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Abstract Mosquitoes are prolific vectors of human pathogens, therefore a clear and accurate understanding of the organization of their antimicrobial defenses is crucial for informing the development of transmission control strategies. The canonical infection response in insects, as described in the insect model Drosophila melanogaster, is pathogen type-dependent, with distinct stereotypical responses to Gram-negative bacteria and Gram-positive bacteria/fungi mediated by the activation of the Imd and Toll pathways, respectively. To determine whether this pathogen-specific discrimination is shared by mosquitoes, we used RNAseq to capture the genome-wide transcriptional response of Aedes aegypti and Anopheles gambiae (s.l.) to systemic infection with Gram-negative bacteria, Gram-positive bacteria, yeasts, and filamentous fungi, as well as challenge with heat-killed Gram-negative, Gram-positive, and fungal pathogens. From the resulting data, we found that Ae. aegypti and An. gambiae both mount a core response to all categories of infection, and this response is highly conserved between the two species with respect to both function and orthology. When we compared the transcriptomes of mosquitoes infected with different types of bacteria, we observed that the intensity of the transcriptional response was correlated with both the virulence and growth rate of the infecting pathogen. Exhaustive comparisons of the transcriptomes of Gram-negative-challenged versus Gram-positive-challenged mosquitoes yielded no difference in either species. In Ae. aegypti, however, we identified transcriptional signatures specific to bacterial infection and to fungal infection. The bacterial infection response was dominated by the expression of defensins and cecropins, while the fungal infection response included the disproportionate upregulation of an uncharacterized family of glycine-rich proteins. These signatures were also observed in Ae. aegypti challenged with heat-killed bacteria and fungi, indicating that this species can discriminate between molecular patterns that are specific to bacteria and to fungi.

Membrane lipids extensively modulate the activation gating of voltage-gated potassium channels (KV), however, much less is known about the mechanisms of ceramide and glucosylceramide actions including which structural element is the main intramolecular target and whether there is any contribution of indirect, membrane biophysics-related mechanisms to their actions. We used two-electrode voltage-clamp fluorometry capable of recording currents and fluorescence signals to simultaneously monitor movements of the pore domain (PD) and the voltage sensor domain (VSD) of the KV1.3 ion channel after attaching an MTS-TAMRA fluorophore to a cysteine introduced into the extracellular S3-S4 loop of the VSD. We observed rightward shifts in the conductance-voltage (G-V) relationship, slower current activation kinetics, and reduced current amplitudes in response to loading the membrane with C16-ceramide (Cer) or C16-glucosylceramide (GlcCer). When analyzing VSD movements, only Cer induced a rightward shift in the fluorescence signal-voltage (F-V) relationship and slowed fluorescence activation kinetics, whereas GlcCer exerted no such effects. These results point at a distinctive mechanism of action with Cer primarily targeting the VSD, while GlcCer only the PD of KV1.3. Using environment-sensitive probes and fluorescence-based approaches, we show that Cer and GlcCer similarly increase molecular order in the inner, hydrophobic regions of bilayers, however, Cer induces a robust molecular reorganization at the membrane-water interface. We propose that this unique ordering effect in the outermost membrane layer in which the main VSD rearrangement involving an outward sliding of the top of S4 occurs can explain the VSD targeting mechanism of Cer, which is unavailable for GlcCer.

Analyses of inequalities related to prevention and cancer therapeutics/care show disparities between countries with different economic standing, and within countries with high Gross Domestic Product. The development of basic technological and biological research provides clinical and prevention opportunities that make their implementation into healthcare systems more complex, mainly due to the growth of Personalized/Precision Cancer Medicine (PCM). Initiatives like the USA‐Cancer Moonshot and the EU‐Mission on Cancer and Europe's Beating Cancer Plan are initiated to boost cancer prevention and therapeutics/care innovation and to mitigate present inequalities. The conference organized by the Pontifical Academy of Sciences in collaboration with the European Academy of Cancer Sciences discussed the inequality problem, dependent on the economic status of a country, the increasing demands for infrastructure supportive of innovative research and its implementation in healthcare and prevention programs. Establishing translational research defined as a coherent cancer research continuum is still a challenge. Research has to cover the entire continuum from basic to outcomes research for clinical and prevention modalities. Comprehensive Cancer Centres (CCCs) are of critical importance for integrating research innovations to preclinical and clinical research, as for ensuring state‐of‐the‐art patient care within healthcare systems. International collaborative networks between CCCs are necessary to reach the critical mass of infrastructures and patients for PCM research, and for introducing prevention modalities and new treatments effectively. Outcomes and health economics research are required to assess the cost‐effectiveness of new interventions, currently a missing element in the research portfolio. Data sharing and critical mass are essential for innovative research to develop PCM. Despite advances in cancer research, cancer incidence and prevalence is growing. Making cancer research infrastructures accessible for all patients, considering the increasing inequalities, requires science policy actions incentivizing research aimed at prevention and cancer therapeutics/care with an increased focus on patients' needs and cost‐effective healthcare.

Blockchain technology offers businesses many opportunities for more efficient operation and safer data management. It also becomes easy tostore and share employee data, while the blockchain guarantees that it does not fall into unauthorized hands. The management of financial transactions and the automation of the payment process are also a great advantage for businesses, which can manage the payment of wages andbenefits more efficiently. Another area of application of blockchain technology is the creation of more efficient workflows that can improve productivity and reduce costs. The management of work schedules and optimized work processes will also be easier with the help of the blockchain, so businesses can become more efficient and effective. In this article, the relationship between HR and blockchains was explored through a meta-analysis based on available related publications.

Introduction Type 2 diabetes mellitus is a risk factor for severe COVID-19 infection and is associated with increased risk of complications. The present study aimed to investigate effectiveness and persistence of different COVID vaccines in persons with or without diabetes during the Delta wave in Hungary.Research design and methods Data sources were the national COVID-19 registry data from the National Public Health Center and the National Health Insurance Fund on the total Hungarian population. The adjusted incidence rate ratios and corresponding 95% CIs were derived from a mixed-effect negative binomial regression model.Results A population of 672 240 cases with type 2 diabetes and a control group of 2 974 102 non-diabetic persons free from chronic diseases participated. Unvaccinated elderly persons with diabetes had 2.68 (95% CI 2.47 to 2.91) times higher COVID-19-related mortality rate as the ‘healthy’ controls. Primary immunization effectively equalized the risk of COVID-19 mortality between the two groups. Vaccine effectiveness declined over time, but the booster restored the effectiveness against mortality to over 90%. The adjusted vaccine effectiveness of the primary Pfizer-BioNTech against infection in the 14–120 days of postvaccination period was 71.6 (95% CI 66.3 to 76.1)% in patients aged 65–100 years with type 2 diabetes and 64.52 (95% CI 59.2 to 69.2)% in the controls. Overall, the effectiveness tended to be higher in individuals with diabetes than in controls. The booster vaccines could restore vaccine effectiveness to over 80% concerning risk of infection (eg, patients with diabetes aged 65–100 years: 89.1 (88.1–89.9)% with Pfizer-on-Pfizer, controls 65–100 years old: 86.9 (85.8–88.0)% with Pfizer-on-Pfizer, or patients with diabetes aged 65–100 years: 88.3 (87.2–89.2)% with Pfizer-on-Sinopharm, controls 65–100 years old: 87.8 (86.8–88.7)% with Pfizer-on-Sinopharm).Conclusions Our data suggest that people with type 2 diabetes may have even higher health gain when getting vaccinated as compared with non-diabetic persons, eliminating the marked, COVID-19-related excess risk of this population. Boosters could restore protection.

Objectives Lung cancer (LC) is the leading cause of cancer death in 2020, responsible for almost one in five (18.0%) deaths. This paper provides an overview of the descriptive epidemiology of LC based on national mortality estimates for 2020 from the International Agency for Research on Cancer (IARC), and in the context of recent tobacco control policies.Design and setting For this descriptive study, age-standardised mortality rates per 100 000 person-years of LC for 185 countries by sex were obtained from the GLOBOCAN 2020 database and stratified by Human Development Index (HDI). LC deaths were projected to 2040 based on demographic changes alongside scenarios of annually increasing, stable or decreasing rates from the baseline year of 2020.Results LC mortality rates exhibited marked variations by geography and sex. Low HDI countries, many of them within sub-Saharan Africa, tend to have low levels of mortality and an upward trend in LC deaths is predicted for both sexes until 2040 according to demographic projections, irrespective of trends in rates. In very high HDI countries, including Europe, Northern America and Australia/New Zealand, there are broadly decreasing trends in men whereas in women, rates are still increasing or reaching a plateau.Conclusion The current and future burden of LC in a country or region largely depends on the present trajectory of the smoking epidemic in its constituent populations, with distinct gender differences in smoking patterns, both in transitioning and transitioned countries. Further elevations in LC mortality are expected worldwide, raising important social and political questions, especially in low-income and middle-income countries.

Although the COVID-19 pandemic is profoundly changing, data on the effect of vaccination and duration of protection against infection and severe disease can still be advantageous, especially for patients with COPD, who are more vulnerable to respiratory infections. The Hungarian COVID-19 registry was retrospectively investigated for risk of infection and hospitalization by time since the last vaccination, and vaccine effectiveness (VE) was calculated in adults with COPD diagnosis and an exact-matched control group during the Delta variant of concern (VOC) wave in Hungary (September–December 2021). For the matching, sex, age, major co-morbidities, vaccination status, and prior infection data were obtained on 23 August 2021. The study population included 373,962 cases divided into COPD patients (age: 66.67 ± 12.66) and a 1:1 matched group (age: 66.73 ± 12.67). In both groups, the female/male ratio was 52.2:47.7, respectively. Among the unvaccinated, there was no difference between groups in risk for infection or hospitalization. Regarding vaccinated cases, in the COPD group, a slightly faster decline in effectiveness was noted for hospitalization prevention, although in both groups, the vaccine lost its significant effect between 215 and 240 days after the last dose of vaccination. Based on a time-stratified multivariate Cox analysis of the vaccinated cases, the hazard was constantly higher in the COPD group, with an HR of 1.09 (95%: 1.05–1.14) for infection and 1.87 (95% CI: 1.59–2.19) for hospitalization. In our study, COPD patients displayed lower vaccine effectiveness against SARS-CoV-2 infection and hospitalization but a similar waning trajectory, as vaccines lost their preventive effect after 215 days. These data emphasize revaccination measures in the COPD patient population.

Regulation of H2S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H2S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H2S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H2S synthesis from accumulating homocysteine, which suggests a control of H2S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H2S homeostasis.

Every cell biological textbook teaches us that the main role of the plasma membrane is to separate cells from their neighborhood to allow for a controlled composition of the intracellular space. The mostly hydrophobic nature of the cell membrane presents an impenetrable barrier for most hydrophilic molecules larger than 1 kDa. On the other hand, cell-penetrating peptides (CPPs) are capable of traversing this barrier without compromising membrane integrity, and they can do so on their own or coupled to cargos. Coupling biologically and medically relevant cargos to CPPs holds great promise of delivering membrane-impermeable drugs into cells. If the cargo is able to interact with certain cell types, uptake of the CPP–drug complex can be tailored to be cell-type-specific. Besides outlining the major membrane penetration pathways of CPPs, this review is aimed at deciphering how properties of the membrane influence the uptake mechanisms of CPPs. By summarizing an extensive body of experimental evidence, we argue that a more ordered, less flexible membrane structure, often present in the very diseases planned to be treated with CPPs, decreases their cellular uptake. These correlations are not only relevant for understanding the cellular biology of CPPs, but also for rationally improving their value in translational or clinical applications.

Abstract Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Mosquitoes transmit numerous pathogens, but large gaps remain in our understanding of their physiology. To facilitate explorations of mosquito biology, we have created Aegypti-Atlas (http://aegyptiatlas.buchonlab.com/), an online resource hosting RNAseq profiles of Ae. aegypti body parts (head, thorax, abdomen, gut, Malpighian tubules, ovaries), gut regions (crop, proventriculus, anterior and posterior midgut, hindgut), and a gut time course of blood meal digestion. Using Aegypti-Atlas, we provide insights into regionalization of gut function, blood feeding response, and immune defenses. We find that the anterior and posterior midgut possess digestive specializations which are preserved in the blood-fed state. Blood feeding initiates the sequential induction and repression/depletion of multiple cohorts of peptidases. With respect to defense, immune signaling components, but not recognition or effector molecules, show enrichment in ovaries. Basal expression of antimicrobial peptides is dominated by holotricin and gambicin, which are expressed in carcass and digestive tissues, respectively, in a mutually exclusive manner. In the midgut, gambicin and other effectors are almost exclusively expressed in the anterior regions, while the posterior midgut exhibits hallmarks of immune tolerance. Finally, in a cross-species comparison between Ae. aegypti and Anopheles gambiae midguts, we observe that regional digestive and immune specializations are conserved, indicating that our dataset may be broadly relevant to multiple mosquito species. We demonstrate that the expression of orthologous genes is highly correlated, with the exception of a ‘species signature’ comprising a few highly/disparately expressed genes. With this work, we show the potential of Aegypti-Atlas to unlock a more complete understanding of mosquito biology.

Background Lockdown during the pandemic has had significant impacts on public mental health. Previous studies suggest an increase in self-harm and suicide in children and adolescents. There has been little research on the roles of stringent lockdown. Aims To investigate the mediating and predictive roles of lockdown policy stringency measures in self-harm and emergency psychiatric presentations. Method This was a retrospective cohort study. We analysed data of 2073 psychiatric emergency presentations of children and adolescents from 23 hospital catchment areas in ten countries, in March to April 2019 and 2020. Results Lockdown measure stringency mediated the reduction in psychiatric emergency presentations (incidence rate ratio of the natural indirect effect [IRRNIE] = 0.41, 95% CI [0.35, 0.48]) and self-harm presentations (IRRNIE = 0.49, 95% CI [0.39, 0.60]) in 2020 compared with 2019. Self-harm presentations among male and looked after children were likely to increase in parallel with lockdown stringency. Self-harm presentations precipitated by social isolation increased with stringency, whereas school pressure and rows with a friend became less likely precipitants. Children from more deprived neighbourhoods were less likely to present to emergency departments when lockdown became more stringent, Conclusions Lockdown may produce differential effects among children and adolescents who self-harm. Development in community or remote mental health services is crucial to offset potential barriers to access to emergency psychiatric care, especially for the most deprived youths. Governments should aim to reduce unnecessary fear of help-seeking and keep lockdown as short as possible. Underlying mediation mechanisms of stringent measures and potential psychosocial inequalities warrant further research.

Orthohepevirus A genotype 7 is a novel zoonotic variant of hepatitis E virus. To clarify infection in the animal reservoir, we virologically monitored 11 dromedary dam–calf pairs. All calves became infected during the first 6 months of life and cleared the virus after an average of 2 months. Dams did not become infected.

Abstract Aims/Introduction The relationship of chromogranin A (CgA) levels above the normal range with various outcomes, such as glycated hemoglobin levels, enterochromaffin‐like cell hyperplasia and autoimmune gastritis, was investigated in type 1 diabetes patients with special regard to the progression of comorbidities. Materials and Methods A cohort study on 153 type 1 diabetes patients was carried out with a prospective branch on clinical and laboratory data, and a retrospective branch on histological data obtained by gastroscopy. Results Patients with CgA levels above the upper limit of the normal range (n = 28) had significantly higher glycated hemoglobin levels (P = 0.0160) than those with CgA in the normal range (n = 125). The correlation between CgA and glycated hemoglobin was significant (P

Cyclodextrins (CDs) are cyclic oligosaccharides capable of forming water-soluble complexes with a variety of otherwise poorly soluble molecules including cholesterol and different drugs. Consistently, CDs are widely used in research and clinical practice to deplete cholesterol from cellular membranes or to increase solubility and bioavailability of different pharmaceuticals at local concentrations in the millimolar range. Effects of CDs exerted on cellular functions are generally thought to originate from reductions in cholesterol levels. Potential direct, ligand-like CD effects are largely neglected in spite of several recent studies reporting direct interaction between CDs and proteins including AMP-activated protein kinase, β-amyloid peptides, and α-synuclein. In this study, by using patch-clamp technique, time-resolved quantitation of cholesterol levels and biophysical parameters and applying cholesterol-extracting and non-cholesterol-extracting CDs at 1 and 5 mM concentrations, we provide evidence for a previously unexplored ligand-like, cholesterol-independent current inhibitory effect of CDs on KV1.3, a prototypical voltage-gated potassium channel with pathophysiological relevance in various autoimmune and neurodegenerative disorders. Our findings propose that potential direct CD effects on KV channels should be taken into consideration when interpreting functional consequences of CD treatments in both research and clinical practice. Furthermore, current-blocking effects of CDs on KV channels at therapeutically relevant concentrations might contribute to additional beneficial or adverse effects during their therapeutic applications.

Cyclodextrins, representing a versatile family of cyclic oligosaccharides, have extensive pharmaceutical applications due to their unique truncated cone-shaped structure with a hydrophilic outer surface and a hydrophobic cavity, which enables them to form non-covalent host–guest inclusion complexes in pharmaceutical formulations to enhance the solubility, stability and bioavailability of numerous drug molecules. As a result, cyclodextrins are mostly considered as inert carriers during their medical application, while their ability to interact not only with small molecules but also with lipids and proteins is largely neglected. By forming inclusion complexes with cholesterol, cyclodextrins deplete cholesterol from cellular membranes and thereby influence protein function indirectly through alterations in biophysical properties and lateral heterogeneity of bilayers. In this review, we summarize the general chemical principles of direct cyclodextrin–protein interactions and highlight, through relevant examples, how these interactions can modify protein functions in vivo, which, despite their huge potential, have been completely unexploited in therapy so far. Finally, we give a brief overview of disorders such as Niemann–Pick type C disease, atherosclerosis, Alzheimer’s and Parkinson’s disease, in which cyclodextrins already have or could have the potential to be active therapeutic agents due to their cholesterol-complexing or direct protein-targeting properties.

The human factor is an essential aspect of the operability and safety of many technical systems. This paper focuses on the analysis of human errors in the railway domain. The subject of human reliability analysis is the behavior of operators of station-signaling systems responsible for rail traffic management. We use a technique for human-error rate prediction as the 1st generation human reliability analysis to deal with task analyses, error identification and representation, and the quantification of human error probabilities. The paper contributes to the comparison of three technologically different railway traffic control systems, having different degrees of automation—from the manually operated (electro-mechanical), through semi-automated (relay-based) to almost fully automated (computer-based) station-signaling systems. We observe the frequency of individual operations performed in time intervals and calculate human error probability and human success probability values for each operation. Thus, we can analyze human reliability and compare the workload of operators working with control systems of different degrees of automation.

Although the largely positive intramembrane dipole potential (DP) may substantially influence the function of transmembrane proteins, its investigation is deeply hampered by the lack of measurement techniques suitable for high-throughput examination of living cells. Here, we describe a novel emission ratiometric flow cytometry method based on F66, a 3-hydroxiflavon derivative, and demonstrate that 6-ketocholestanol, cholesterol and 7-dehydrocholesterol, saturated stearic acid (SA) and ω-6 γ-linolenic acid (GLA) increase, while ω-3 α-linolenic acid (ALA) decreases the DP. These changes do not correlate with alterations in cell viability or membrane fluidity. Pretreatment with ALA counteracts, while SA or GLA enhances cholesterol-induced DP elevations. Furthermore, ALA (but not SA or GLA) increases endo-lysosomal escape of penetratin, a cell-penetrating peptide. In summary, we have developed a novel method to measure DP in large quantities of individual living cells and propose ALA as a physiological DP lowering agent facilitating cytoplasmic entry of penetratin.

The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated instrument considered as the gold standard for assessing tics in patients with Tourette's Syndrome and other tic disorders. Previous psychometric investigations of the YGTSS exhibit different limitations such as small sample sizes and insufficient methods. To overcome these shortcomings, we used a subsample of the large-scale “European Multicentre Tics in Children Study” (EMTICS) including 706 children and adolescents with a chronic tic disorder and investigated convergent, discriminant and factorial validity, as well as internal consistency of the YGTSS. Our results confirm acceptable convergent and good to very good discriminant validity, respectively, indicated by a sufficiently high correlation of the YGTSS total tic score with the Clinical Global Impression Scale for tics (rs = 0.65) and only low to medium correlations with clinical severity ratings of attention deficit/hyperactivity symptoms (rs = 0.24), obsessive–compulsive symptoms (rs = 27) as well as internalizing symptoms (rs = 0.27). Internal consistency was found to be acceptable (Ω = 0.58 for YGTSS total tic score). A confirmatory factor analysis supports the concept of the two factors “motor tics” and “phonic tics,” but still demonstrated just a marginal model fit (root mean square error of approximation = 0.09 [0.08; 0.10], comparative fit index = 0.90, and Tucker Lewis index = 0.87). A subsequent analysis of local misspecifications revealed correlated measurement errors, suggesting opportunities for improvement regarding the item wording. In conclusion, our results indicate acceptable psychometric quality of the YGTSS. However, taking the wide use and importance of the YGTSS into account, our results suggest the need for further investigations and improvements of the YGTSS. In addition, our results show limitations of the global severity score as a sum score indicating that the separate use of the total tic score and the impairment rating is more beneficial.

Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency are two rare genetic disorders that are caused by impairment of the mitochondrial enzyme sulfite oxidase. Sulfite oxidase is catalyzing the terminal reaction of cellular cysteine catabolism, the oxidation of sulfite to sulfate. Absence of sulfite oxidase leads to the accumulation of sulfite, which has been identified as a cellular toxin. However, the molecular pathways leading to the production of sulfite are still not completely understood. In order to identify novel treatment options for both disorders, the understanding of cellular cysteine catabolism – and its alterations upon loss of sulfite oxidase – is of utmost importance. Here we applied a new detection method of sulfite in cellular extracts to dissect the contribution of cytosolic and mitochondrial glutamate oxaloacetate transaminase (GOT) in the transformation of cysteine sulfinic acid to sulfite and pyruvate. We found that the cytosolic isoform GOT1 is primarily responsible for the production of sulfite. Moreover, loss of sulfite oxidase activity results in the accumulation of sulfite, H2S and persulfidated cysteine and glutathione, which is consistent with an increase of SQR protein levels. Surprisingly, none of the known H2S-producing pathways were found to be upregulated under conditions of sulfite toxicity suggesting an alternative route of sulfite-induced shift from oxidative to H2S dependent cysteine catabolism.

A data-driven adaptive reduced order modelling approach is presented for the reconstruction of impulsively started and vortex-dominated flows. A residual-based error metric is presented for the first time in the framework of the adaptive approach. The residual-based adaptive Reduced Order Modelling selects locally in time the most accurate reduced model approach on the basis of the lowest residual produced by substituting the reconstructed flow field into a finite volume discretisation of the Navier–Stokes equations. A study of such an error metric was performed to assess the performance of the resulting residual-based adaptive framework with respect to a single-ROM approach based on the classical proper orthogonal decomposition, as the number of modes is varied. Two- and three-dimensional unsteady flows were considered to demonstrate the key features of the method and its performance.

Background: Tourette Syndrome (TS) is a neurodevelopmental disorder that presents with motor and vocal tics early in childhood. The aim of this study was to investigate genetic variants in the 3' untranslated region (3'UTR) of TS candidate genes with a putative link to microRNA (miRNA) mediated regulation or gene expression.Methods: We used an in silico approach to identify 32 variants in the 3'UTR of 18 candidate genes putatively changing the binding site for miRNAs. In a sample composed of TS cases and controls (n = 290), as well as TS family trios (n = 148), we performed transmission disequilibrium test (TDT) and meta-analysis.Results: We found positive association of rs3750486 in the LIM homeobox 6 (LHX6) gene (p = 0.021) and rs7795011 in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene (p = 0.029) with TS in our meta-analysis. The TDT showed an over-transmission of the A allele of rs1042201 in the arylacetamide deacetylase (AADAC) gene in TS patients (p = 0.029).Conclusion: This preliminary study provides further support for the involvement of LHX6, IMMP2L, and AADAC genes, as well as epigenetic mechanisms, such as altered miRNA mediated gene expression regulation in the etiology of TS.

The epidermal growth factor (EGF) receptor (EGFR) undergoes ligand-dependent dimerization to initiate transmembrane signaling. Although crystallographic structures of the extracellular and kinase domains are available, ligand binding has not been quantitatively analyzed taking the influence of both domains into account. Here, we developed a model explicitly accounting for conformational changes of the kinase and extracellular domains, their dimerizations and ligand binding to monomeric and dimeric receptor species. The model was fitted to ligand binding data of suspended cells expressing receptors with active or inactive kinase conformations. Receptor dimers with inactive, symmetric configuration of the kinase domains exhibit positive cooperativity and very weak binding affinity for the first ligand, whereas dimers with active, asymmetric kinase dimers are characterized by negative cooperativity and subnanomolar binding affinity for the first ligand. The homodimerization propensity of EGFR monomers with active kinase domains is ∼100-times higher than that of dimers with inactive kinase domains. Despite this fact, constitutive, ligand-independent dimers are mainly generated from monomers with inactive kinase domains due to the excess of such monomers in the membrane. The experimental finding of increased positive cooperativity at high expression levels of EGFR was recapitulated by the model. Quantitative prediction of ligand binding to different receptor species revealed that EGF binds to receptor monomers and dimers in an expression-level dependent manner without significant recruitment of monomers to dimers upon EGF stimulation below the phase transition temperature of the membrane. Results of the fitting offer unique insight into the workings of the EGFR.

Abstract Background Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure. Methods Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6–15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non-ADHD control group regarding low weight (BMI ≤ 3rd percentile), low height (≤3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age (

Objective: The short-term safety of methylphenidate (MPH) has been widely demonstrated; however the long-term safety is less clear. The aim of this study was to investigate the safety of MPH in relation to pubertal maturation and to explore the monitoring of bone age. Method: Participants from ADDUCE, a two-year observational longitudinal study with three parallel cohorts (MPH group, no-MPH group, and a non-ADHD control group), were compared with respect to Tanner staging. An Italian subsample of medicated-ADHD was further assessed by the monitoring of bone age. Results: The medicated and unmedicated ADHD groups did not differ in Tanner stages indicating no higher risk of sexual maturational delay in the MPH-treated patients. The medicated subsample monitored for bone age showed a slight acceleration of the bone maturation after 24 months, however their predicted adult height remained stable. Conclusion: Our results do not suggest safety concerns on long-term treatment with MPH in relation to pubertal maturation and growth.

Objective: Short-term RCTs have demonstrated that MPH-treatment significantly reduces ADHD-symptoms, but is also associated with adverse events, including sleep problems. However, data on long-term effects of MPH on sleep remain limited. Methods: We performed a 2-year naturalistic prospective pharmacovigilance multicentre study. Participants were recruited into three groups: ADHD patients intending to start MPH-treatment (MPH-group), those not intending to use ADHD-medication (no-MPH-group), and a non-ADHD control-group. Sleep problems were assessed with the Children's-Sleep-Habits-Questionnaire (CSHQ). Results: 1,410 participants were enrolled. Baseline mean CSHQ-total-sleep-scores could be considered clinically significant for the MPH-group and the no-MPH-group, but not for controls. The only group to show a significant increase in any aspect of sleep from baseline to 24-months was the control-group. Comparing the MPH- to the no-MPH-group no differences in total-sleep-score changes were found. Conclusion: Our findings support that sleep-problems are common in ADHD, but don't suggest significant negative long-term effects of MPH on sleep.

Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H2S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-β-synthase (CBS) activities and bioavailable H2S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD+, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle.

The dipole potential generating an electric field much stronger than any other type of membrane potential influences a wide array of phenomena, ranging from passive permeation to voltage-dependent conformational changes of membrane proteins. It is generated by the ordered orientation of lipid carbonyl and membrane-attached water dipole moments. Theoretical considerations and indirect experimental evidence obtained in model membranes suggest that the dipole potential is larger in liquid-ordered domains believed to correspond to lipid rafts in cell membranes. Using three different dipole potential-sensitive fluorophores and four different labeling approaches of raft and nonraft domains, we showed that the dipole potential is indeed stronger in lipid rafts than in the rest of the membrane. The magnitude of this difference is similar to that observed between the dipole potential in control and sphingolipid-enriched cells characteristic of Gaucher's disease. The results established that the heterogeneity of the dipole potential in living cell membranes is correlated with lipid rafts and imply that alterations in the lipid composition of the cell membrane in human diseases can lead to substantial changes in the dipole potential.

Surface characteristics play an important role in the implant-bone integration that is required for the long-term reliability of dental and orthopedic implants. In this paper, we investigate the effect of acid etching on the mass reduction and roughness of grade 2 and grade 5 Ti under controlled experimental conditions. Three different etching compounds were investigated: 30% HCl, 85% H3PO4 and the compound of 30% (COOH)2 × 2H2O and 30% H2O2 in various treatment intervals under controlled temperature. Stereo microscopy, scanning electron microscopy, roughness and weight measurements were carried out on the samples. We found that neither 85% H3PO4 nor the compound of 30% (COOH)2 × 2H2O and 30% H2O2 were able to remove the machining marks from the surface of Ti discs in our experimental setting. On the other hand, etching in 30% HCl yielded even surfaces both on Ti grade 2 and 5 discs. We also found that etching at higher temperatures in 30% HCl resulted in significant mass loss.

Abstract Directed capillary ingrowth has long been considered synonymous with tumor vascularization. However, the vasculature of primary tumors and metastases is not necessarily formed by endothelial cell sprouting; instead, malignant tumors can acquire blood vessels via alternative vascularization mechanisms, such as intussusceptive microvascular growth, vessel co-option, and glomeruloid angiogenesis. Importantly, in response to anti-angiogenic therapies, malignant tumors can switch from one vascularization mechanism to another. In this article, we briefly review the biological features of these mechanisms and discuss on their significance in medical oncology.

There is scarce information on the influence of dairy consumption between main meals on the overall diet quality through childhood, constituting the main aim of this research. From the Identification and prevention of Dietary- and lifestyle induced health EFfects In Children and infantS (IDEFICS) study, and based on the data availability in each period due to drop outs, 8807 children aged 2 to 9.9 years from eight European countries at baseline (T0: 2007−2008); 5085 children after two years (T1); and 1991 after four years (T3), were included in these analyses. Dietary intake and the Diet Quality Index (DQI) were assessed by two 24 hours dietary recalls (24-HDR) and food frequency questionnaire. Consumption of milk and yogurt (p = 0.04) and cheese (p < 0.001) at snack meal occasions was associated with higher DQI scores in T0; milk and yogurt (p < 0.001), and cheese (p < 0.001) in T1; and cheese (p = 0.05) in T3. Consumers of milk (p = 0.02), yogurt (p < 0.001), or cheese (p < 0.001) throughout T0 and T1 at all snack moments had significantly higher scores of DQI compared to non-consumers. This was also observed with the consumption of cheese between T1 and T3 (p = 0.03). Consumption of dairy products at snack moments through childhood is associated with a better overall diet quality, being a good strategy to improve it in this period.

Knowledge about immunity to Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels is essential for infection control and vaccination. A longitudinal study of 11 dam–calf pairs showed that calves lose maternal MERS-CoV antibodies 5–6 months postparturition and are left susceptible to infection, indicating a short window of opportunity for vaccination.

This paper deals with a possibility of a modeling of a block system. A created modeling tool contains a graphic editor of a track section configuration and a graphic editor of control algorithms, which serves on a writing of behavior algorithms of exterior devices of the block system. In order to the modeling of the block system was possible general models of basic exterior devices and a programming language for the writing of control algorithms to a source code form had to be created. It describes a work with different parts of the modeling tool and their possibilities on a selected example of an automatic block. The paper also describes an ability of to simulate a modeled block system activity and an ability to simulate the movement of the train in track section

Camels carry Middle East respiratory syndrome coronavirus, but little is known about infection age or prevalence. We studied >800 dromedaries of all ages and 15 mother–calf pairs. This syndrome constitutes an acute, epidemic, and time-limited infection in camels

An analysis of risks related to controlled process and related hazards identification is an important activity during the development of the safety related control system (SRCS). The mistake of the operational staff during the execution of the safety relevant operations related to controlled process can be the cause of hazard. Influence of the operator on controlled process safety depends on operation mode of the SRCS and on technical safety of the SRCS. This contribution deals with the issue of the safety assessment of the operator effect on the safety of the controlled process.

The mechanism of action of elisidepsin (PM02734, Irvalec®) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug’s binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.

Although the genetic basis of Tourette Syndrome (TS) remains unclear, several candidate genes have been implicated. Using a set of 382 TS individuals of European ancestry we investigated four candidate genes for TS (HDC, SLITRK1, BTBD9 and SLC6A4) in an effort to identify possibly causal variants using a targeted re-sequencing approach by next generation sequencing technology. Identification of possible disease causing variants under different modes of inheritance was performed using the algorithms implemented in VAAST. We prioritized variants using Variant ranker and validated five rare variants via Sanger sequencing in HDC and SLITRK1, all of which are predicted to be deleterious. Intriguingly, one of the identified variants is in linkage disequilibrium with a variant that is included among the top hits of a genome-wide association study tolerance to citalopram treatment, an antidepressant drug with off-label use also in obsessive compulsive disorder. Our findings provide additional evidence for the implication of these two genes in TS susceptibility and the possible role of these proteins in the pathobiology of TS should be revisited.

In this essay, we reconstruct a keyword for communication—affordance. Affordance, adopted from ecological psychology, is now widely used in technology studies, yet the term lacks a clear definition. This is especially problematic for scholars grappling with how to theorize the relationship between technology and sociality for complex socio-technical systems such as machine-learning algorithms, pervasive computing, the Internet of Things, and other such “smart” innovations. Within technology studies, emerging theories of materiality, affect, and mediation all necessitate a richer and more nuanced definition for affordance than the field currently uses. To solve this, we develop the concept of imagined affordance. Imagined affordances emerge between users’ perceptions, attitudes, and expectations; between the materiality and functionality of technologies; and between the intentions and perceptions of designers. We use imagined affordance to evoke the importance of imagination in affordances—expectations for technology that are not fully realized in conscious, rational knowledge. We also use imagined affordance to distinguish our process-oriented, socio-technical definition of affordance from the “imagined” consensus of the field around a flimsier use of the term. We also use it in order to better capture the importance of mediation, materiality, and affect. We suggest that imagined affordance helps to theorize the duality of materiality and communication technology: namely, that people shape their media environments, perceive them, and have agency within them because of imagined affordances.

Recenze publikace - Bureš, Pavel; Faix, Martin; Svaček, Ondřej: Vznik a uznání státu – Aktuální pohled mezinárodního práva Praha: Leges, 2013, 144 s.

In mathematical models, for forecasting prices on commodity exchanges different mathematical methods are used. In the paper the numerical model based on the exponential approximation of commodity stock exchanges was derived. The price prognoses of aluminium on the London Metal Exchange were determined as numerical solution of the Cauchy initial problem for the 1st order ordinary differential equation. To make the numerical model more accurate the idea of the modification of the initial condition value by the aluminium price (stock exchange) was realised. The derived numerical model was verified by determining the influence of the length of the initial condition drift on the accuracy of the obtained prognoses. The types of the initial condition drift during different movements of aluminium prices were studied. The most accurate prognoses were the most often obtained by using the longest initial condition drift. In this type of drift the initial condition value was replaced by aluminium stock exchange in the month in which the absolute percentage error of the prognosis had at least selected value. The advantage of this drift was manifested especially in the stable price course and within larger changes in prices. If there was price fluctuating within the observing period, in the next forecasting the most accurate was the drift the initial condition value of which had been replaced by the price that was the nearest to the stock exchange price evolution.

This paper remarks on the possibility of the ciphering algorithm use based on the standard encoding techniques from the linear error - correcting coding area. The quality of deciphering algorithms is determined for (n, k) Hamming codes and the valid code word lengths are recommended for practical use. The presented principle can be generalised for another type of the algebraic codes.

For any CR-holomorphic vector bundle (in the sense of N. Tanaka, [16]) E, over a strictly pseudoconvex CR manifold M, equipped with a convex complex Finsler structure F, we build a connection D in the pullback bundle π∗E of E by π : E \ {0} −→M, similar to the Rund connection (cf. M. Abate – G. Patrizio, [1]) in complex Finsler geometry.

Autor chce týmto príspevkom oboznámiť verejnosť s výsledkami archeologického výskumu, realizovanom v centre Trnavy pracovníkmi SNM – Archeologického múzea v máji–auguste roku 2009. Na pomerne malej skúmanej ploche sa tu odkrylo 51 objektov. Z ich charakteru možno konštatovať, že tu boli skúmané zadné časti parciel medzi ulicami Hornopotočná a Hollého a takmer všetky objekty boli súčasťou hospodárskeho zázemia budov, nachádzajúcich sa pravdepodobne bližšie k týmto uliciam. Najpočetnejšími objekt mi (8) na nami skúmanej ploche boli tie, ktoré sme identifikovali ako ľadnice (17.–20. storočie). Rovnako početnou skupinou objektov (8) boli piecky (13.–16. storočie). Ďalej studne (5), z ktorých štyri sú datované do 13.–14. storočia a jedna na začiatok 20. storočia. Objektmi veľmi bohatými na nálezy boli stredoveké žumpy (3), datované na prelom 13. a 14. storočia. Zo stredovekých objektov treba ešte spomenúť konštrukčne zaujímavú zásobnicovú jamu – objekt 14/2009, ktorej steny boli vypletané prútím (14. storočie). Publikovaním nálezov z tohto výskumu sa autor snaží doplniť poznatky o živote v stredovekej a novovekej Trnave, známe z doteraz vydaných publikácií.

Autori nadväzujú na štúdiu o keramických dlaždiciach spred dvoch rokov publikovanú v tomto zborníku. Predmetom ich záujmu sú tentoraz keramické potrubia, ktoré nielen na Slovensku, ale aj v okolitých krajinách patria medzi doposiaľ podrobnejšie nezhodnotený druh archeologických nálezov a v užšom zmysle aj keramických výrobkov. Pri potrubiach rozlišujú, či ide o vodovodné, alebo dymovodné potrubia. Predstavujú doposiaľ známe nálezy zo Slovenska v kontexte s ich nálezovými okolnosťami a excerptmi z histórie samotných lokalít, čo do značnej miery napomáha datovaniu nálezov. Vodovodné keramické potrubia pochádzajú z Borinky (19. storočie), Bratislavy (18.–19. storočie), Častej – hradu Červený Kameň (17. storočie), Hronského Beňadiku (16.–17. storočie), Nitry (18.–19. storočie), Smoleníc (19.–20. storočie), Svätého Jura (hradisko Neštich, hrad Biely Kameň, intravilán mesta, 13.–18. storočie) a Trnavy (17. storočie). Nálezy dymovodných potrubí sú známe z Banskej Štiavnice (18.–19. storočie), Bratislavy (16.–19. storočie), Bratislavy – hradu Devín (16.–17. storočie) a Fiľakova (16.–17. storočie). Publikovaním tohto druhu keramiky sa autori snažia vzbudiť záujem aj o ďalšie aspekty štúdia s nimi spojeného (stavebný kontext, výroba, datovanie, argumenty pre ich používanie v konfrontácii s inomateriálovými výrobkami a pod.).

OBJECTIVE: To examine variations in infant weight gain between children of parents with and without migrant background and to investigate how these differences are explained by pre- and perinatal factors. METHODS: We used data on birth weight and weight at six months from well-child check-up books that were collected from a population-based German sample of children in the IDEFICS study (n = 1,287). We calculated unadjusted and adjusted means for weight z-scores at birth and six months later. We applied linear regression for change in weight z-score and we calculated odds ratios and 95% confidence intervals (95% CI) for rapid weight gain by logistic regression, adjusted for biological, social and behavioural factors. RESULTS: Weight z-scores for migrants and Germans differed slightly at birth, but were markedly increased for Turkish and Eastern European infants at age six months. Turkish infants showed the highest change in weight z-score during the first 6 months (ß = 0.35; 95% CI 0.14-0.56) and an increased probability of rapid weight gain compared with German infants. Examination of the joint effect of migrant and socioeconomic status (SES) showed the greatest change in weight z-scores in Turkish infants from middle SES families (ß = 0.77; 95% CI 0.40-1.14) and infants of parents from Eastern European countries with high SES (ß = 0.72; 95% CI 0.13-1.32). CONCLUSIONS: Our results support the hypothesis that migrant background is an independent risk factor for infant weight gain and suggest that the onset of health inequalities in overweight starts in early infancy.

Levels of the selective autophagy substrate p62 have been established in recent years as a specific readout for basal autophagic activity. Here we compared different experimental approaches for using this assay in Drosophila larvae. Similar to the more commonly used western blots, quantifying p62 dots in immunostained fat body cells of L3 stage larvae detected a strong accumulation of endogenous p62 aggregates in null mutants for Atg genes and S6K. Importantly, genes whose mutation or silencing results in early stage lethality can only be analyzed by microscopy using clonal analysis. The loss of numerous general housekeeping genes show a phenotype in large-scale screens including autophagy, and the p62 assay was potentially suitable for distinguishing bona fide autophagy regulators from silencing of a DNA polymerase subunit or a ribosomal gene that likely has a non-specific effect on autophagy. p62 accumulation upon RNAi silencing of known autophagy regulators was dependent on the duration of the knockdown effect, unlike in the case of starvation-induced autophagy. The endogenous p62 assay was more sensitive than a constitutively overexpressed p62-GFP reporter, which showed self-aggregation and large-scale accumulation even in control cells. We recommend western blots for following the conversion of overexpressed p62-GFP reporters to estimate autophagic activity if sample collection from mutant larvae or adults is possible. In addition, we also showed that overexpressed p62 or Atg8 reporters can strongly influence the phenotypes of each other, potentially giving rise to false or contradicting results. Overexpressed p62 aggregates also incorporated Atg8 reporter molecules that might lead to a wrong conclusion of strongly enhanced autophagy, whereas expression of an Atg8 reporter transgene rescued the inhibitory effect of a dominant-negative Atg4 mutant on basal and starvation-induced autophagy.

In the past decade, creativity researchers have attempted to explore how creative fixed and growth mindsets shape creative outcomes and effort. Previous studies found a strong association between creative mindsets and self-perceptions. However, research on the relationship between creative mindsets and performance led to mixed results. In an attempt to explain these confusing findings, many advocated the idea that creative mindsets may influence how learners utilize their domain knowledge and skills in creative performance. To empirically test this assumption, we investigated the influence of domain knowledge and skills on the relationship between creative mindsets and performance among college students (n = 125) in the context of ESL/EAL writing. Our results show that a fixed creative mindset, but not growth, together with ESL/EAL writing proficiency contribute to ESL/EAL creative writing performance. We also found that domain-specific knowledge and skills play a role in how creative mindsets translate to creative performance: while endorsing a fixed mindset was detrimental for students at all ESL/EAL writing proficiency levels, a growth mindset was beneficial at high proficiency levels only. These findings contradict the assumption that cultivating a growth creative mindset will lead to positive creative outcomes for all. Practical implications, limitations, and future research directions are discussed.