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Phthalocyanines play fundamental roles as electron-acceptors in many different fields; thus, the study of structural features affecting electron-accepting properties of these macrocycles is highly desirable. A series of low-symmetry zinc(II) phthalocyanines, in which one, three, or four benzene rings were replaced for pyrazines, was prepared and decorated with electron-neutral (alkylsulfanyl) or strongly electron-withdrawing (alkylsulfonyl) groups to study the role of the macrocyclic core as well as the effect of peripheral substituents. Electrochemical studies revealed that the first reduction potential (Ered1) is directly proportional to the number of pyrazine units in the macrocycle. Introduction of alkylsulfonyl groups had a very strong effect and resulted in a strongly electron-deficient macrocycle with Ered1= −0.48 V vs SCE (in THF). The efficiency of intramolecular-charge transfer (ICT) from the peripheral bis(2-methoxyethyl)amine group to the macrocycle was monitored as a decrease in the sum of ΦΔ+ ΦFand correlated well with the determined Ered1values. The strongest quenching by ICT was observed for the most electron-deficient macrocycle. Importantly, an obvious threshold at −1.0 V vs SCE was observed over which no ICT occurs. Disclosed results may substantially help to improve the design of electron-donor systems based on phthalocyanines.

The article focuses on the increasing emphasis on Diversity, Equity, and Inclusion (DE&I) initiatives, predicting a significant rise in global spending on such programs by 2026. Topics include the impact of globalization and technology on promoting diversity, discussions at the World Economic Forum Annual Conference on 'Rebuilding Trust,' and ongoing efforts to address challenges and promote DE&I policies globally.

The investigation into human butyrylcholinesterase (hBChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with a selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype. Notably, compounds 28(hBChE IC50= 0.171 ± 0.063 μM) and 33(hBChE IC50= 0.167 ± 0.018 μM) emerged as top-ranked hBChE inhibitors. In silicosimulations elucidated the binding modes of these compounds within hBChE. CNS availability was predicted using the BBB score algorithm, corroborated by in vitropermeability assessments with the most potent derivatives. Compound 33was also inspected for aqueous solubility, microsomal and plasma stability. Chemoinformatics analysis validated these hBChE inhibitors for oral administration, indicating favorable gastrointestinal absorption in compliance with Lipinski's and Veber's rules. Safety assessments, crucial for the chronic administration typical in AD treatment, were conducted through cytotoxicity testing on human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines.

•We evaluated alemtuzumab (ALZ) effect on neurodegeneration in RRMS.•SyMRI (brain atrophy) and OCT (retinal layer) were used to assess neurodegeneration.•Continued brain and retinal layer atrophy were seen in RRMS with disease activity.•Disease activity free patients showed signs of remyelination.

Aim:The Ostomy Life Study 2019 aimed to obtain a better understanding of the challenges faced by people with stoma.Methods:Online survey with participants from 17 countries.Findings:Of the 54 614 individuals invited to take part, 5187 responded; 62% of the respondents avoided physical and social activities because of their stoma and 37% had never consulted their stoma care nurse to have the fit of their stoma product checked. In a subgroup receiving questions on leakage (n=4209), output under the baseplate and leakage onto clothes were experienced within the previous month by 76% and 26% of respondents, respectively. Higher chance of leakage was associated with an irregular stoma shape and peristomal body profile; a stoma level at or below the skin surface; and the presence of creases, folds and other changes in the peristomal area.Conclusion:Leakage and access to a stoma care nurse to provide the necessary care and guidance remain important concerns for individuals with a stoma.

Reproducible expert-independent flow-cytometric criteria for the differential diagnoses between mature B-cell neoplasms are lacking. We developed an algorithm-driven classification for these lymphomas by flow cytometry and compared it to the WHO gold standard diagnosis. Overall, 662 samples from 662 patients representing 9 disease categories were analyzed at 9 laboratories using the previously published EuroFlow 5-tube-8-color B-cell chronic lymphoproliferative disease antibody panel. Expression levels of all 26 markers from the panel were plotted by B-cell entity to construct a univariate, fully standardized diagnostic reference library. For multivariate data analysis, we subsequently used canonical correlation analysis of 176 training cases to project the multidimensional space of all 26 immunophenotypic parameters into 36 2-dimensional plots for each possible pairwise differential diagnosis. Diagnostic boundaries were fitted according to the distribution of the immunophenotypes of a given differential diagnosis. A diagnostic algorithm based on these projections was developed and subsequently validated using 486 independent cases. Negative predictive values exceeding 92.1% were observed for all disease categories except for follicular lymphoma. Particularly high positive predictive values were returned in chronic lymphocytic leukemia (99.1%), hairy cell leukemia (97.2%), follicular lymphoma (97.2%), and mantle cell lymphoma (95.4%). Burkitt and CD10+diffuse large B-cell lymphomas were difficult to distinguish by the algorithm. A similar ambiguity was observed between marginal zone, lymphoplasmacytic, and CD10−diffuse large B-cell lymphomas. The specificity of the approach exceeded 98% for all entities. The univariate immunophenotypic library and the multivariate expert-independent diagnostic algorithm might contribute to increased reproducibility of future diagnostics in mature B-cell neoplasms.

Because cancer is the second leading cause of death globally, investigation of new photosensitizers for photodynamic therapy is highly desirable. In this work, different peripherally substituted subphthalocyanines (SubPcs) with either a benzocrown moiety (CE-) or a tyrosine methyl ester (Tyr-) as the axial ligand have been prepared. Target SubPcs showed high ΦΔvalues, >0.50 in EtOH. Both CE- and Tyr- moieties increased substantially the hydrophilicity of the compounds (log P= 1.79–2.63, n-octanol/PBS). Uptake to cells, subcellular localization, and monitoring of the progression of cell death over time are described. Improved spectroscopic behavior of the CE- series in cell culture medium resulted in higher photodynamic activity versus that of the Tyr- series. In particular, the peripherally triethylsulfanyl SubPc-CE exhibited extraordinarily low EC50values of 2.3 and 4.4 nM after light activation and high TC50values of 14.49 and 5.25 μM (i.e., dark toxicity without activation) on SK-MEL-28 and HeLa cells, respectively, which rank it among the best photosensitizers ever.

Background: An increasing number of patients are receiving left ventricle assist devices as a bridge to heart transplantation. The aim of this study was to determine the difference between patients who received transplants from a left ventricle assist device and those who underwent heart transplantation without a prior left ventricle assist device implantation.Material and methods: The study included patients who underwent heart transplantation in our institute between January 2010 and November 2018. The following clinical variables were evaluated: donor characteristics, patient’s pre-transplant demographical data, post-transplant data, and patient survival. Cardiac allograft vasculopathy progression was prospectively examined (after 1 month and 12 months after heart transplantation) by coronary optical coherence tomography. We were interested in the difference in 1- and 5-year survival between the left ventricle assist device and non-left ventricle assist device groups.Results: A total of 248 patients were identified; out of them, 48 patients received a left ventricle assist device before heart transplantation, whereas 200 had transplants with no prior left ventricle assist device implantation. There were no significant differences in any donor characteristics. The mean duration of cardiopulmonary bypass time in the non-left ventricle assist device group was 156 versus 175 min in the left ventricle assist device group (p= 0.009), blood loss was 650 versus 1045 mL (p< 0.001), the need to implant an extracorporeal membrane oxygenation was 10% versus 23% (p= 0.02). There was no difference in cardiac allograft vasculopathy progression between the groups 1 year after heart transplantation (p= 0.528). The 1- and 5-year survival, according to Kaplan–Meier, was 80% and 70% in the left ventricle assist device group, compared to 80% and 73%, respectively, in the non-left ventricle assist device group (Log-rank test: p= 0.945).Conclusion: Our results indicate that patients undergoing heart transplantation from left ventricle assist devices suffer significantly more from intraoperative and post-operative complications; however, only insignificant cardiac allograft vasculopathy progression and survival differences between the two groups were observed.

Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide toward the relevant classification panel and final diagnosis. In this study, we designed and validated an algorithm for automated (database-supported) gating and identification (AGI tool) of cell subsets within samples stained with ALOT. A reference database of normal peripheral blood (PB, n= 41) and bone marrow (BM; n= 45) samples analyzed with the ALOT was constructed, and served as a reference for the AGI tool to automatically identify normal cells. Populations not unequivocally identified as normal cells were labeled as checks and were classified by an expert. Additional normal BM (n= 25) and PB (n= 43) and leukemic samples (n= 109), analyzed in parallel by experts and the AGI tool, were used to evaluate the AGI tool. Analysis of normal PB and BM samples showed low percentages of checks (<3% in PB, <10% in BM), with variations between different laboratories. Manual analysis and AGI analysis of normal and leukemic samples showed high levels of correlation between cell numbers (r2> 0.95 for all cell types in PB and r2> 0.75 in BM) and resulted in highly concordant classification of leukemic cells by our previously published automated database-guided expert-supervised orientation tool for immunophenotypic diagnosis and classification of acute leukemia (Compass tool). Similar data were obtained using alternative, commercially available tubes, confirming the robustness of the developed tools. The AGI tool represents an innovative step in minimizing human intervention and requirements in expertise, toward a “sample-in and result-out” approach which may result in more objective and reproducible data analysis and diagnostics. The AGI tool may improve quality of immunophenotyping in individual laboratories, since high percentages of checks in normal samples are an alert on the quality of the internal procedures.

Much effort has been made to fabricate engineered tissues on a scale that is clinically relevant to humans; however, scale-up remains one of the most significant technological challenges of tissue engineering to date. To address this limitation, our laboratory has developed tissue-engineered skeletal muscle units (SMUs) and engineered neural conduits (ENCs), and modularly scaled them to clinically relevant sizes for the treatment of volumetric muscle loss (VML). The goal of this study was to evaluate the SMUs and ENCs in vitro, and to test the efficacy of our SMUs and ENCs in restoring muscle function in a clinically relevant large animal (sheep) model. The animals received a 30% VML injury to the peroneus tertius muscle and were allowed to recover for 3 months. The animals were divided into three experimental groups: VML injury without a repair (VML only), repair with an SMU (VML+SMU), or repair with an SMU and ENC (VML+SMU+ENC). We evaluated the SMUs before implantation and found that our single scaled-up SMUs were characterized by the presence of contracting myotubes, linearly aligned extracellular matrix proteins, and Pax7+satellite cells. Three months after implantation, we found that the repair groups (VML+SMU and VML+SMU+ENC) had restored muscle mass and tetanic force production to a level that was statistically indistinguishable from the uninjured contralateral muscle after 3 months in vivo. Furthermore, we demonstrated the ability of our ENCs to effectively bridge the gap between native nerve and the repair site by eliciting a muscle contraction through direct electrical stimulation of the re-routed nerve.Impact statementThe fabrication of tissues of clinically relevant sizes is one of the largest obstacles preventing engineered tissues from achieving widespread use in the clinic. This study aimed to combat this limitation by developing a fabrication method to scale-up tissue-engineered skeletal muscle for the treatment of volumetric muscle loss in a large animal (sheep) model and evaluating the efficacy of the tissue-engineered constructs after a 3-month recovery.

The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amphiphilic cationic) were investigated, with the aim of revealing reasons for such differences. In vitroassays on HeLa, MCF-7, and HCT-116 cells confirmed higher photoactivity for cationic Pcs (EC50∼ 3–50 nM) than for anionic Pcs (EC50∼ 0.3–10 μM), the latter being additionally significantly more active in serum-free medium. The environmental pH, binding to serum proteins, interaction with biomembranes, differences in subcellular localization, and relocalization after irradiation were found to be the main factors contributing to the generally lower photoactivity of anionic Pcs than that of the cationic derivatives. This result is not limited only to the presented derivatives and should be considered in the design of novel photosensitizers.

Background Allergic rhinitis is the most common allergic disorder. Although the management of the disease is successful in many patients, based on guidelines, some of them remain with symptoms uncontrolled with pharmacotherapy. Presently, there is no substantiated information on the control of allergic rhinitis in patients who underwent sublingual immunotherapy.Objective The purpose of this prospective follow-up study was to assess the control of allergic rhinitis in adults after a three-year course of house dust mite sublingual immunotherapy.Methods This prospective real-life study was designed to include adults with moderate to severe allergic rhinitis sensitized to house dust mite who underwent a three-year course of sublingual immunotherapy. Control of symptoms was assessed by Rhinitis Control Assessment Test (RCAT) after three years of house dust mite sublingual immunotherapy. Additionally, patients assessed their symptoms by utilizing a visual analog scale.Results A total number of 86 consecutively enrolled patients (46 (53.49%) men; mean age 26.10 years (SD = 5.85)) with moderate to severe allergic rhinitis and clinically relevant sensitization to house dust mite were evaluated. When assessed by RCAT on the third year, 74 (86.05%) had well-controlled symptoms and 20 (27.03%) of them were completely controlled. A significant reduction in visual analog scale scores—from 7.52 cm at baseline to 2.31 cm—was established (P< 0.0001). There was a strong negative correlation between RCAT scores and visual analog scale (r = −0.65; P< 0.01).Conclusion This study provided evidence that a three-year course of house dust mite sublingual immunotherapy appears effective in controlling the symptoms of allergic rhinitis.

The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic.

The sulfonamide function is used extensively as a general building block in various inhibitory scaffolds and, more specifically, as a zinc-binding group (ZBG) of metalloenzyme inhibitors. Here, we provide biochemical, structural, and computational characterization of a metallopeptidase in complex with inhibitors, where the mono- and bisubstituted sulfamide functions are designed to directly engage zinc ions of a bimetallic enzyme site. Structural data showed that while monosubstituted sulfamides coordinate active-site zinc ions via the free negatively charged amino group in a canonical manner, their bisubstituted counterparts adopt an atypical binding pattern divergent from expected positioning of corresponding tetrahedral reaction intermediates. Accompanying quantum mechanics calculations revealed that electroneutrality of the sulfamide function is a major factor contributing to the markedly lower potency of bisubstituted compounds by considerably lowering their interaction energy with the enzyme. Overall, while bisubstituted uncharged sulfamide functions can bolster favorable pharmacological properties of a given inhibitor, their use as ZBGs in metalloenzyme inhibitors might be less advantageous due to their suboptimal metal–ligand properties.

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+(PtII56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.

Radiosynovectomy with yttrium-90 silicate may be effective and safe for the treatment of recurrent hemarthrosis in hemophilia patients. Hemarthrosis is escape or discharge of blood into a joint or its cavity. Radiosynovectomy is irradiation of the lining of a joint by injection of radioactive material to destroy inflamed tissue. A study examined bleeding frequency and joint mobility in 16 joints of 14 hemophilia patients one year before and three to six years after radiosynovectomy with yttrium-90 silicate. One year after treatment, radiosynovectomy had decreased the frequency of bleeding in 94% of the joints. Mobility was also improved by more than 10 deg in nine joints. Three to six years after radiosynovectomy, bleeding was still infrequent in 63% of the joints. Only one patient developed a complication as a result of treatment with radiosynovectomy.

Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC50and promising antiproliferation activity in multiple myeloma (MM) cells.

Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications.

Three new alkaloids, bersavine (3), muraricine (4), and berbostrejdine (8), together with seven known isoquinoline alkaloids (1–2, 5–7, 9, and 10) were isolated from an alkaloidal extract of the root bark of Berberis vulgaris. The structures of the isolated compounds were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and optical rotation, and by comparison of the obtained data with those in the literature. The NMR data of berbamine (5), aromoline (6), and obamegine (7) were completely assigned employing 2D NMR experiments. Alkaloids isolated in sufficient amounts were evaluated for their in vitro acetylcholinesterase, butyrylcholinesterase (BuChE), prolyl oligopeptidase, and glycogen synthase kinase-3β inhibitory activities. Selected compounds were studied for their ability to permeate through the blood–brain barrier. Significant human BuChE (hBuChE) inhibitory activity was demonstrated by 6(IC50= 0.82 ± 0.10 μM). The in vitro data were further supported by computational analysis that showed the accommodation of 6in the active site of hBuChE.

ABSTRACTThis contribution aims to compare and contrast the evolution of “EU shared values” debate in the EU's external policy over the period from 2015 to 2018. In this introductory comment, we look at how the “values vs interests” dilemma plays out in recent EU's strategic documents such as the European Global Strategy, as well as at the state of debate in mass media, academia and civil society. We ask: Is the EU's external action becoming more normatively oriented or more pragmatic in response to internal and external contestation? How are changes in responses communicated, and how does contestation affect and how does the EU reflect such communicative processes? The two subsequent contributions, dealing with trade policy and the European Neighbourhood Policy, provide a detailed analysis of the evolving role values play in these two external policies.

Prolonged QT interval is an independent risk factor for development of ventricular arrhythmias. Haloperidol is one of the drugs inducing QT prolongation. Previous studies showed that haloperidol affects not only QT duration but also heart rate (RR interval). The present work focused on relationship between QT and RR and its changes under acute and chronic haloperidol administration. The study included 14 male guinea pigs divided into control and haloperidol-treated group. After 21-days administration of haloperidol or vehiculum, electrograms in isolated hearts were recorded. QT/RR and dQT/dRR coupling were calculated. Chronic haloperidol administration significantly decreases the coupling between QT and RR. Acute haloperidol exposure significantly decreases the dQT/dRR coupling in both treated and untreated guinea pig hearts. Flatter QT/RR relationship reveals a lack of QT adaptation to increased heart rate. It should be emphasized that in such situation ECG recording will not show significant QT prolongation evaluated according to clinical rules. However, if QT interval does not adapt to increased heart rate sufficiently, the risk of ventricular arrhythmias may be increased despite practically normal QT interval length. The results are supported by findings in biochemical analyses, which proved eligibility of the used model.

To assess the impact of cities on climate, modelling is used with inclusion of urban parameterisation which is important when applying higher resolution. It is essential to assess uncertainties of urban effect parameterisations. To estimate this we performed experiments with available settings of urban canopy models over central Europe for 2001-2010. We have used RegCM4 and WRF in 10 km resolution, three surface schemes and five urban canopy parameterisations available. Selected WRF options were tested for urbanised weather prediction in 3 km resolution to show the effect in a single extreme case study. Urban heat island was detected in all simulations, for summer night the strongest on average was a few °C. We demonstrate that for cities like Prague it can in extremes approach 5°C, for larger city such as Budapest it is 8°C. In weather prediction mode, WRF model captured these effects in a single heat wave with selected parameterisations well.

Phenotypic drug screening identified the clinical PKC inhibitor midostaurin to have potent activity in several lung cancer cells independently of inhibiting PKC. Network-based integration of chemo- and phosphoproteomics data highlighted multiple midostaurin targets and signaling pathways. Functional validation determined a complex polypharmacology mechanism involving the midostaurin targets TBK1, PDPK1 and AURKA and the downstream node PLK1. Combination of midostaurin with the potent PLK1 inhibitor BI2536 further enhanced the cells' network vulnerability and resulted in strong synergy.

Abstract The need for prevention of venous thromboembolism (VTE) after total hip or knee replacement is obvious. However, the optimal regimen to achieve this remains to be defined. In patients [...]

A series of dinuclear octahedral PtIVcomplexes trans,trans,trans-[{Pt(N3)2(py)2(OH)(OC(O)CH2CH2C(O)NH)}2R] containing pyridine (py) and bridging dicarboxylate [R = −CH2CH2– (1), trans-1,2-C6H10– (2), p-C6H4– (3), −CH2CH2CH2CH2– (4)] ligands have been synthesized and characterized, including the X-ray crystal structures of complexes 1·2MeOH and 4, the first photoactivatable dinuclear PtIVcomplexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N3→ Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm2, 1 h), including A2780 human ovarian and esophageal OE19 cells with IC50values of 8.8–78.3 μM, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRC5 lung fibroblasts), with IC50values >100 μM, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear PtIVcomplexes. Liquid chromatography–mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.

The β-adrenergic signaling pathways and antioxidant defence mechanisms play important roles in maintaining proper heart function. Here, we examined the effect of chronic normobaric hypoxia (CNH, 10% O2, 3 weeks) on myocardial β-adrenergic signaling and selected components of the antioxidant system in spontaneously hypertensive rats (SHR) and in a conplastic SHR-mtBN strain characterized by the selective replacement of the mitochondrial genome of SHR with that of the more ischemia–resistant Brown Norway strain. Our investigations revealed some intriguing differences between the two strains at the level of β-adrenergic receptors (β-ARs), activity of adenylyl cyclase (AC) and monoamine oxidase A (MAO-A), as well as distinct changes after CNH exposure. The β2-AR/β1-AR ratio was significantly higher in SHR-mtBN than in SHR, apparently due to increased expression of β2-ARs. Adaptation to hypoxia elevated β2-ARs in SHR and decreased the total number of β-ARs in SHR-mtBN. In parallel, the ability of isoprenaline to stimulate AC activity was found to be higher in SHR-mtBN than that in SHR. Interestingly, the activity of MAO-A was notably lower in SHR-mtBN than in SHR, and it was markedly elevated in both strains after exposure to hypoxia. In addition to that, CNH markedly enhanced the expression of catalase and aldehyde dehydrogenase-2 in both strains, and decreased the expression of Cu/Zn superoxide dismutase in SHR. Adaptation to CNH intensified oxidative stress to a similar extent in both strains and elevated the IL-10/TNF-α ratio in SHR-mtBN only. These data indicate that alterations in the mitochondrial genome can result in peculiar changes in myocardial β-adrenergic signaling, MAO-A activity and antioxidant defence and may, thus, affect the adaptive responses to hypoxia.

Precise classification of acute leukemia (AL) is crucial for adequate treatment. EuroFlow has previously designed an AL orientation tube (ALOT) to guide towards the relevant classification panel (T-cell acute lymphoblastic leukemia (T-ALL), B-cell precursor (BCP)-ALL and/or acute myeloid leukemia (AML)) and final diagnosis. Now we built a reference database with 656 typical AL samples (145 T-ALL, 377 BCP-ALL, 134 AML), processed and analyzed via standardized protocols. Using principal component analysis (PCA)-based plots and automated classification algorithms for direct comparison of single-cells from individual patients against the database, another 783 cases were subsequently evaluated. Depending on the database-guided results, patients were categorized as: (i) typical T, B or Myeloid without or; (ii) with a transitional component to another lineage; (iii) atypical; or (iv) mixed-lineage. Using this automated algorithm, in 781/783 cases (99.7%) the right panel was selected, and data comparable to the final WHO-diagnosis was already provided in >93% of cases (85% T-ALL, 97% BCP-ALL, 95% AML and 87% mixed-phenotype AL patients), even without data on the full-characterization panels. Our results show that database-guided analysis facilitates standardized interpretation of ALOT results and allows accurate selection of the relevant classification panels, hence providing a solid basis for designing future WHO AL classifications.

Histone deacetylase 11 (HDAC11) is a sole member of the class IV HDAC subfamily with negligible intrinsic deacetylation activity. Here, we report in vitroprofiling of HDAC11 deacylase activities, and our data unequivocally show that the enzyme efficiently removes acyl moieties spanning 8–18 carbons from the side chain nitrogen of the lysine residue of a peptidic substrate. Additionally, N-linked lipoic acid and biotin are removed by the enzyme, although with lower efficacy. Catalytic efficiencies toward dodecanoylated and myristoylated peptides were 77 700 and 149 000 M–1s–1, respectively, making HDAC11 the most proficient fatty-acid deacylase of the HDAC family. Interestingly, HDAC11 is strongly inhibited by free myristic, palmitic, and stearic acids with inhibition constants of 6.5, 0.9, and 1.6 μM, respectively. At the same time, its deacylase activity is stimulated more than 2.5-fold by both palmitoyl-coenzyme A and myristoyl-coenzyme A, pointing toward metabolic control of the enzymatic activity by fatty-acid metabolites. Our data reveal novel enzymatic activity of HDAC11 that can, in turn, facilitate the uncovering of additional biological functions of the enzyme as well as the design of isoform-specific HDAC inhibitors.

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system. The glycosphingolipid sulfatide, a lipid particularly enriched in the myelin sheath, has been shown to be involved the maintenance of this specific membrane structure. Sulfatide in cerebrospinal fluid (CSF) may reflect demyelination, a dominating feature of MS. We investigated the diagnostic utility of CSF sulfatide isoform levels to separate different courses or phenotypes of MS disease.

Water management in the Czech Republic has undergone a complete transformation since the Velvet Revolution and the fall of communism in 1989. European Union directives have driven this process, culminating [...]

The synthesis of micro-/mesoporous beta zeolite by employing a solid precursor was described and its activity in the isopropylation of naphthalene was tested. The precursor was prepared by spray-drying of a homogenous mixture of silica sol, polyaluminum chloride solution and acidophilus milk, the presence of the latter induced formation of mesopores. The volume of mesopores of the synthesized beta zeolites ranged from 0.13 to 0.6 cm3/g and strongly depended on the concentration of tetraethylammonium hydroxide (TEAOH) in the reaction mixtures at the hydrothermal synthesis. Micro-/mesoporous beta zeolites exhibit positive effects of mesopores on the naphtalene conversion in its isopropylation by isopropyl alcohol, by improving the availability of active sites. With an increasing volume of mesopores, the conversion of naphthalene proportionally increases from 12 up to 27% for the volume of mesopores 0.6 cm3/g, while the selectivity to isopropylnaphthalene decreases from 92 to 55–66% for beta zeolites with 0.15–0.45 cm3of mesopores/g, followed by selectivity increase up to mesopore volume 0.6 cm3/g reaching 81% at conversion 27%. A yield of isopropylnaphthalene is increasing in the whole range, particularly when the volume of mesopores exceeds 0.4 cm3/g. A zeolite with the highest volume of mesopores provides 1.8 times higher yield of isopropylnaphthalene then a microporous beta zeolite without mesopores. The increasing conversion of naphthalene is accompanied by a decrease in the selectivity to isopropylnaphthalene for zeolites with a low volume of mesopores, but an increasing selectivity to isopropylnaphthalene in the case of zeolites with a volume of mesopores above 0.4 cm3/g. This unusual effect can be explained by the mesoporosity of zeolites. Mesopores improve the availability of active centers, so they react faster, but the by-products are also formed faster and later undesired reactions run more easily as active centers are gradually blocked by by-products. Zeolites with the largest pores provide not only better availability of active centers, but the reaction products can also leave the zeolitic phase more easily and undesirable reactions have less chance to occur. This method of micro/mesoporous beta zeolite synthesis is advantageous for its low cost.

The chloride permeability of concrete (UHPC) was evaluated by means of the Rapid chloride permeation test and and standard difusion test. The tests are different in the voltage applied for accelerating the transport through the concrete specimen. The permeability strongly depends on quality and curing time of the concrete.

A fully-standardized EuroFlow 8–color antibody panel and laboratory procedure was stepwise designed to measure minimal residual disease (MRD) in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) patients with a sensitivity of ≤10−5, comparable to real-time quantitative polymerase chain reaction (RQ-PCR)–based MRD detection via antigen-receptor rearrangements. Leukocyte markers and the corresponding antibodies and fluorochromes were selected based on their contribution in separating BCP-ALL cells from normal/regenerating BCP cells in multidimensional principal component analyses. After 5 multicenter design-test-evaluate-redesign phases with a total of 319 BCP-ALL patients at diagnosis, two 8-color antibody tubes were selected, which allowed separation between normal and malignant BCP cells in 99% of studied patients. These 2 tubes were tested with a new erythrocyte bulk-lysis protocol allowing acquisition of high cell numbers in 377 bone marrow follow-up samples of 178 BCP-ALL patients. Comparison with RQ-PCR–based MRD data showed a clear positive relation between the percentage concordant cases and the number of cells acquired. For those samples with >4 million cells acquired, concordant results were obtained in 93% of samples. Most discordances were clarified upon high-throughput sequencing of antigen-receptor rearrangements and blind multicenter reanalysis of flow cytometric data, resulting in an unprecedented concordance of 98% (97% for samples with MRD < 0.01%). In conclusion, the fully standardized EuroFlow BCP-ALL MRD strategy is applicable in >98% of patients with sensitivities at least similar to RQ-PCR (≤10−5), if sufficient cells (>4 × 106, preferably more) are evaluated.

Background: Anthracycline antibiotic doxorubicin (DOX) is a very potent and extensively prescribed chemotherapeutic drug. It is widely utilized in the therapy of variety of haematological and solid tumours, although its administration is commonly accompanied with several severe side effects. The most serious one is a development of dose-dependent and cumulative cardiotoxicity. In the course of time, many strategies have been investigated in order to avoid or at least to diminish DOX-induced cardiac dysfunction; these include reduction of toxic effect by coadministration with iron chelators (dexrazoxane), trastuzumab, taxanes, statins, and ACE-inhibitors. However, the attenuation of cardiotoxic effect is still not satisfactory yet. Objective: This review represents an overall appraisal of studies concerning with the utilization of various doxorubicinloaded nanoparticles in the cancer treatment with specific emphasis on those studies evaluating their influence on the reduction of heart tissue damage. Conclusion: Introduction of nanoscale drug delivery systems undoubtedly represents nowadays one of the most promising tools for lowering systemic toxicity. Nanoparticles enable to target the therapeutic payload directly towards the tumor tissue, thus leading to the increased accumulation of the drug in the desired tissue and simultaneously protecting surrounding healthy tissues.

Fe7Se8exists as a hexagonal NiAs-like crystal structure with a large number of ordered intrinsic vacancies. It is an ideal candidate for studying the effect of defects on properties such as magnetism and electrical transport. In this work, highly crystalline Fe7Se8with the 3c crystal structure was synthesized by a solid-state reaction. Sharp changes in the magnetization at 100 K confirm a rotation of the spins from the abplane to the caxis with decreasing temperature. We observe an interesting metal–insulator transition at the same temperature as the spin-direction changes. We propose that locked spins in the grain boundaries induce electron localization and result in the metal–insulator transition. Electron localization is confirmed by X-ray photoelectron spectroscopy of the Fe 2p peaks, which exhibit two characteristic satellite peaks. This mechanism is also verified by comparing it with the properties of the 4c-Fe7Se8crystal structure.

Aggregation of phthalocyanines (Pcs) represents a problematic feature that decreases the potential of these macrocycles in a number of applications. In this work, we present a supramolecular approach based on the interaction of aminoadamantyl-substituted Pcs with bulky and hydrophilic cucurbit[7]uril (CB[7]) to increase the levels of Pc monomers in water. A series of zinc(II) Pcs substituted at positions α or β by an aminoadamantyl substituent (with a different level of alkylation of nitrogen) were prepared from the corresponding phthalonitriles. A 1H nuclear magnetic resonance study of the interaction of phthalonitriles with CB[7] in water confirmed the formation of an inclusion complex with an aminoadamantyl moiety with Kavalues of ∼1012M–1. The interaction of CB[7] with Pcs in water substantially weakened H-type aggregation and improved both fluorescence and singlet oxygen production, confirming that this approach is efficient for the monomerization of Pcs. In vitroevaluation of the photodynamic activity of prepared Pcs led to EC50values in the submicromolar range on HeLa and SK-MEL-28 cells. However, the activity decreased for at least an order of magnitude after host–guest interaction with CB[7] despite better photophysical properties. This was attributed to a much lower uptake by cells due to the very bulky and hydrophilic character of the Pc-CB[7] assembly.

The effects of live yeast Saccharomyces cerevisiae(strain CNCM I-4407; Actisaf Sc 47; Phileo Lesaffre Animal Care, Marcq-en-Baroeul, France) administration on nutrient digestibility and fecal microflora in dogs were investigated. The study included 24 young beagle dogs. They were allocated in control and live yeast (LY) groups (6 males and 6 females in each). During the Adaptation (d 1 to 28) and Trial (d 29 to 70) periods, the dogs received a standard dry pelleted diet. In the Trial period, the LY dogs were given capsuled Actisaf Sc 47 at 1 g/kg live weight with Saccharomyces cerevisiaeat 2.9 × 108cfu/g. The control dogs received empty capsules. Live weight and feed consumption were recorded. Blood samples for complete blood count (CBC) and serum biochemistry (urea, creatinine, alkaline phosphatase, and alanine aminotransferase) and fecal samples for pH, microbiology, DM, lactic acid, and ammonia and digestibility evaluation were collected during the Trial period from each dog. The LY dogs had a higher (P< 0.05) weight gain during the Trial period than the control ones. Feed consumption was not adversely affected by LY. The CBC values and urea, creatinine, alkaline phosphatase, and alanine aminotransferase were not adversely affected by LY. Live yeast did not significantly influence pH of fresh feces. Fecal lactic acid and ammonia concentrations were not affected. The LY dogs showed lower (P< 0.05) Escherichia coli and fecal enterococci counts in feces than the control ones. Lactic acid bacteria, Clostridium perfringens, and total coliforms did not show any significant differences between the treatments. The LY dogs showed a higher (P< 0.05) apparent digestibility of NDF. Digestibilities of DM, ash, crude fiber, CP, and fat were not influenced.

•A novel rickettsia was detected in Ixodes ricinusticks feeding on various hosts and in questing ticks.•Phylogenetic analysis revealed a basal position of the novel species in the proximity of R. bellii.•This is the first report of a basal group rickettsia in Europe.•‘CandidatusRickettsia mendelii’ was proposed to designate this microorganism.

The aim of this study was to describe an instrumental activities of daily living (IADL) measure: Functional Activities Questionnaire (FAQ), which is often used in clinical settings as a self- or informant-based measure of IADL. However, the FAQ’s relationship with age or education in healthy aging has not been investigated. FAQ and a neuropsychological battery were administered to old and very old Czech adults (n= 540). Participants met strict inclusion criteria for the absence of any active or past neurodegenerative disorders. FAQ is significantly dependent on age and education, but not gender. Younger subjects and those with higher education have the lowest scores in the FAQ and show a higher degree of functional independence. FAQ moderately correlates with speed of processing, visual–perceptual and executive functions measures (Trail Making Tests, Stroop Test) and depressive symptoms, but not with episodic memory (WMS-III logical memory). We present normative percentile values for different age groups from 60 to 96 years of age. The present study shows conclusively that IADL measures, such as FAQ, should not be used without appropriate normative data, especially in very old adults. Thus, it has the ability to differentiate functional dependence due to age-related decline from neurodegenerative disease.

The article informs about responsibilities in art in impossibility of articulating its own paradigm along with dichotomies such as modern/postmodern or capitalist/ post-capitalist. Topics include noise of eccentric modernities running independently of each other in time and space in a world that resembles a buzzing factory; and last space of articulation outside of the capitalocentric vision with anti- monuments of historical consciousness.

•There is an increase in the MS relapse incidence after COVID-19 infection.•There is a mild increase in the MS relapse incidence after COVID-19 vaccination.•Lower age was associated with MS relapse after vaccination or infection.•The results in NMOSD patients were broadly consistent with those of MS patients.

For understanding and describing the materials behaviour during phase transformations, dilatometer measurements are commonly used in the scientific community. Generally, standard CCT diagrams are generated by means of dilatometer experiments. However, in many cases, real weld cycles are more suitable for studying the materials behaviour instead of using CCT diagrams. In this regard we talk about so-called in-situ diagrams.In this work, two different devices have been used to obtain CCT as well as in-situ diagrams of a low alloyed steel 10GN2MFA. The goal was to compare the results obtained on the one hand by using a widely used standard dilatometer (Bähr DIL-805A/D) and on the other hand by the usage of a thermomechanical simulator called Gleeble®3800. The paper should finally show advantages as well as disadvantages of using different devices and to keep in mind that the optimal measurement method depends on different parameters. Realized experiments also have revealed the range of operational and diagnostic potential of used devices.

Ticks were collected from captive reptiles, wild birds, and incidentally from humans at two locations in Honduras and part of these were tested for the presence of Rickettsiausing polymerase chain reaction. The following species of ticks were found: Amblyomma dissimileon Iguanidae reptiles, Amblyomma longirostreand Amblyomma nodosumon birds, and Amblyomma mixtum(Amblyomma cajennensecomplex) on humans. A. dissimilewas infected with Rickettsiasp. strain Colombianensi. Both A. longirostreand A. mixtumwere infected with Candidatus‘Rickettsia amblyommii’. This study provides the first report of rickettsial infections in ticks from reptiles, birds and humans in Honduras. New host – Amblyommatick associations are documented.

The present work has been undertaken to research effects of structure, morphology, volume fraction, spatial arrangement of magnetostrictive intermetallic FeGa alloy particles dispersed in modified polyurethane matrix. Correlation of composite magnetic behavior with structure and mechanical properties has been obtained by measurements of magnetostriction, remanent magnetization anisotropy, SEM, and dynamical mechanical analysis. Anisotropic chain structures of magnetic particles within the polymer with different interparticle interactions were observed. The increase of the magnetostrictive response with tailor-made magnetic anisotropy induced by magnetic particles volume fraction has been demonstrated