interpunctella, we can undertake different pest-management strategies for protection of stored dried fruits.By assessing the degree of resistance of stored products to infestation by insect pests and correlating it with physical, chemical and nutritional characteristics of products, we could gain a real insight in these pests feeding preferences, and consequently in their biology and ecology. The aim of this study was to assess the degree of resistance of five dried berry species (strawberry, raspberry, blackberry, black chokeberry and cranberry) to infestation caused by the major pest of dried berries, Plodia interpunctella. Susceptibility was rated based on the Index of susceptibility (IS) for insect development and the Susceptibility rating. Dried cranberries were absolutely resistant to infestation by P. interpunctella (IS = 0) - no larvae reached the adult stage. Four other dried berry species were also resistant (IS ranged 2.01 – 2.44). In other words, dried cranberries are very unsuitable food for P. interpunctella, while other four tested species were slightly more suitable. The content of total sugars in dried berries varied from 24.2% (black chokeberry) to 72.8% (strawberry), but important correlation between IS and total sugar content was not found. By analysing feeding preferences of P. interpunctella, we can undertake different pest-management strategies for protection of stored dried fruits

The Ho2O3 Concentration Influence on BaTiO3 – ceramics Fractal Structures

An influence of dopant concentration on microstructure and dielectric properties of doped BaTiO3-ceramics is developed based on fractal geometry. Using different technological parameters and different additives the structure of BaTiO3 based ceramics materials can be controlled. In this research, BaTiO3 samples with different concentration of Ho2O3 are used. The ratio of dopant concentration ranges from 0.05% to 1%. The sintering temperature of 1350°C is chosen. Selected specimens of BaTiO3 were documented using SEM (Scanning Electron Microscope) equipped with EDS analysis. As it is expected, the influence of impurities on intergranular capacity and other electrical properties is significant which is demonstrated and confirmed in this paper. Using the method of fractal modeling, a reconstruction of microstructure configurations, like grains shapes or intergranular contacts is performed. Such interdisciplinary research is important for opening new frontiers in electronics, and give us a fine perspective in dielectric materials. A merit of such perspective is definition of a bond between microelectronics and materials and components made for sensors and actuators

Comparative analysis of life span of imago Plodia interpunctella (Hübner) grown on three different types of nuts

Bakrenasti plamenac brašna (Plodia interpunctella, Lepidoptera, Pyralidae) predstavlja ekonomski najznačajniju štetočinu uskladištenih prehrambenih proizvoda. Cilj istraživanja bio je da se utvrdi da li postoje razlike u dužini života imaga P. interpunctella gajenog na izlomljenim jezgrama oraha, lešnika i badema. Najduži životni vek od 7,69 dana imala su imaga gajena na orahu. Na bademu i lešniku ova vrednost se statistički značajno ne razlikuje, i iznosi 7,07 i 6,73 dana, po podlogama. Na osnovu rezultata možemo zaključiti da je orah najpogodniji supstrat za razviće P. interpunctella.Indian Meal Moth (Plodia interpunctella, Lepidoptera, Pyralidae) is one of the most important pests of stored food products. The aim of this study was to determine the influence of different nutrient medium (broken kernels of walnuts, hazelnuts and almonds) on life span of imago P. interpunctella. The longest life span (7,69 days) was recorded on walnut. On hazelnut and almond, this value was statistically not significantly different, amounting to 7,07 and 6,73 days, respectively. According to obtained results, it can be concluded that the walnut is the most suitable nutrient medium for the development P. interpunctella

Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats.

Dendritic cells (DC) are responsible for the initiation and shaping of the adaptive immune response and are in the focus of autoimmunity research. We were interested in comparison of DC obtained from autoimmunity-prone Dark Agouti (DA) rats and autoimmunity-resistant Albino Oxford (AO) rats. DC were generated from bone marrow precursors and matured (mDC) by lipopolysaccharide. Tolerogenic DC (tolDC) obtained by vitamin D3 treatment were studied in parallel. Profile of cytokine production was different in AO and DA mDC and tolDC. Expression of MHC class II molecules and CD86 were higher in DA DC, while vitamin D3 reduced their expression in dendritic cells of both strains. Allogeneic proliferation of CD4+ T cells was reduced by AO tolDC, but not with DA tolDC in comparison to respective mDC. Finally, expression of various genes identified as differentially expressed in human mDC and tolDC was also analyzed in AO and DA DC. Again, AO and DA DC differed in the expression of the analyzed genes. To conclude, AO and DA DC differ in production of cytokines, expression of antigen presentation-related molecules and in regulation of CD4+ T proliferation. The difference is valuable for understanding the divergence of the strains in their susceptibility to autoimmunity

BaTiO3 – ceramics and Fractal Microstructure Analyses

Ceramics grain structure is difficult to describe by using traditional analytical methods based on Euclidean geometry. Using the fractal geometric/analytic methods instead, the new approach is offered in this paper. There are a many materials that can be doped to BaTiO3, in order to gain different characteristics and in this study we are using Ho2O3. Different concentrations has been used, as well as different sintering temperatures. For selected contacted grains, the SEM (Scanning Electron Microscope) pictures are taken providing suitable configuration for an electrical model study. It is shown that ferroelectric, optoelectric and piezoelectric properties, are influenced by fractal structure of grains and intergrains contacts, distribution of pores and inner dynamics during sintering process. Nowadays the material science is aware of importance of taking fractal properties of different ceramics and a new analytic and numerical models are suggested. The similar behavior is discovered in thin films and nano technologies as well