Charles University in Prague
  • Prague, CZ, Czechia
Recent publications
Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.
SARS-CoV-2 is suspected to be the product of a natural or artificial recombination of two viruses – one adapted to the horseshoe bat and the other, donor of the spike protein gene, adapted to an unknown species. Here we used a new method to search for the original host of the ancestor of the SARS-CoV-2 virus and for the donor of its gene for the spike protein, the molecule responsible for binding to and entering human cells. We computed immunological T-distances (the number of different peptides which are present in the viral proteins but absent in proteins of the host) between 11 species of coronaviruses and 38 representatives of the main mammal clades. Analyses of pentapeptides, the presumed principal targets of T-cell non-self recognition, showed the smallest T-distance of the spike protein of SARS-CoV-2 to humans, while the rest of SARS-CoV-2 proteome to the horseshoe bat. This suggests that the ancestor of SARS-CoV-2 was adapted to bats, but the spike gene donor was adapted to humans. Further analyses suggest that the ancestral coronavirus adapted to bats was shortly passaged in treeshrews, while the donor of the spike gene was shortly passaged in rats before the recombination event. Keywords: SARS-CoV-2; Covid-19; host specificity; immunological distance; origin; alignment-free method; peptide vocabulary analysis
The immune system is important for elimination of residual leukemic cells during acute myeloid leukemia (AML) therapy. Anti-leukemia immune response can be inhibited by various mechanisms leading to immune evasion and disease relapse. Selected markers of immune escape were analyzed on AML cells from leukapheresis at diagnosis (N = 53). Hierarchical clustering of AML immunophenotypes yielded distinct genetic clusters. In the absence of DNMT3A mutation, NPM1 mutation was associated with decreased HLA expression and low levels of other markers (CLIP, PD-L1, TIM-3). Analysis of an independent cohort confirmed decreased levels of HLA transcripts in patients with NPM1 mutation. Samples with combined NPM1 and DNMT3A mutations had high CLIP surface amount suggesting reduced antigen presentation. TIM-3 transcript correlated not only with TIM-3 surface protein but also with CLIP and PD-L1. In our cohort, high levels of TIM-3/PD-L1/CLIP were associated with lower survival. Our results suggest that AML genotype is related to blast immunophenotype, and that high TIM-3 transcript levels in AML blasts could be a marker of immune escape. Cellular pathways regulating resistance to the immune system might contribute to the predicted response to standard therapy of patients in specific AML subgroups and should be targeted to improve AML treatment.
The current nosological concept of α-synucleinopathies characterized by the presence of Lewy bodies (LBs) includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB), for which the term “Lewy body disease” (LBD) has recently been proposed due to their considerable clinical and pathological overlap. However, even this term does not seem to describe the true nature of this group of diseases. The subsequent discoveries of α-synuclein (αSyn), SNCA gene, and the introduction of new immunohistochemical methods have started intensive research into the molecular-biological aspects of these diseases. In light of today’s knowledge, the role of LBs in the pathogenesis and classification of these nosological entities remains somewhat uncertain. An increasingly more important role is attributed to other factors as the presence of various LBs precursors, post-translational αSyn modifications, various αSyn strains, the deposition of other pathological proteins (particularly β-amyloid), and the discovery of selective vulnerability of specific cells due to anatomical configuration or synaptic dysfunction. Resulting genetic inputs can undoubtedly be considered as the main essence of these factors. Molecular–genetic data indicate that not only in PD but also in DLB, a unique genetic architecture can be ascertained, predisposing to the development of specific disease phenotypes. The presence of LBs thus remains only a kind of link between these disorders, and the term “diseases with Lewy bodies” therefore results somewhat more accurate.
Background Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. Methods ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. Results Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. Conclusions The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.
Background Management and monitoring of pain and sedation to reduce discomfort as well as side effects, such as over- and under-sedation, withdrawal syndrome and delirium, is an integral part of pediatric intensive care practice. However, the current state of management and monitoring of analgosedation across European pediatric intensive care units (PICUs) remains unknown. The aim of this survey was to describe current practices across European PICUs regarding the management and monitoring of pain and sedation. Methods An online survey was distributed among 357 European PICUs assessing demographic features, drug choices and dosing, as well as usage of instruments for monitoring pain and sedation. We also compared low- and high-volume PICUs practices. Responses were collected from January to April 2021. Results A total of 215 (60% response rate) PICUs from 27 European countries responded. Seventy-one percent of PICUs stated to use protocols for analgosedation management, more frequently in high-volume PICUs (77% vs 63%, p = 0.028). First-choice drug combination was an opioid with a benzodiazepine, namely fentanyl (51%) and midazolam (71%) being the preferred drugs. The starting doses differed between PICUs from 0.1 to 5 mcg/kg/h for fentanyl, and 0.01 to 0.5 mg/kg/h for midazolam. Daily assessment and documentation for pain (81%) and sedation (87%) was reported by most of the PICUs, using the preferred validated FLACC scale (54%) and the COMFORT Behavioural scale (48%), respectively. Both analgesia and sedation were mainly monitored by nurses (92% and 84%, respectively). Eighty-six percent of the responding PICUs stated to use neuromuscular blocking agents in some scenarios. Monitoring of paralysed patients was preferably done by observation of vital signs with electronic devices support. Conclusions This survey provides an overview of current analgosedation practices among European PICUs. Drugs of choice, dosing and assessment strategies were shown to differ widely. Further research and development of evidence-based guidelines for optimal drug dosing and analgosedation assessment are needed.
Background Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. Methods We searched PubMed and EMBASE covering the period between January 1 st 2020 and August 6 th , 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. “traditional” vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. Results Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18–27%) of subjects after the first dose of vaccine and in 29% (95% CI 23–35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10–12% of cases. No differences were detected across different vaccines or by mRNA-based vs. “traditional” ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. Conclusions Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40–60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.
Background Amphetamine-type stimulants (ATS) are globally widely used. Scientific literature generally defines four phases of substance use (initiation, continuation, increase and decrease); however, there is limited understanding of what influences these different phases of ATS use. The ATTUNE study investigated which factors shape individual phases of use, or ATS use patterns. In this article, we report on these phases into and out of ATS use, and propose a set of recommendations for prevention, harm reduction and treatment of the different phases of ATS use. Methods Qualitative, semi-structured interviews ( n = 237) were conducted in five different European countries with participants who had used ATS, varying from a few times in a lifetime to daily. Results Amphetamine and MDMA were the most commonly used ATS. Yet, types of ATS used differed between the countries. We found that people who use ATS have various motives for and dynamic patterns of ATS use with alternating phases of increase, continuation, decrease and sometimes dependence. Cessation was pursued in different ways and for diverse reasons, such as mental health problems and maturing out. Availability seemed not an issue, regardless of the type of ATS, phase or country. Conclusions These findings demonstrate that tailor-made interventions are needed for the diverse types of people who use ATS and different phases or patterns of ATS use, to reduce possible harms of use. We recommended a set of interventions for the different ATS phases. These include drug checking services, peer-led information, self-management of ATS use, mental health support to help people cope with stressful life events and prevent uncontrolled use, and follow-up support after treatment.
Understanding the physical basis of corneal transparency has been a subject of interest amongst physicists, basic scientists and ophthalmologists. Impairment of corneal clarity is a significant cause of visual morbidity worldwide. Thus, it is essential to understand the mechanisms behind corneal transparency and how the alterations due to corneal pathologies affect vision. We use Maxwell’s equations to model light propagation in ocular tissues and a nodal discontinuous Galerkin method combined with an explicit Runge-Kutta method to simulate light propagation in normal and pathological corneas. Our simulation results illustrate that an increase in the diameter of some fibres causes an increase in backscattering. Thus, these may represent some of the physical changes in the cornea that might result in loss of transparency and visual morbidity.
The known CUS assessment (1) of pleural fluid volume largely underestimates reality in severely consolidated lungs surrounded by potentially misleadingly thin layer of circumferential effusion. The prediction error may be greatly reduced by calculating with pleural separation above the posterior axillary line which enables better evaluation of the benefits of pleural drainage versus the risks of complications in anticoagulated patients on ECMO (Fig.1).
In this work, we introduce a notion of dissipative weak solution for a system describing the evolution of a heat-conducting incompressible non-Newtonian fluid. This concept of solution is based on the balance of entropy instead of the balance of energy and has the advantage that it admits a weak–strong uniqueness principle, justifying the proposed formulation. We provide a proof of existence of solutions based on finite element approximations, thus obtaining the first convergence result of a numerical scheme for the full evolutionary system including temperature dependent coefficients and viscous dissipation terms. Then we proceed to prove the weak–strong uniqueness property of the system by means of a relative energy inequality.
Objectives Bilirubin is a potent endogenous antioxidant and immunomodulating substance, which is also implicated in both cell signalling and various metabolic pathways. Mild elevation of systemic bilirubin concentrations provides substantial protection against many diseases of civilization. Rare published reports have suggested that serum bilirubin might also be relevant to sports performance. The purpose of the current study was to evaluate serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in elite athletes. Methods The study was carried out in 536 consecutive healthy elite athletes and in 2594 individuals of the Czech post-MONICA study representing the general Czech population. Serum bilirubin concentrations, the prevalence of benign hyperbilirubinemia > 17 µmol/L (1 mg/dL, a phenotypic sign of GS), and a variant of the UGT1A1 gene promoter responsible for GS manifestation in Caucasians (rs81753472) were evaluated in study subjects. Results Compared to the general Czech population, significantly higher serum bilirubin concentrations were found in elite athletes (9.6 vs. 11.6 µmol/L, p < 0.001), both in men (11.3 vs. 12.6 µmol/L, p < 0.001) and women (8.3 vs. 10.5 µmol/L, p < 0.001). Furthermore, the prevalence of GS was also significantly higher in elite athletes (9.6 vs. 22%, p < 0.001) together with the tendency to higher frequencies of the genotypes (TA) 7/7 and (TA) 6/7 UGT1A1 . Conclusion Elite athletes have significantly higher concentrations of serum bilirubin, the most potent endogenous antioxidant substance known. Simultaneously, the prevalence of GS syndrome is also much higher in elite athletes, suggesting that a mild elevation of serum bilirubin might predispose to better sports performance.
Optical absorbers have many applications in the field of optoelectronics, photovoltaics, and energy harvesting because of their capability to absorb electromagnetic waves, as well as their ability to adjust the absorption of specific wavelengths in the mid-IR region. In this study, a perfect optical absorber was designed, which included a gold reflective substrate, Al 2 O 3 grating, a phosphorene layer, and air. By using the finite element method, the effects of irregularities on the geometry of the grating were investigated. Results show that, in the designed structure, irregular grating did not cause a significant change in the amount of absorption, and the absorption value for the phosphor layer remained at 99.9%. This perfect absorber also showed a stable wide range of absorption of up to 7.5 µm. Changing the incident light angle in the range of 0 to 50 degrees reduced the absorption in the phosphor layer by less than 10%.
Graphite is a fascinating material with unique properties, thus making it irreplaceable for a wide range of applications. However, its current processing route is highly energy demanding as it requires dwelling for several hours at high temperatures (2500-3000°C). We report on the near full consolidation (relative density greater than 95%) at room temperature of graphite flakes under a mild uniaxial or isostatic pressure (100-500 MPa). The application of an external pressure promoted the formation of van der Walls bonds between the flakes, and the consolidation (pore removal) was mostly achieved by interplanar slipping. Despite the room temperature processing, with embodied energy below 1 MJ/kg, the resulting compact had in plane electrical and thermal conductivities as high as 0.77×10⁶ S/m and 620 W/m·K (exceeding commercial isotropic graphite ≈0.09×10⁶ S/m and 120 W/m·K). The bulks were thermally stable up to 1800°C. Because of the reversible nature on the van der Walls bonding, the cold pressed pellets were fully recyclable (i.e., easily milled and re-shaped) with a mild degradation of the electrical conductivity from 0.77 to 0.19×10⁶ S/m after ten cycles.
A set of sets is called a family. Two families A and B of sets are said to be cross-intersecting if each member of A intersects each member of B. For any two integers n and k with 1≤k≤n, let ([n]≤k) denote the family of subsets of [n]={1,…,n} that have at most k elements. We show that if A is a non-empty subfamily of ([n]≤r), B is a non-empty subfamily of ([n]≤s), r≤s, and A and B are cross-intersecting, then|A|+|B|≤1+∑i=1s((ni)−(n−ri)), and equality holds if A={[r]} and B is the family of sets in ([n]≤s) that intersect [r].
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Martin Nekola
  • Institute of Sociological Studies
Ales Vicha
  • Department of Paediatric Haematology and Oncology (2. LF)
Vladimir Krylov
  • Department of Cell Biology (PF)
Ales Hahn
  • Department of Otorhinolaryngology (3. LF)
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Ovocný trh 5, 11636, Prague, CZ, Czechia
Head of institution
Prof. MUDr. Tomáš Zima, DrSc., MBA
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http://www.cuni.cz/ukeng-1.html
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