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Heart failure is a serious medical condition with a poor prognosis. Current treatments can only help manage the symptoms and slow the progression of heart failure. However, there is currently no cure to prevent and reverse cardiac remodeling. Transcription factors are in a central role in various cellular processes, and in the heart, GATA4 and NKX2-5 transcription factors mediate hypertrophic responses and remodeling. We have identified compounds that modulate the synergistic interaction of GATA4 and NKX2-5 and shown that the most promising compound (1, 3i-1000) is cardioprotective in vitro and in vivo. However, direct evidence of its binding site and mechanism of action has not been available. Due to the disordered nature of transcription factors, classical target engagement approaches cannot be utilized. Here, we synthesized a small-molecule ligand-binding pulldown probe of compound 1 to utilize affinity chromatography alongside CETSA, AlphaScreen, and molecular modeling to study ligand binding. These results provide the first evidence of direct physical binding of compound 1 selectively to GATA4. While developing drugs that target transcription factors presents challenges, advances in technologies and knowledge of intrinsically disordered proteins enable the identification of small molecules that can selectively target transcription factors. [ABSTRACT FROM AUTHOR]

The populational heterogeneity of a disease, in part due to comorbidity, poses several complexities. Individual comorbidity profiles, on the other hand, contain useful information to refine phenotyping, prognostication, and risk assessment, and they provide clues to underlying biology. Nevertheless, the spectrum and the implications of the diagnosis profiles remain largely uncharted. Here we mapped comorbidity patterns in 100 common diseases using 4-year retrospective data from 526,779 patients and developed an online tool to visualize the results. Our analysis exposed disease-specific patient subgroups with distinctive diagnosis patterns, survival functions, and laboratory correlates. Computational modeling and real-world data shed light on the structure, variation, and relevance of populational comorbidity patterns, paving the way for improved diagnostics, risk assessment, and individualization of care. Variation in outcomes and biological correlates of a disease emphasizes the importance of evaluating the generalizability of current treatment strategies, as well as considering the limitations that selective inclusion criteria pose on clinical trials. [ABSTRACT FROM AUTHOR]

Our aim was to synthesize the published literature on factors that potentially affect the delivery of bronchodilators using valved holding chambers (VHC) in preschool children. We also aimed to identify those attributes that are not yet incorporated or clearly stated in the guidelines and those topics that are still lacking sufficient data. There is strong evidence supporting several recommendations in current guidelines. Based on present knowledge, bronchodilators should be delivered by VHC administering each puff separately. Face mask should be omitted as soon as the child can hold the mouthpiece of the VHC tightly between the lips and teeth. Based on the review, we suggest adding a specific note to current guidelines about the effect of chamber volume and the impact of co-operation during drug administration. Calming the child and securing a tight face-to-mask seal is critical for successful drug delivery. There is not enough evidence to make specific recommendations on the most reliable VHC and face mask for children. There is an urgent need for studies that evaluate and compare the effectiveness of VHCs in various clinical settings in wide age-groups and respiratory patterns. In addition, there is insufficient data on ideal chamber volume, material, and effective antistatic treatment. What is Known: • Valved holding chambers (VHC) should not be considered interchangeable when used with pressurized metered dose inhalers (pMDI). • Drug delivery is influenced by VHC volume, aerodynamic and electrostatic properties; mask fit; respiratory pattern and co-operation during inhalation; and the number of puffs actuated. What is New: • The impact of co-operation, VHC volume, and good mask-to-face fit during drug inhalation is not stressed enough in the guidelines. • Studies are urgently needed to evaluate the effectiveness of different VHCs in various clinical settings focusing on VHC electrostatic properties, respiratory patters, face masks, and ideal pMDI+VHC combinations. [ABSTRACT FROM AUTHOR]

Background: In this exploratory study, the impact of local irradiation on systemic changes in stress and immune parameters was investigated in eight patients treated with intensity-modulated radiation therapy (IMRT) or stereotactic ablative body radiotherapy (SABR) for prostate adenocarcinoma to gain deeper insights into how radiotherapy (RT) modulates the immune system. Patients and methods: RT-qPCR, flow cytometry, metabolomics, and antibody arrays were used to monitor a panel of stress- and immune-related parameters before RT, after the first fraction (SABR) or the first week of treatment (IMRT), after the last fraction, and 3 weeks later in the blood of IMRT (N = 4) or SABR (N = 4) patients. Effect size analysis was used for comparison of results at different timepoints. Results: Several parameters were found to be differentially modulated in IMRT and SABR patients: the expression of TGFB1, IL1B, and CCL3 genes; the expression of HLA-DR on circulating monocytes; the abundance and ratio of phosphatidylcholine and lysophosphatidylcholine metabolites in plasma. More immune modulators in plasma were modulated during IMRT than SABR, with only two common proteins, namely GDF-15 and Tim‑3. Conclusion: Locally delivered RT induces systemic modulation of the immune system in prostate adenocarcinoma patients. IMRT and SABR appear to specifically affect distinct immune components. [ABSTRACT FROM AUTHOR]

Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1–3 µM markedly reduced (60%) hiPSC-CM viability already within 48 h, while a 14-day treatment with 100 nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2 weeks (30 mg/kg/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Bipartite networks provide an insightful representation of many systems, ranging from mutualistic networks of species interactions to investment networks in finance. The analyses of their topological structures have revealed the ubiquitous presence of properties which seem to characterize many—apparently different—systems. Nestedness, for example, has been observed in biological plant-pollinator as well as in country-product exportation networks. Due to the interdisciplinary character of complex networks, tools developed in one field, for example ecology, can greatly enrich other areas of research, such as economy and finance, and vice versa. With this in mind, we briefly review several entropy-based bipartite null models that have been recently proposed and discuss their application to real-world systems. The focus on these models is motivated by the fact that they show three very desirable features: analytical character, general applicability, and versatility. In this respect, entropy-based methods have been proven to perform satisfactorily both in providing benchmarks for testing evidence-based null hypotheses and in reconstructing unknown network configurations from partial information. Furthermore, entropy-based models have been successfully employed to analyze ecological as well as economic systems. As an example, the application of entropy-based null models has detected early-warning signals, both in economic and financial systems, of the 2007-2008 world crisis. Moreover, they have revealed a statistically-significant export specialization phenomenon of country export baskets in international trade, a result that seems to reconcile Ricardo’s hypothesis in classical economics with recent findings on the (empirical) diversification industrial production at the national level. Finally, these null models have shown that the information contained in the nestedness is already accounted for by the degree sequence of the corresponding graphs. [ABSTRACT FROM AUTHOR]

Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure-toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10 nM up to 30 µM on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure-toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives. [ABSTRACT FROM AUTHOR]

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Copyright of Operative Orthopädie und Traumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

During the last decades, focused electron beam induced deposition (FEBID) has become a successful approach for direct-write fabrication of nanodevices. Such a deposition technique relies on the precursor supply to the sample surface which is typically accomplished by a gas injection system using a tube-shaped injector nozzle. This precursor injection strategy implies a position-dependent concentration gradient on the surface, which affects the geometry and chemistry of the final nanodeposit. Although simulations already proposed the local distribution of nozzle-borne gas molecules impinging on the surface, this isolated step in the FEBID process has never been experimentally measured yet. This work experimentally investigates the local distribution of impinging gas molecules on the sample plane, isolating the direct impingement component from surface diffusion or precursor depletion by deposition. The experimental setup used in this work maps and quantifies the local impinging rate of argon gas over the sample plane. This setup simulates the identical conditions for a precursor molecule during FEBID. Argon gas was locally collected with a sniffer tube, which is directly connected to a residual gas analyzer for quantification. The measured distribution of impinging gas molecules showed a strong position dependence. Indeed, a 300-µm shift of the deposition area to a position further away from the impingement center spot resulted in a 50 % decrease in the precursor impinging rate on the surface area. With the same parameters, the precursor distribution was also simulated by a Monte Carlo software by Friedli and Utke and showed a good correlation between the empirical and the simulated precursor distribution. The results hereby presented underline the importance of controlling the local precursor flux conditions in order to obtain reproducible and comparable deposition results in FEBID. [ABSTRACT FROM AUTHOR]

This paper determines the characteristic air mass types over the Carpathian Basin for the winter (December, January, and February) and summer (June, July and August) months dependant on levels of the main air pollutants. Based on the ECMWF data set, daily sea-level pressure fields analysed at 00 UTC were prepared for each air mass type (cluster) in order to relate sea-level pressure patterns with the level of air pollutants in Szeged. The data comprise daily values of twelve meteorological and eight pollutant parameters for the period 1997–2001. Objective definition of the characteristic air mass types is achieved by using the methods of Factor Analysis and Cluster Analysis. According to the results, during the winter months five air mass types (clusters) were detected based on higher concentrations of primary pollutants that occur with high irradiance and low wind speed. This is the case when an anticyclone is found over the Carpathian Basin and over the region south of Hungary, influencing the weather of the country. Low levels of pollutants occur when zonal currents exert influence over Hungary. During the summer months anticyclones and anticyclone ridge situations are found over the Carpathian Basin. (During the prevalence of anticyclone ridge situations, the Carpathian Basin is found at the edge of a high pressure centre.) As a result of high irradiance and very low NO levels, secondary pollutants are highly enriched. [ABSTRACT FROM AUTHOR]

Abstract Seven different two-photon excitable dipyrrylmetheneboron difluoride labels (dipyrrylmethene-BF2 labels) and a frequently used TAMRA label were conjugated to mouse IgG against a-fetoprotein in variable substitution degrees. Altogether 40 IgG conjugates were prepared, and studied with respect to one-photon absorption and emission properties, and two-photon fluorescence efficiency using 1064 nm laser as illumination source. Performance of the IgG conjugates as tracers in a separation-free immunometric assay of a-fetoprotein was evaluated using two-photon excitation assay technology, ArcDiaTM TPX. The results show that the dipyrrylmethene-BF2 labels provide subpicomolar sensitivity, which is an order of magnitude better than that of TAMRA label. The effect of chromophore structure and substitution degree of IgG-label conjugates on the assay performance is discussed. [ABSTRACT FROM AUTHOR]

Objective. To assess the effect of ciprofloxacin on the pharmacokinetics of ropivacaine. Methods. In a double-blind, randomised, cross-over study, nine healthy volunteers were treated for 2.5 days with 500 mg oral ciprofloxacin or placebo twice daily. On day 3, they received a single dose of 0.6 mg/kg ropivacaine intravenously over 30 min. Ropivacaine, 3-hydroxyropivacaine (3-OH-ropivacaine), and (S)-2′,6′-pipecoloxylidide (PPX) in venous plasma and urine were measured for up to 12 h and 24 h, respectively. Results. Ciprofloxacin decreased the mean clearance (CL) of ropivacaine by 31% (P<0.05), with a considerable inter-individual variation (range from -52% to +39%). It also decreased the area under the plasma concentration–time curve (AUC) of 3-OH-ropivacaine by 38% (P<0.05) and urinary excretion of 3-OH-ropivacaine by 27% (P<0.05). Ciprofloxacin increased the AUC of PPX by 71% (P<0.01) and urinary excretion of PPX by 97% (P<0.01). Conclusion. Ciprofloxacin modestly decreased the mean ropivacaine CL by inhibiting the CYP1A2-mediated formation of 3-OH-ropivacaine. At the same time, the CYP3A4-mediated formation of PPX was increased. There was a marked inter-individual variation in the extent of the interaction, and, for some individuals, the concomitant use of ciprofloxacin with ropivacaine might produce toxic symptoms. [ABSTRACT FROM AUTHOR]

The object of the study is to develop a discrete precipitation model which is able to simulate local, daily series of precipitation occurrences. The model is fitted to the observed data of two stations, Szeged and Szombathely, in Hungary (1951–1995), with pronounced attention to the reproduction of long dry periods, as characteristic features of the climate in Central Europe. The point of the approach is to model the duration of consecutive dry and wet series, i.e., spells, instead of individual wet or dry days. After having comparisons of three different aspects performed, the selected precipitation threshold is 0.1 mm. This threshold keeps the duration of dry and wet periods more or less balanced, whereas the value of the threshold does not fundamentally influence either the conditional distribution of macrocirculation types or the local weather statistics related to the so defined wet or dry days. The duration of both wet and dry spells are found to be independent of the length of either the preceding (opposite) or the last, but one (identical) state. It is also demonstrated that mixed distributions fairly fit to the wet and dry spells, whereas the simple geometric does not, especially due to the erroneous lack of long dry sequences. Weighted sum of two geometric distributions, as well as that of one geometric and one Poisson distribution exhibits good fitting for the dry spells, whereas only the latter one can be advised to employ for the wet periods. Parameters of the distributions obviously depend on the season and the site, in question. [ABSTRACT FROM AUTHOR]

The expression of mRNA coding for AMPA selective glutamate (Glu) R2 receptor and kainate selective GluR5 receptor was studied in the rat hippocampal formation in two animal models of limbic seizures evoked by systemic administration of pilocarpine (400 mg/kg ip) or kainate (15 mg/kg ip). As shown by an in situ hybridization study, pilocarpine decreased the GluR2 flip mRNA level in CA1 and CA3 areas of the hippocampus after 3h and kainate after 24 h, e.g. at the time preceding neuronal degeneration. No changes in the GluR2 flop or GluR5 mRNA level were found in those regions. In the dentate gyrus, resistant to neurodegeneration, pilocarpine and kainate differentialy affected the expression of GluR2 and GluR5 mRNAs. After 72 h pilocarpine, but not kainate, increased the GluR2 flop mRNA level and decreased the flip one, which suggests attenuation of the GluR2 sensitivity. On the other hand, kainate, elevated the GluR2 flip and GluR5 mRNA level in the dentate gyrus after 72 h. All in all the above data suggest that changes in the GluR2 gene expression may play some role in the neuronal damage to vulnerable areas (CA1, CA3). However, differences in the kainate- and pilocarpine-induced changes in the dentate gyrus at the late time points indicate that alterations in the stoichiometry of GluR2 forms or GluR5 gene expression in this brain region are not a common causal factor responsible for delayed neuronal hyperexcitability. [ABSTRACT FROM AUTHOR]

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Copyright of Microchimica Acta is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Microchimica Acta is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Zeitschrift für Analytische Chemie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Zeitschrift für Analytische Chemie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Zeitschrift für Analytische Chemie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A letter to the editor is presented regarding the biological embedding of stress through inflammation processes during childhood.