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Abstract: Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS). We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein–protein-interactioninhibitor-focused libraries to gain a better understanding of how these libraries were designed. The most common were ligand- and structure-based approaches, along with various filtering steps, using molecular descriptors. Often, these methods were combined to obtain the final library. We recognized the abundance of targeted libraries offered and complimented by the inclusion of analytical data; however, serious concerns had to be raised. Namely, vendors lack the information on the library design and the references to the primary literature. Few references to active compounds were also provided when using the ligand-based design and usually only protein classes or a general panel of targets were listed, along with a general reference to the methods, such as molecular docking for the structure-based design. No receptor data, docking protocols or even references to the applied molecular docking software (or other HTVS software), and no pharmacophore or filter design details were given. No detailed functional group or chemical space analyses were reported, and no specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode well for the use of the reviewed libraries in drug design and lend themselves to commercial drug companies to focus on and improve.
Keywords: targeted libraries, focused libraries, computer-aided drug design, virtual screening, in silico drug design, high-throughput virtual screening
Published in DKUM: 09.04.2025; Views: 0; Downloads: 3
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Abstract: This paper describes the non-contact vibration monitoring of prestressed reinforced concrete railway sleepers. The monitoring was carried out using physical measuring equipment consisting of a seismograph and geophones, a robotic total station (RTS) and scanning laser Doppler vibrometry (SLDV) equipment. Measurements of the dynamic response of sleepers to the dynamic loading induced by the running of train sets provides data that give an insight into the actual state of the sleeper structure at the moment when it is most stressed. The main objective of the study was to identify the most appropriate form of monitoring to monitor events related to the occurrence of cracks in the rail sill, which can also be caused by the impact of vibration. As is well-known, monitoring the dynamic response of railway sleepers is very important for the sustainable management and maintenance of railway lines. The vibration analysis was carried out in the field on the Ormož–Ptuj section of the railway line, in Velika Nedelja and in the laboratory of the UM FGPA, where the vibration was simulated using a hydraulic kit with a static and pulsed force of 100 kN. Several cycles of measurement were carried out and the results were compared with the results of the field monitoring. The vibration parameters measured for the concrete sleepers are necessary to develop a realistic dynamic model of the railway line, which will be able to predict its response to impact loads and the possible occurrence of damage, as has recently been observed for concrete sleepers in several European Union countries.
Keywords: monitoring, measurement equipment, railway line, displacements, deformations
Published in DKUM: 12.03.2025; Views: 0; Downloads: 4
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Abstract: Introduction: The clinical-histologic correlation in diabetic nephropathy is not completely known. Methods: We analyzed nephrectomy specimens from 90 patients with diabetes and diverse degrees of proteinuria and glomerular filtration rate (GFR). Results: Thirty-six (40%) subjects had normoalbuminuria, 33 (37%) microalbuminuria, and 21 (23%) non-nephrotic proteinuria. Mean estimated GFR (eGFR) was 65±23 (40% <60 ml/min per 1.73 m2). About 170 glomeruli per patient were analyzed, and all samples included vascular tissue. Six subjects (7%) were classified in diabetic nephropathy class I, 61 (68%) in class II-a, 13 (14%) in class II-b, 9 (10%) class III, and 1 (1%) in class IV. Eighty percent to 90% of those with normoalbuminuria or microalbuminuria were classified in class II-a or II-b and <10% in class III; 52% of those with proteinuria were in class II-a, 15% in class II-b, and 19% in class III. Nodular sclerosis (57%) and mesangial expansion (15%) were more frequent in cases with proteinuria than in normoalbuminuria (28% and 8%; P = 0.028 and 0.017). About 20% to 30% of all cases, regardless the level of albuminuria or proteinuria or the histologic class had tubular atrophy, interstitial fibrosis, or inflammation in >10% to 20% of the sample. Moderate hyalinosis and arteriolar sclerosis were observed in 80% to 100% of cases with normoalbuminuria, microalbuminuria, proteinuria, as well as in class I, II, or III. Conclusions: Weak correspondence between analytical parameters and kidney histology was found. Thus, disease may progress undetected from the early clinical stages of the disease. Finally, vascular damage was a very common finding, which highlights the role of ischemic intrarenal disease in diabetes.
Keywords: albuminuria, chronic kidney disease, diabetes, diabetic nephropathy, histology, normoalbuminuria
Published in DKUM: 06.12.2024; Views: 0; Downloads: 5
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Abstract: Vzpon digitalnih medijev in družbenih omrežij je omogočil prihod novih načinov komuniciranja za podjetja. TikTok je v zadnjem času eno izmed bolj priljubljenih družbenih omrežij. Ob nastanku družbenih omrežij je nastal tudi vplivnostni marketing, ki je del digitalnega marketinga in za svojo komuniciranje uporablja digitalne marketinške kanale. Pomemben vidik so vplivneži, ki s svojo avtentičnostjo in kreativnostjo vplivajo na nakupne odločitve uporabnikov družbenih omrežij. Ti imajo ključno vlogo pri promociji podjetja, saj imajo močan vpliv na zaupanje in percepcijo svojih sledilcev. Diplomsko delo se osredotoča na uporabo TikTok vplivnežev in njihov vpliv na nakupne odločitve slovenskih uporabnikov TikToka.
Keywords: TikTok, vplivnež, nakupne odločitve, družbeno omrežje, vplivnostni marketing
Published in DKUM: 19.09.2024; Views: 0; Downloads: 57
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Abstract: In the vast majority of cases, glomerular filtration rate (GFR) is estimated using serum creatinine, which is highly influenced by age, sex, muscle mass, body composition, severe chronic illness and many other factors. This often leads to misclassification of patients or potentially puts patients at risk for inappropriate clinical decisions. Possible solutions are the use of cystatin C as an alternative endogenous marker or performing direct measurement of GFR using an exogenous marker such as iohexol. The purpose of this review is to highlight clinical scenarios and conditions such as extreme body composition, Black race, disagreement between creatinine- and cystatin C–based estimated GFR (eGFR), drug dosing, liver cirrhosis, advanced chronic kidney disease and the transition to kidney replacement therapy, non-kidney solid organ transplant recipients and living kidney donors where creatinine-based GFR estimation may be invalid. In contrast to the majority of literature on measured GFR (mGFR), this review does not include aspects of mGFR for research or public health settings but aims to reach practicing clinicians and raise their understanding of the substantial limitations of creatinine. While including cystatin C as a renal biomarker in GFR estimating equations has been shown to increase the accuracy of the GFR estimate, there are also limitations to eGFR based on cystatin C alone or the combination of creatinine and cystatin C in the clinical scenarios described above that can be overcome by measuring GFR with an exogenous marker. We acknowledge that mGFR is not readily available in many centres but hope that this review will highlight and promote the expansion of kidney function diagnostics using standardized mGFR procedures as an important milestone towards more accurate and personalized medicine.
Keywords: biomarker, chronic kidney disease, clinical indications, creatinine, cystatin C, kidney function, measured glomerular filtration rate
Published in DKUM: 12.08.2024; Views: 52; Downloads: 11
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