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Abstract Given high costs of Oncotype DX (ODX) testing, widely used in recurrence risk assessment for early-stage breast cancer, studies have predicted ODX using quantitative clinicopathologic variables. However, such models have incorporated only small cohorts. Using a cohort of patients from the National Cancer Database (NCDB, n = 53,346), we trained machine learning models to predict low-risk (0-25) or high-risk (26-100) ODX using quantitative estrogen receptor (ER)/progesterone receptor (PR)/Ki-67 status, quantitative ER/PR status alone, and no quantitative features. Models were externally validated on a diverse cohort of 970 patients (median follow-up 55 months) for accuracy in ODX prediction and recurrence. Comparing the area under the receiver operating characteristic curve (AUROC) in a held-out set from NCDB, models incorporating quantitative ER/PR (AUROC 0.78, 95% CI 0.77–0.80) and ER/PR/Ki-67 (AUROC 0.81, 95% CI 0.80–0.83) outperformed the non-quantitative model (AUROC 0.70, 95% CI 0.68–0.72). These results were preserved in the validation cohort, where the ER/PR/Ki-67 model (AUROC 0.87, 95% CI 0.81–0.93, p = 0.009) and the ER/PR model (AUROC 0.86, 95% CI 0.80–0.92, p = 0.031) significantly outperformed the non-quantitative model (AUROC 0.80, 95% CI 0.73–0.87). Using a high-sensitivity rule-out threshold, the non-quantitative, quantitative ER/PR and ER/PR/Ki-67 models identified 35%, 30% and 43% of patients as low-risk in the validation cohort. Of these low-risk patients, fewer than 3% had a recurrence at 5 years. These models may help identify patients who can forgo genomic testing and initiate endocrine therapy alone. An online calculator is provided for further study.

The long-term use of steel strip in various industries makes it an important semi-finished product, which makes it necessary to improve its chemical composition and mechanical properties, reduce its thickness and weight, expand the range of new types of steel strip and increase its production. This entails a large number of technological operations dependent on precise temperature measurement and control. In some industrial plants, the steel strip is in continuous motion, which makes the use of contact measuring devices impossible. When using non-contact measuring devices such as pyrometers or thermal imaging cameras, the emissivity of the materials being measured is a problematic parameter, as setting an incorrect emissivity value to the measuring device results in inaccurate temperature readings. The essence of this research was to establish a measurement method and to perform experimental measurements of the emissivity of a polished steel strip used in a continuous annealing line, the subsequent processing of the data from these measurements and their evaluation. The emissivity measurements were carried out for 5 types of steel strip of different parameters, while the measurement itself was carried out in the long wavelength range of 7.5–14 µm and at strip temperatures of 100–300 °C. Depending on the type of steel strip, the mean emissivity values ranged from 0.0835– to 0.1143. The emissivity of the steel strip increased with increasing strip temperature, and it was not a linear dependence. The emissivity values determined in this research could be applied to measuring equipment in actual production, which could improve the accuracy of temperature measurement in the heat treatment of polished steel strip. Thermal camera measurements in the long wavelength range, taking thermal images and their processing and determining the emissivity value of polished steel strips are the parts of this research that make it different from other already published research.

Reducing energy consumption and increasing energy efficiency have been especially topical issues recently, affecting all areas of energy consumption, including industrial sectors. Continuous annealing lines, as important industrial production facilities, operate with high energy consumption, which can be analyzed and optimized using predictive mathematical models. For the purpose of this paper, a mathematical model was developed to compare five variants of different excess combustion air operating with the same heat input and fuel consumption. The reference variant had an excess combustion air with a value of 1.279 and the steel strip temperature at the outlet of the heating chamber was 609.5 °C. In terms of energy savings, variant 1 can be considered as the optimal variant, which had an excess combustion air value of 1.15 and a steel strip temperature at the outlet of the heating chamber of 637.3 °C.

Animal husbandry is one of man’s oldest occupations. It began with the domestication of animals and developed continuously, in parallel with the evolution of human society. The selection and improvement of goats in Romania was not a clearly defined objective until around 1980. In recent years, with the increasing economic value given to goats, breeding programs are becoming established. In Romania, a few goat genetic studies using microsatellites and mtDNA have been carried out; however, a systematic characterization of the country’s goat genomic resources remains missing. In this study, we analyzed the genetic variability of Carpatina goats from four distinct geographical areas (northern, north-eastern, eastern and southern Romania), using the Illumina OvineSNP60 (RefSeq ARS1) high-density chip for 67 goats. Heterozygosity values, inbreeding coefficients and effective population size across all autosomes were calculated for those populations that inhabit high- and low-altitude and high- and low-temperature environments. Diversity, as measured by expected heterozygosity (HE), ranged from 0.413 in the group from a low-temperature environment to 0.420 in the group from a high-temperature environment. Within studied groups, the HT (high temperature) goats were the only group with a positive but low average inbreeding coefficient value, which was 0.009. After quality control (QC) analysis, 46,965 SNPs remained for analysis (MAF < 0.01). LD was calculated for each chromosome separately. The Ne has been declining since the time of domestication, having recently reached 123, 125, 185 and 92 for the HA (high altitude), LA (low altitude), HT (high temperature) and LT (low temperature) group, respectively. Our study revealed a low impact of inbreeding in the Carpatina population, and the Ne trend also indicated a steep decline in the last hundred years. These results will contribute to the genetic improvement of the Carpatina breed.

Antibodies to SARS-CoV-2 are central to recovery and immunity from COVID-19. However, the relationship between disease severity and the repertoire of antibodies against specific SARS-CoV-2 epitopes an individual develops following exposure remains incompletely understood. Here, we studied seroprevalence of antibodies to specific SARS-CoV-2 and other betacoronavirus antigens in a well-annotated, community sample of convalescent and never-infected individuals obtained in August 2020. One hundred and twenty-four participants were classified into five groups: previously exposed but without evidence of infection, having no known exposure or evidence of infection, seroconverted without symptoms, previously diagnosed with symptomatic COVID-19, and recovered after hospitalization with COVID-19. Prevalence of IgGs specific to the following antigens was compared between the five groups: recombinant SARS-CoV-2 and betacoronavirus spike and nucleocapsid protein domains, peptides from a tiled array of 22-mers corresponding to the entire spike and nucleocapsid proteins, and peptides corresponding to predicted immunogenic regions from other proteins of SARS-CoV-2. Antibody abundance generally correlated positively with severity of prior illness. A number of specific immunogenic peptides and some that may be associated with milder illness or protection from symptomatic infection were identified. No convincing association was observed between antibodies to Receptor Binding Domain(s) (RBDs) of less pathogenic betacoronaviruses HKU1 or OC43 and COVID-19 severity. However, apparent cross-reaction with SARS-CoV RBD was evident and some predominantly asymptomatic individuals had antibodies to both MERS-CoV and SARS-CoV RBDs. Findings from this pilot study may inform development of diagnostics, vaccines, and therapeutic antibodies, and provide insight into viral pathogenic mechanisms.

In goats, k-casein (CSN3) locus is highly polymorphic with up to 16 allele currently characterized. They produce 13 protein variants (CSN3) that were classified in two groups (AIEF and BIEF), according to their isoelectric point. Isoelectric focusing (IEF) of milk samples allows the detection of these two CSN3 groups, but for correct identification of CSN3 alleles DNA based genotyping methods are needed. Therefore the objective of this study was to identify the types of alleles occurring at the CSN3 locus in Carpathian goat breed by using a combined IEF and DNA sequencing approach. IEF analysis of milk samples collected from two Carpathian goat populations reared in Romania revealed two distinct CSN3 patterns. Amplification and sequencing of CSN3 cDNA obtained from these goats revealed four polymorphic sites located in the exon 4 that are responsible for amino acids substitutions, as compared with the reference sequence of A allele. By comparative analysis of IEF and cDNA sequencing data obtained from the two populations, we shown that AIEF alleles are represented by B allele, while BIEF alleles are represented by D allele. However, the variation of CSN3 locus in Carpathian goat breed could be more complex, therefore further studies are needed to characterize it.

The development and function of mammary gland is mainly controlled by growth hormone and prolactin, two protein hormones secreted by the anterior pituitary gland. Their synthesis is under regulatory influence of pituitary factor 1 (PIT1 or POU1F1), a protein factor produced in hypothalamic nuclei. In cattle, it was shown that a HinfI polymorphism located in exon 6 of PIT1 gene may have significant influence on milk quantity. In particular A allele was associated with a higher milk yield and could be a valuable genetic marker for improving milk quantity in cattle. In an effort to better understand the possible influence of this polymorphism on mammary gland development and function in cattle, we have studied the frequency this polymorphism in Romanian Black and White breed, a high milk production cattle breed versus Romanian Grey Steppe breed, a primitive breed with very low milk production. In both breeds the frequency of B allele is much higher as compared with the frequency of A allele. The study of PIT1 polymorphism in Romanian cattle breeds is a part of a more complex study targeting several key genes involved in mammary gland function

Given the importance of quantum reference frames (QRFs) to both quantum and gravitational physics, it is pertinent to develop a systematic method for switching between the descriptions of physics relative to different choices of QRFs, which is valid in both fields. Here we continue with such a unifying approach, begun in [Quantum 4, 225 (2020)], whose key ingredient is a symmetry principle, which enforces physics to be relational. Thanks to gauge related redundancies, this leads to a perspective-neutral structure which contains all frame choices at once and via which frame perspectives can be consistently switched. Formulated in the language of constrained systems, the perspective-neutral structure is the constraint surface classically and the gauge invariant Hilbert space in the Dirac quantized theory. By contrast, a perspective relative to a specific frame corresponds to a gauge choice and the associated reduced phase and Hilbert space. QRF changes thus amount to a gauge transformation. We show that they take the form of `quantum coordinate changes'. We illustrate this in a general mechanical model, namely the relational $N$-body problem in 3D space with rotational and translational symmetry. This model is especially interesting because it features the Gribov problem so that globally valid gauge fixing conditions, and hence relational frame perspectives, are absent. The constraint surface is topologically non-trivial and foliated by 3-, 5- and 6-dimensional gauge orbits, where the lower dimensional orbits are a set of measure zero. The $N$-body problem also does not admit globally valid canonically conjugate pairs of Dirac observables. These challenges notwithstanding, we exhibit how one can construct the QRF transformations for the 3-body problem. Our construction also sheds new light on the generic inequivalence of Dirac and reduced quantization through its interplay with QRF perspectives.

Modern heating furnaces use combined modes of heating the charge. At high heating temperatures, more radiation heating is used; at lower temperatures, more convection heating is used. In large heating furnaces, such as pusher furnaces, it is necessary to monitor the heating of the material zonally. Zonal heating allows the appropriate thermal regime to be set in each zone, according to the desired parameters for heating the charge. The problem for each heating furnace is to set the optimum thermal regime so that at the end of the heating, after the material has been cross-sectioned, there is a uniform temperature field with a minimum temperature differential. In order to evaluate the heating of the charge, a mathematical model was developed to calculate the heat fluxes of the moving charge (slabs) along the length of the pusher furnace. The obtained results are based on experimental measurements on a test slab on which thermocouples were installed, and data acquisition was provided by a TERMOPHIL-stor data logger placed directly on the slab. Most of the developed models focus only on energy balance assessment or external heat exchange. The results from the model created showed reserves for changing the thermal regimes in the different zones. The developed model was used to compare the heating evaluation of the slabs after the rebuilding of the pusher furnace. Changing the furnace parameters and altering the heat fluxes or heating regimes in each zone contributed to more uniform heating and a reduction in specific heat consumption. The developed mathematical heat flux model is applicable as part of the powerful tools for monitoring and controlling the thermal condition of the charge inside the furnace as well as evaluating the operating condition of such furnaces.

Existing work on quantum causal structure assumes that one can perform arbitrary operations on the systems of interest. But this condition is often not met. Here, we extend the framework for quantum causal modelling to situations where a system can suffer $\textit{sectorial constraints}$, that is, restrictions on the orthogonal subspaces of its Hilbert space that may be mapped to one another. Our framework (a) proves that a number of different intuitions about causal relations turn out to be equivalent; (b) shows that quantum causal structures in the presence of sectorial constraints can be represented with a directed graph; and (c) defines a fine-graining of the causal structure in which the individual sectors of a system bear causal relations. As an example, we apply our framework to purported photonic implementations of the quantum switch to show that while their coarse-grained causal structure is cyclic, their fine-grained causal structure is acyclic. We therefore conclude that these experiments realize indefinite causal order only in a weak sense. Notably, this is the first argument to this effect that is not rooted in the assumption that the causal relata must be localized in spacetime.

Beef aging is one of the most common methods used for improving its qualities. The main goal of the present study was to analyse the influence of different cold pressed oils and aromatic herbs during marination process on the nutritional, textural, and sensory attributes of the final grilled sirloin samples. In order to fulfil this goal, methods like GC-MS, HPLC/DAD/ESI-MS, HLPC-RID were performed to quantify fatty acids, phenolic acids, and organic acids, respectively. Textural and sensory analysis were performed with CT 3 Texture Analyser and hedonic test. The results showed high improvement of the meat grilled samples regarding the content of phenolic acids, and textural and sensory characteristics. Pearson values indicate strong positive correlations between raw and grilled samples regarding their content in phenolic acids. Hardness, chewiness, gumminess decreased during marination, meanwhile, resilience, and cohesiveness increased. Sensory analysis highlighted that meat samples marinated with olive oil and rosemary for 120 h reached the highest hedonic score among the tested samples.

We argue that the quantum-theoretical structures studied in several recent lines of research cannot be adequately described within the standard framework of quantum circuits. This is in particular the case whenever the combination of subsystems is described by a nontrivial blend of direct sums and tensor products of Hilbert spaces. We therefore propose an extension to the framework of quantum circuits, given by $\textit{routed linear maps}$ and $\textit{routed quantum circuits}$. We prove that this new framework allows for a consistent and intuitive diagrammatic representation in terms of circuit diagrams, applicable to both pure and mixed quantum theory, and exemplify its use in several situations, including the superposition of quantum channels and the causal decompositions of unitaries. We show that our framework encompasses the `extended circuit diagrams' of Lorenz and Barrett [arXiv:2001.07774 (2020)], which we derive as a special case, endowing them with a sound semantics.

Oxygen-enhanced combustion (OEC) is a useful method for improving the efficiency of thermal plants and for decreasing greenhouse gas (GHG) emissions. Basic and modified burner designs utilizing OEC in the aluminum melting process in a rotary tilting furnace were studied. A combined approach comprising experimental measurement and simulation modeling was adopted aimed at assessing GHG emissions production. Reduction of up to 60% fuel consumption of the total natural gas used in the laboratory-scale furnace was achieved. The optimal oxygen concentration in the oxidizer regarding the amount of total GHG emissions produced per charge expressed as CO2 equivalent was 35% vol. Its further increase led only to marginal fuel savings, while the nitrogen oxide emissions increased rapidly. Using the modified burner along with OEC led to around 10% lower CO2 emissions and around 15% lower total GHG emissions, compared to using a standard air/fuel burner. CFD simulations revealed the reasons for these observations: improved mixing patterns and more uniform temperature field. Modified burner application, moreover, enables furnace productivity to be increased by shortening the charge melting time by up to 16%. The presented findings demonstrate the feasibility of the proposed burner modification and highlight its better energy and environmental performance indicators, while indicating the optimal oxygen enrichment level in terms of GHG emissions for the OEC technology applied to aluminum melting.

Every clock is a physical system and thereby ultimately quantum. A naturally arising question is thus how to describe time evolution relative to quantum clocks and, specifically, how the dynamics relative to different quantum clocks are related. This is a particularly pressing issue in view of the multiple choice facet of the problem of time in quantum gravity, which posits that there is no distinguished choice of internal clock in generic general relativistic systems and that different choices lead to inequivalent quantum theories. Exploiting a recent unifying approach to switching quantum reference systems [Vanrietvelde et al 2020 Quantum 4 225; Vanrietvelde et al 2018 arXiv:1809.05093[quant-ph])], we exhibit a systematic method for switching between different clock choices in the quantum theory. We illustrate it by means of the parametrized particle, which, like gravity, features a Hamiltonian constraint. We explicitly switch between the quantum evolution relative to the non-relativistic time variable and that relative to the particle’s position, which requires carefully regularizing the zero-modes in the so-called time-of-arrival observable. While this toy model is simple, our approach is general and, in particular, directly amenable to quantum cosmology. It proceeds by systematically linking the reduced quantum theories relative to different clock choices via the clock-choice-neutral Dirac quantized theory, in analogy to coordinate changes on a manifold. This method suggests a new perspective on the multiple choice problem, indicating that it is rather a multiple choice feature of the complete relational quantum theory, taken as the conjunction of Dirac quantized and quantum deparametrized theories. Precisely this conjunction permits one to consistently switch between different temporal reference systems, which is a prerequisite for a quantum notion of general covariance. Finally, we show that quantum uncertainties generically lead to a discontinuity in the relational dynamics when switching clocks, in contrast to the classical case.

Treating reference frames fundamentally as quantum systems is inevitable in quantum gravity and also in quantum foundations once considering laboratories as physical systems. Both fields thereby face the question of how to describe physics relative to quantum reference systems and how the descriptions relative to different such choices are related. Here, we exploit a fruitful interplay of ideas from both fields to begin developing a unifying approach to transformations among quantum reference systems that ultimately aims at encompassing both quantum and gravitational physics. In particular, using a gravity inspired symmetry principle, which enforces physical observables to be relational and leads to an inherent redundancy in the description, we develop a perspective-neutral structure, which contains all frame perspectives at once and via which they are changed. We show that taking the perspective of a specific frame amounts to a fixing of the symmetry related redundancies in both the classical and quantum theory and that changing perspective corresponds to a symmetry transformation. We implement this using the language of constrained systems, which naturally encodes symmetries. Within a simple one-dimensional model, we recover some of the quantum frame transformations of \cite{Giacomini:2017zju}, embedding them in a perspective-neutral framework. Using them, we illustrate how entanglement and classicality of an observed system depend on the quantum frame perspective. Our operational language also inspires a new interpretation of Dirac and reduced quantized theories within our model as perspective-neutral and perspectival quantum theories, respectively, and reveals the explicit link between them. In this light, we suggest a new take on the relation between a `quantum general covariance' and the diffeomorphism symmetry in quantum gravity.

The domestic water buffalo is native to the Asian continent but through historical migrations and recent importations, nowadays has a worldwide distribution. The two types of water buffalo, i.e., river and swamp, display distinct morphological and behavioral traits, different karyotypes and also have different purposes and geographical distributions. River buffaloes from Pakistan, Iran, Turkey, Egypt, Romania, Bulgaria, Italy, Mozambique, Brazil and Colombia, and swamp buffaloes from China, Thailand, Philippines, Indonesia and Brazil were genotyped with a species-specific medium-density 90K SNP panel. We estimated the levels of molecular diversity and described population structure, which revealed historical relationships between populations and migration events. Three distinct gene pools were identified in pure river as well as in pure swamp buffalo populations. Genomic admixture was seen in the Philippines and in Brazil, resulting from importations of animals for breed improvement. Our results were largely consistent with previous archeological, historical and molecular-based evidence for two independent domestication events for river- and swamp-type buffaloes, which occurred in the Indo-Pakistani region and close to the China/Indochina border, respectively. Based on a geographical analysis of the distribution of diversity, our evidence also indicated that the water buffalo spread out of the domestication centers followed two major divergent migration directions: river buffaloes migrated west from the Indian sub-continent while swamp buffaloes migrated from northern Indochina via an east-south-eastern route. These data suggest that the current distribution of water buffalo diversity has been shaped by the combined effects of multiple migration events occurred at different stages of the post-domestication history of the species.

Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.

Here, we describe a novel porcine β-casein (CNS2) polymorphism, initially identified using the isoelectric focusing (IEF) technique, and provide its distribution in five European breeds. Porcine CSN2 cDNA samples, from sows identified using IEF as carriers of polymorphic variants, were sequenced, and based on the sequence alignments, a genotyping assay was developed. The distribution of the polymorphism was investigated by genotyping 167 sows. Population genetic indexes were computed using POPGENE32 version 1.32. Sequence alignments revealed that the mutation which caused the different β-casein IEF migration profiles was c.647G>A, a substitution located in exon 7, which modifies the amino acid from position 201 of the mature protein from arginine to glutamine. The frequency of the G allele was 0.965 in the investigated Landrace population (number of individuals genotyped n = 67), one in the Pietrain population (n = 40), 0.705 in the Large White population (n = 36), 0.885 in the Bazna population (n = 13), and 0.555 in the Mangalita population (n = 11). For all breeds, except Pietrain (monomorphic), the genotype distribution was in accordance with the Hardy−Weinberg equilibrium. Given that β-casein is the most important protein in sows’ milk, a polymorphism like the one described here may prove interesting for marker-assisted selection.

The paper presents the results of the optimisation of burner nozzle diameters during the combustion of natural gas under the conditions of increasing oxygen concentrations in the oxidizer in aluminium melting processes in drum rotary furnaces. The optimisation of outlet nozzle diameters was performed employing the method of experimental measurements, the results of which can be used for aluminium melting in hearth furnaces. The measurements were carried out using an experimental upstream burner with 13.5 kW input power. The monitored oxygen concentrations in the oxidizer ranged from 21% to 50%. The measurements were performed and evaluated in two variations of the burner configuration (geometry). In the first study, the impact of the enriched oxidizer on the melting of aluminium ingots was evaluated with the defined diameter of the air nozzle, which resulted in a reduction of the aluminium charge melting time by 50% at 45.16% oxygen concentration in the oxidizer, thus achieving savings in the consumption of fuel used for melting. In the second study, the diameter was optimised depending on the combustion rate of the natural gas and oxidizer mixture. The optimisation of the nozzle parameters resulted in the reduction of the charge melting time by 23.66%, while the same 25% enriched oxidizer was used. With the rise of the enrichment level to 35%, further reduction by approximately 12% was observed. The measurement results prove considerable influence of the parameter (geometry) optimisation of the outlet nozzles and oxidizer enrichment. Appropriately selected parameters of the burner can contribute to achieving comparable results at a lower enrichment of the oxidizer. The obtained results demonstrate the intensification of the heat transfer in the current thermal aggregates. The research conclusions confirm that oxygen-enhanced combustion and modification of existing burners reduces the specific energy consumption on the process and reduces CO2 emissions.

Jules Romains did not go to the front, but he made an unremitting effort to fight against war. He wrote numerous essays and a long poem entitled Europe, where he enjoins European peoples to say no to the war. He also recounted the Battle of Verdun in Men of Good Will. He evokes the life behind the lines, but also in the trenches, and he succeeds in bearing witness to the war experience. He consulted public and private archives, and his literary empathy permits him to live intensely the life of an enlisted man as well as the life of a general. However, he does not want to glorify a war he did not make. That is why he splits himself into two characters. He has two fictional brothers: the first one stays in Paris, the second one goes to Verdun. This dissociation between the ordinary individual and the poet who is able to crystallize the universal psyche allows Romains to cause both the hymn to the soldiers’ courage and the elegy which deplores the war’s atrocity to resonate.

The main aim of the European union energy policy is to ensure a continuous supply of natural gas for the member states. The Russian gas is transported through the Belarus, Ukraine, Slovakia (SR) and Czech Republic to Germany. This article shortly describes the transit system of Slovakia and compressor station KS1 – Vel'ké Kapušany. The throughput of this compressor station plays an important role in gas transport, because this station is the entry to the transit system of SR. To find the best combination of the aggregates used in gas transport a simulation algorithm was devised. We present the architecture of this simulation software together with the description of its development phases. The software was evaluated against data gained from the KS1 compressor station operation. The combinations of aggregates were found as dependent on inlet pressure, ambient temperature and compression ratio.

The aim of the paper was to improve the economy of rolling mill production and to extend the control range of cooling capacity of the accelerated cooling unit by choosing the optimal dimensions of the cooling chamber. The object of research was the interstand cooling unite for accelerated cooling of the hot-rolled products of round section in the line of continuous rolling mill in order to reduce the machine time rolling or even eliminate completely the requirement for heat treatment of the hot-rolled products in heat-treatment furnaces. The influence of the design parameters of the cooling chamber on the expanding the control range, retaining a high cooling capacity of the chamber, was investigated by the numerical model based on the finite difference method. The diagrams presented in the paper allow determining the diameters of the cooling chamber, which provide a wide control range of the chamber cooling capacity and minimization of energy consumption of the electric water pump.

Through subtle cues, some of the friends who accompanied Gide to the USSR in 1936 – namely Jacques Schiffrin, Jef Last and Pierre Herbart – made him understand that they feared that the publication of his highly critical travel account (Return from the USSR, November 1936) would be untimely. Gide, for his part, grammatically paints, in the letters he sends shortly after his return from the USSR, his self-portrait as a traveller who cannot fail to tell in the near future what he has seen in the recent past.

Objectives: Literature suggests that a high-fat diet (HFD) potentially increases the risk of chemical/drug-induced toxicity after an acute overdose. Drug/chemical-induced hepatotoxicity has been well studied, and the mechanism that regulates this toxicity has been extensively examined using different experimental animal models. Our study focuses on drug-induced hepatotoxicity in HFD-fed female Balb/C mice. This study addresses the effect of nutrition on the magnitude of acetaminophen (APAP)-induced hepatotoxicity at different time intervals., Materials and Methods: Female Balb/C mice, after the weaning period separated into two different groups, normal diet (ND) and HFD receiving groups; after 15 weeks, they were dosed with a single dose (300 mg/kg per os ( p.o. ) of APAP. Blood samples were collected at different time intervals (0, 6 and 24 hours), and liver samples were collected at the end time point. Liver injury parameters [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)], antioxidant assay (sodium dismutase, glutathione, and catalase), and histopathology study were conducted. Pharmacokinetic (PK) analysis was done using the RP-HPLC system and Phoenix WinNonlin 8.3 software., Results: APAP-induced liver injury decreased AST and ALT in the HFD group compared with the ND group at 6 and 24 hours ( p < 0.01 and p < 0.001), respectively. Antioxidant enzyme levels remained constant in the HFD group, whereas histopathology showed remarkable changes. The PK's of APAP in HFD indicate lower plasma concentrations of APAP ( p < 0.05), with two-fold higher clearance and volume of distribution., Conclusion: HFD significantly reduced susceptibility to APAP-mediated liver injury in Balb/C mice compared with ND mice. Our study mimics the clinical scenario where the same dose of the drug is prescribed to the normal and obese population. Our results suggest the potential need for dose titration to assess an individual's nutritional state in a clinical scenario., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (Copyright© 2024 The Author. Published by Galenos Publishing House on behalf of Turkish Pharmacists’ Association.)

Parkinson's disease (PD), affecting millions of people worldwide and expected to impact 10 million by 2030, manifests a spectrum of motor and non-motor symptoms linked to the decline of dopaminergic neurons. Current therapies manage PD symptoms but lack efficacy in slowing disease progression, emphasizing the urgency for more effective treatments. Resveratrol (RSV), recognized for its neuroprotective and antioxidative properties, encounters challenges in clinical use for PD due to limited bioavailability. Researchers have investigated lipid-based nanoformulations, specifically solid lipid nanoparticles (SLNs), to enhance RSV stability. Oral drug delivery via SLNs faces obstacles, prompting exploration into transdermal delivery using SLNs integrated with microneedles (MNs) for improved patient compliance. In this study, an RSV-loaded SLNs (RSV -SLNs) incorporated into the MN patch was developed for transdermal RSV delivery to improve its stability and patient compliance. Characterization studies demonstrated favorable physical properties of SLNs with a sustained drug release profile of 78.36 ± 0.74%. The developed MNs exhibited mechanical robustness and skin penetration capabilities. Ex vivo permeation studies displayed substantial drug permeation of 68.39 ± 1.4% through the skin. In an in vivo pharmacokinetic study, the RSV-SLNs delivered through MNs exhibited a significant increase in C max , T max , and AUC 0 - t values, alongside a reduced elimination rate in blood plasma in contrast to the administration of pure RSV via MNs. Moreover, an in vivo study showcased enhanced behavioral functioning and increased brain antioxidant levels in the treated animals. In-vivo skin irritation study revealed no signs of irritation till 24 h which permits long-term MNs application. Histopathological analysis showed notable changes in the brain regions of the rat, specifically the striatum and substantia nigra, after the completion of the treatment. Based on these findings, the development of an RSV-SLN loaded MNs (RSVSNLMP) patch presents a novel approach, with the potential to enhance the drug's efficiency, patient compliance, and therapeutic outcomes for PD, offering a promising avenue for advanced PD therapy., (© 2024. Controlled Release Society.)

The scaffolding protein family Fe65, composed of Fe65, Fe65L1, and Fe65L2, was identified as an interaction partner of the amyloid precursor protein (APP), which plays a key function in Alzheimer's disease. All three Fe65 family members possess three highly conserved interaction domains, forming complexes with diverse binding partners that can be assigned to different cellular functions, such as transactivation of genes in the nucleus, modulation of calcium homeostasis and lipid metabolism, and regulation of the actin cytoskeleton. In this article, we rule out putative new intracellular signaling mechanisms of the APP-interacting protein Fe65 in the regulation of actin cytoskeleton dynamics in the context of various neuronal functions, such as cell migration, neurite outgrowth, and synaptic plasticity.

Astrocytes and oligodendrocytes in different brain regions form panglial networks and the topography of such networks can correlate with neuronal topography and function. Astrocyte-oligodendrocyte networks in the lateral superior olive (LSO)-an auditory brainstem nucleus-were found to be anisotropic with a preferred orientation orthogonally to the tonotopic axis. We hypothesized that such a specialization might be present in other tonotopically organized brainstem nuclei, too. Thus, we analyzed gap junctional coupling in the center of the inferior colliculus (IC)-another nucleus of the auditory brainstem that exhibits tonotopic organization. In acute brainstem slices obtained from mice, IC networks were traced employing whole-cell patch-clamp recordings of single sulforhodamine (SR) 101-identified astrocytes and concomitant intracellular loading of the gap junction-permeable tracer neurobiotin. The majority of dye-coupled networks exhibited an oval topography, which was preferentially oriented orthogonal to the tonotopic axis. Astrocyte processes showed preferentially the same orientation indicating a correlation between astrocyte and network topography. In addition to SR101-positive astrocytes, IC networks contained oligodendrocytes. Using Na + imaging, we analyzed the capability of IC networks to redistribute small ions. Na + bi-directionally diffused between SR101-positive astrocytes and SR101-negative cells-presumably oligodendrocytes-showing the functionality of IC networks. Taken together, our results demonstrate that IC astrocytes and IC oligodendrocytes form functional anisotropic panglial networks that are preferentially oriented orthogonal to the tonotopic axis. Thus, our data indicate that the topographic specialization of glial networks seen in IC and LSO might be a general feature of tonotopically organized auditory brainstem nuclei.

Background: Antibiotics are life-saving drugs but severely affect the gut microbiome with short-term consequences including diarrhea and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers., Methods: We performed a randomized controlled trial in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in 2 parallel groups, with or without DAV132 coadministration. Two control goups of 8 volunteers each receiving DAV132 alone, or a nonactive substitute, were added., Results: The coadministration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex vivo., Conclusions: DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments., Clinical Trials Registration: NCT02176005., (© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Neuronal inhibition is mediated by glycine and/or GABA. Inferior colliculus (IC) neurons receive glycinergic and GABAergic inputs, whereas inhibition in hippocampus (HC) predominantly relies on GABA. Astrocytes heterogeneously express neurotransmitter transporters and are expected to adapt to the local requirements regarding neurotransmitter homeostasis. Here we analyzed the expression of inhibitory neurotransmitter transporters in IC and HC astrocytes using whole-cell patch-clamp and single-cell reverse transcription-PCR. We show that most astrocytes in both regions expressed functional glycine transporters (GlyTs). Activation of these transporters resulted in an inward current (I Gly ) that was sensitive to the competitive GlyT1 agonist sarcosine. Astrocytes exhibited transcripts for GlyT1 but not for GlyT2. Glycine did not alter the membrane resistance (R M ) arguing for the absence of functional glycine receptors (GlyRs). Thus, I Gly was mainly mediated by GlyT1. Similarly, we found expression of functional GABA transporters (GATs) in all IC astrocytes and about half of the HC astrocytes. These transporters mediated an inward current (I GABA ) that was sensitive to the competitive GAT-1 and GAT-3 antagonists NO711 and SNAP5114, respectively. Accordingly, transcripts for GAT-1 and GAT-3 were found but not for GAT-2 and BGT-1. Only in hippocampal astrocytes, GABA transiently reduced R M demonstrating the presence of GABA A receptors (GABA A Rs). However, I GABA was mainly not contaminated by GABA A R-mediated currents as R M changes vanished shortly after GABA application. In both regions, I GABA was stronger than I Gly . Furthermore, in HC the I GABA /I Gly ratio was larger compared to IC. Taken together, our results demonstrate that astrocytes are heterogeneous across and within distinct brain areas. Furthermore, we could show that the capacity for glycine and GABA uptake varies between both brain regions.

Astrocytes form large gap junctional networks that contribute to ion and neurotransmitter homeostasis. Astrocytes concentrate in the lateral superior olive (LSO), a prominent auditory brainstem center. Compared to the LSO, astrocyte density is lower in the region dorsal to the LSO (dLSO) and in the internuclear space between the LSO, the superior paraolivary nucleus (SPN). We questioned whether astrocyte networks exhibit certain properties that reflect the precise neuronal arrangement. Employing whole-cell patch-clamp and concomitant injection of a gap junction-permeable tracer, we analyzed size and orientation of astrocyte networks in LSO, dLSO, and SPN-LSO in acute brainstem slices of mice at postnatal days 10-20. The majority of LSO networks exhibited an oval topography oriented orthogonally to the tonotopic axis, whereas dLSO networks showed no preferred orientation. This correlated with the overall astrocyte morphology in both regions, i.e. LSO astrocyte processes were oriented mainly orthogonally to the tonotopic axis. To assess the spread of small ions within LSO networks, we analyzed the diffusion of Na(+) signals between cells using Na(+) imaging. We found that Na(+) not only diffused between SR101(+) astrocytes, but also from astrocytes into SR101(-) cells. Using PLP-GFP mice for tracing, we could show that LSO networks contained astrocytes and oligodendrocytes. Together, our results demonstrate that LSO astrocytes and LSO oligodendrocytes form functional anisotropic panglial networks that are oriented predominantly orthogonally to the tonotopic axis. Thus, our results point toward an anisotropic ion and metabolite diffusion and a limited glial crosstalk between neighboring isofrequency bands in the LSO. GLIA 2016;64:1892-1911., (© 2016 Wiley Periodicals, Inc.)