Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.

Erlotinib inhibits epithelial growth factor receptor (EGFR) kinase activity and is used to treat non-small cell lung cancer (NSCLC). Despite its high efficacy, recurrence can occur in patients who become resistant to the drug. To address the underlying mechanism of Erlotinib resistance, we investigated additional mechanisms related to mode-of-drug-action, by multiple protein-binding interactions, besides EGFR by using drug affinity responsive target stability (DARTS) and liquid chromatography-mass spectrometry (LC-MS/MS) methods with non-labeled Erlotinib. DNA polymerase alpha subunit B (POLA2) was identified as a new Erlotinib binding protein that was validated by the DARTS platform, complemented with cellular thermal shift assays. Genetic knock-down of POLA2 promoted the anti-proliferative effect of the drug in the Erlotinib-resistant cell line H1299 with high POLA2 expression, whereas overexpression of POLA2 restored anti-proliferative effects in the Erlotinib-sensitive cell line HCC827 with low POLA2 expression. Importantly, POLA2 expression levels in four NSCLC cell lines were positively correlated with anti-proliferative Erlotinib efficacy, verified by bio-statistical analysis (Pearson correlation coefficient, R=0.9886). These results suggest that POLA2 is a novel complementary target protein of Erlotinib, and could clinically provide validity as a surrogate marker for drug resistance in patients with NSCLC.

In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.

We have developed an application aiming at federated search for EU and Hungarian legislation and jurisdiction. It now contains above 1 million documents, with daily updates. The database holds documents downloaded from the EU sources EUR-Lex and Curia Online as well as public jurisdiction documents from the Constitutional Court of Hungary and The National Office for The Judiciary. The application is termed Justeus. Justeus provides comprehensible search possibilities. Besides free text and metadata (dropdown list) searches, it features hierarchical data structures (concept hierarchy trees) of directory codes and classification as well as subject terms. Justeus collects all links of a particular document to other documents (court judgements citing other case law documents as well as legislation, national court decisions referring to EU regulation etc.) as tables and directed graph networks. Choosing a document, its relations to other documents are visualized in real time as a network. Network graphs help in identifying key documents influencing or referred by many other documents (legislative and/or jurisdictive) and sets of documents predominantly referring to each other (citation networks).

Magnesium monofluoride is a polar molecule amenable to laser cooling which has caused renewed interest in its spectroscopy. In this work we consider the case of three low-lying electronic excitations, namely $\rm X \, {}^{2}\Sigma \to A \, {}^{2}\Pi, \ \to B \, {}^{2}\Sigma, \ \to C \,{}^{2}\Sigma$, using well developed quantum chemistry approaches, i.e., without reference to the spin-orbit splitting of the $\rm A \, {}^{2}\Pi$ states. Accurate experimental data for these transitions have been available for over 50 years. Here we explore the linear response method at the level of CC2 theory, as well as equation of motion methods at the level of CCSD and CC3, using two families of basis sets. Excellent agreement is obtained for the first three transitions when using the correlation-consistent basis sets and extrapolation to the complete basis limit within EOM-CC3 (at a relative precision of $10^{-4}$), and qualitative agreement for the other two methods. The purpose of this paper is to serve as a guide in how to approach the accurate calculation of excitations in polar diatomic molecules.

We extend a previously developed model for the Stark resonances of the water molecule. The method employs a partial-wave expansion of the single-particle orbitals using spherical harmonics. To find the resonance positions and decay rates, we use the exterior complex scaling approach which involves the analytic continuation of the radial variable into the complex plane and yields a non-hermitian Hamiltonian matrix. The real part of the eigenvalues provides the resonance positions (and thus the Stark shifts), while the imaginary parts $-\Gamma/2$ are related to the decay rates $\Gamma$, i.e., the full-widths at half-maximum of the Breit-Wigner resonances. We focus on the three outermost (valence) orbitals, as they are dominating the ionization process. We find that for forces directed along the three Cartesian co-ordinates, the fastest ionizing orbital always displays a non-monotonic Stark shift. For the case of fields along the molecular axis we show results as a function of the number of spherical harmonics included ($\ell_{\max}=3,4$). Comparison is made with total molecule resonance parameters from the literature obtained with Hartree-Fock and coupled cluster methods.

RNA viruses exhibit a great tendency to mutate. Starting from 2019, the wild type that was labeled Hu-1 has during the last 3 years evolved to produce several dozen new variants, as a consequence of mutations. Mutations cause changes in empirical formulas of new virus strains, which lead to change in thermodynamic properties of biosynthesis and binding. These changes cause changes in the rate of reactions of binding of virus antigen to the host cell receptor and the rate of virus multiplication in the host cell. Changes in thermodynamic and kinetic parameters lead to changes in biological parameters of infectivity and pathogenicity. SARS-CoV-2 has starting from in 2019, until today, evolved towards increase in infectivity and maintaining constant pathogenicity, or for some variants a slight decrease in pathogenicity. In the case of Omicron BQ.1, BQ.1.1, XBB and XBB.1 variants pathogenicity is identical as in the Omicron BA.2.75 variant. On the other hand, infectivity of the Omicron BQ.1, BQ.1.1, XBB and XBB.1 variants is greater than those of previous variants. This will most likely result in the phenomenon of asymmetric coinfection, that is circulation of several variants in the population, some being dominant.

An effort was made to find a relationship between the ratio of average asperities height and lubricant thickness at the point of contact of rolling element ball bearings, and empirical equations to predict the life for bearings under constant motion. Two independent failure mechanisms were considered, fatigue failure and lubricant failure resulting in seizing of the roller bearing. A theoretical formula for both of these methods was established for the combined probability of failure using both of these failure mechanisms. Fatigue failure was modeled with the empirical equations of Lundberg and Palmgren and standardized in DIN/ISO281. The seizure failure, which this effort sought to investigate, was predicted using Greenwood and Williamson's theories on surface roughness and asperities during lubricated contact. These two mechanisms were combined, and compared to predicted cycle lives of commercial roller bearing, and a clear correlation was demonstrated. This effort demonstrated that the Greenwood-Williams theories on the relative height of asperities versus lubricant film thickness can be used to predict the probability of a lubricant failure resulting in a roller bearing seizing during use.

An effort was made to find a relationship between the predicted tribological conditions at the point of contact of ball bearings, and empirical equations to predict the life for bearings under constant motion. The model was modified to predict the temperature dependence, and compare rapid accelerations and decelerations with empirical extrapolations.

The model of T4 phage, Lambda phage and Escherichia coli is often used in research on virus-host interactions. This paper reports for the first time the thermodynamic driving force of biosynthesis, catabolism and metabolism for the three organisms, on the M9 medium. Moreover, the influence of activities of nutrients and metabolic products is analyzed. All three organisms were found to have very similar Gibbs energies of metabolism. Moreover, since they share the same catabolism, their Gibbs energies of catabolism are identical. However, Gibbs energies of biosynthesis differ. The calculated thermodynamic properties have been used to explain the coexistence of both bacteria and phages in a dynamic equilibrium in natural ecosystems.

An investigation was made to determine the effects of tungsten surface coating on the coefficient of friction of sliding contact between lubricated steel surfaces. The four-ball test was modified, using a tungsten carbide ball bearing in the spindle to cause sliding contact onto three hard steel ball bearings coated with tungsten disulfide lamellar dry lubricant coating, with a coating of grease lubrication applied to the ball bearings. The coatings, loads, speed, and grease level was varied to best understand the impact of different conditions to the friction coefficient.

SARS-CoV-2 resembles the ancient mythical creature Hydra. Just like with the Hydra, when one head is cut, it is followed by appearance of two more heads, suppression of one SARS-CoV-2 variant causes appearance of newer variants. Unlike Hydra that grows identical heads, newer SARS-CoV-2 variants are usually more infective, which can be observed as time evolution of the virus at hand, which occurs through acquisition of mutations during time. The appearance of new variants is followed by appearance of new COVID-19 pandemic waves. With the appearance of new pandemic waves and determining of sequences, in the scientific community and general public the question is always raised of whether the new variant will be more virulent and more pathogenic. The two variants characterized in this paper, BA.5.2 and BF.7, have caused a pandemic wave during the late 2022. This paper gives full chemical and thermodynamic characterization of the BA.5.2 and BF.7 variants of SARS-CoV-2. Having in mind that Gibbs energy of binding and biosynthesis represent the driving forces for the viral life cycle, based on the calculated thermodynamic properties we can conclude that the newer variants are more infective than earlier ones, but that their pathogenicity has not changed.

Live attenuated vaccines have through history proved themselves as safe and efficient. Pasteur has developed a vaccine against rabies, through a long process of passage of the virus wild type through rabbits. The result was one of the most efficient attenuated live-virus vaccines. This paper suggests a method based on calculations of biothermodynamic properties of potential tissues for vaccine application, predilected host tissue and virus wild type. Gibbs energy of biosynthesis represents the thermodynamic driving force for virus multiplication. The attenuated strain of the virus should possess Gibbs energy of biosynthesis, which is less negative than the predilected target tissue, but more negative than the vaccine portal tissue. In that way, the attenuated virus strain should be able to multiply in the vaccine portal of entry tissue and cause an immune response, making it efficient. On the other hand, the attenuated strain cannot multiply in the predilected host tissue, making it safe. The attenuation is achieved by adding a gene to the virus, which encodes a ballast protein. Production of the ballast protein would make virus multiplication less favorable, since it would require energy, but be useless to the virus.

During the last 50 years, an interdisciplinary approach in research in various scientific fields has become widely spread. This process significantly deepens and widens our scientific knowledge, but on the other hand makes more difficult choosing a discipline to be used by students and young researchers. The dynamic development of science makes this choice even harder. There is a widely spread opinion that thermodynamics uses a rigorous mathematical apparatus. This paper describes that knowledge of the fundamental principles of thermodynamics is required for deep understanding of crucial biological processes. Thus the effort put into learning classical and nonequilibrium thermodynamics does not make harder, but easier gaining a better knowledge of biological processes. This essay is an attempt to convey personal experience in using thermodynamics to describe biological systems and processes they perform.

The SARS-CoV-2 Hydra with many heads (variants) has been causing the COVID-19 pandemic for 3 years. The appearance of every new head (SARS-CoV-2 variant) causes a new pandemic wave. The last in the series is the XBB.1.5 “Kraken” variant. In the general public (social media) and in the scientific community (scientific journals), during the last several weeks since the variant has appeared, the question was raised of whether the infectivity of the new variant will be greater. This article attempts to provide the answer. Analysis of thermodynamic driving forces of binding and biosynthesis leads to the conclusion that infectivity of the XBB.1.5 variant could be increased to a certain extent. The pathogenicity of the XBB.1.5 variant seems to be unchanged compared to the other Omicron variants.

Although the majority of mobile phone (MP) users do not attribute adverse effects on health or well-being to MP-emitted radiofrequency (RF) electromagnetic fields (EMFs), the exponential increase in the number of RF devices necessitates continuing research aimed at the objective investigation of such concerns. In this work, we investigate the effects of acute exposure from Long Term Evolution (LTE) MP EMFs on thermal pain threshold in healthy young adults. We use a protocol that was validated in a previous study in a capsaicin-induced hyperalgesia model, and was also successfully used to show that exposure from an RF source mimicking a Universal Mobile Telecommunications System (UMTS) MP led to mildly stronger desensitization to repeated noxious thermal stimulation relative to the sham condition. Using the same experimental design, we did not find any effects of LTE exposure on thermal pain threshold. The present results are in accordance with previous evidence suggesting that effects are likely to be placebo/nocebo effects and are unrelated to the brief acute LTE EMF exposure itself. The fact that this is dissimilar to our previous results on UMTS exposure implies that RF modulations might differentially affect pain perception, and points to the necessity of further research in the topic.

Blockchain technology enables a decentralized and distributed environment with no need for a central authority. Transactions are simultaneously secure and trustworthy due to the use of cryptographic principles. In recent years, blockchain technology has become very trendy and penetrated different domains, mostly due to the popularity of cryptocurrencies. One field where blockchain technology has tremendous potential is healthcare, due to the need for a more patient-centric approach to healthcare systems and to connect disparate systems and increase the accuracy of electronic healthcare records (EHRs). In this systematic review, an analysis of state-of-the-art blockchain research in the field of healthcare is conducted. The aim is to reveal the potential applications of the technology and to highlight the challenges and possible directions of blockchain research in healthcare. First, background information is discussed, followed by a description of the exact methodology used in this paper. Next, an analysis of the results is given, which includes a bibliometric overview, an analysis of gathered data and its properties, and the results of a literature quality assessment. Lastly, there is a discussion of the results from the analysis. The findings indicate that blockchain technology research in healthcare is increasing and it is mostly used for data sharing, managing health records and access control. Other scenarios are very rare. Most research is aimed at presenting novel structural designs in the form of frameworks, architectures or models. Findings also show that technical details about the used blockchain elements are not given in most of the analyzed publications and that most research does not present any prototype implementation or implementation details. Often even with a prototype implementation, no details about blockchain elements are given.

Pathogen-host interaction (virus-host, bacteria-host and fungi-host) is analyzed from the perspective of biothermodynamics. A mechanistic model of pathogen-host interactions, which was earlier applied to virus-host interactions, was applied for the first time to bacteria-host and fungi-host interactions. Through a mechanistic model suggested in this research, it is possible to explain the phenomenon of tropism of microorganisms to develop infections in certain tissues. Gibbs energy of biosynthesis represents the driving force for growth of bacteria inside host organisms. A growing bacterial colony represents a thermodynamic system, while the host organism is its surroundings. The permissiveness coefficient determines the possibility of growth of bacteria in an appropriate environment (tissue).

Life sciences are increasingly benefiting from multidisciplinary research, combining biology, chemistry and physics. At their intersection, biothermodynamics applies the quantitative framework of thermodynamics to life processes and is a potentially interesting subject for life science students. Here a method is proposed to teach undergraduate life science students the basics of biothermodynamics, building and expanding on the concept of Gibbs energy learned as a part of the physical or general chemistry course. The discussion begins with the role of Gibbs energy as the driving force of metabolism and growth. Moreover, a biological example is proposed of the enthalpy-entropy combinations resulting in negative Gibbs energy, which should be interesting to life science students. Gibbs energy is then used to explain microorganism growth rates, using a simple thermodynamic growth model. Finally, multiplication of viruses is considered, including SARS-CoV-2, using Gibbs energy to explain the hijacking of host cell metabolism. Implementation of the proposed biothermodynamics material in classroom is discussed. The paper should be useful as material for making lectures for undergraduate students and as a starting point for anyone beginning to do research in biothermodynamics.

Viroids represent the simplest, but are also among the most interesting life-like forms. They represent a great problem in agriculture. Moreover, pathogens similar to viroids, such as the hepatitis Delta virus represent a risk for human health. Viroids encode no proteins, but are still able to hijack their host cells’ metabolism to perform multiplication. This paper attempts to reply three questions about viroids. First, how can viroids hijack their host cells’ metabolism, even though they encode no proteins to achieve this? Second, what advantages do viroids have from their simplicity? Third, what can viroids, as the simplest life-like forms, tell us about life as a natural phenomenon? These questions are discussed from the perspective of biothermodynamics. In order to do this, elemental composition, biosynthesis reactions and standard thermodynamic properties of viroids have been determined and analyzed.

Herpes simplex virus type 1 (HSV-1) is among the most widely spread viruses on the planet. However, the rate of binding to the receptor is not among the greatest ones. Gibbs energy of binding, which represents the driving force for antigen-receptor binding, of HSV-1 is less negative than can be expected. Furthermore, the Gibbs energy of biosynthesis of HSV-1 is among the most negative in nature. This implies high rate of multiplication of HSV-1. Obviously, HSV-1 uses specific strategy in virus-host interaction. While most other viruses increase infectivity through a high rate of antigen-receptor binding and cell entry/ highly negative Gibbs energy of binding, HSV-1 uses another strategy. It is related to a relatively slow reaction of antigen-receptor binding, which is followed by a higher rate of multiplication, which is a consequence of a highly negative Gibbs energy of biosynthesis. We can conclude empirically that both strategies are successful.

HIV-1, like other viruses, represents an open thermodynamic system. This is why it is important to know its thermodynamic properties. Virus-host interactions are performed at the membrane as antigen-receptor binding. Antigen-receptor binding represents a chemical reaction, similar to protein-ligand interactions. The driving force for antigen-receptor binding is Gibbs energy of binding. Knowing Gibbs energy of binding, it is possible to estimate the rate of virus binding and entry into host cells. In this paper, binding equilibrium constants and standard Gibbs energies of binding between the HIV-1 gp120 antigen and the CD4 receptor have been reported at 4°C, 22°C and 37°C.

Biothermodynamics of viruses is among the youngest, but rapidly developing scientific disciplines. During the COVID-19 pandemic, it has closely followed the results published by molecular biologists. Empirical formulas were published for 50 viruses and thermodynamic properties for multiple viruses and virus variants, including all variants of concern of SARS-CoV-2, SARS-CoV, MERS-COV, Ebola virus, Vaccinia and Monkeypox virus. A review of development of biothermodynamics of viruses during the last several decades and intense development during the last 3 years has been described in this paper.

SARS-CoV-2 belongs to the group of RNA viruses with a pronounced tendency to mutate. Omicron BA.2.75 is a subvariant believed to be able to suppress the currently dominant BA.5. Omicron BA.2.75 is characterized by a greater infectivity compared to earlier Omicron variants. However, Gibbs energy of biosynthesis of virus particles is slightly less negative compared to those of other variants. Thus, the multiplication rate of Omicron BA.2.75 is lower than that of other variants. This leads to slower accumulation of newly formed virions and less damage to host cells, indicating evolution of SARS-CoV-2 towards decreasing pathogenicity.

Omicron BA.2.75 may become the next globally dominant strain of COVID-19 in 2022. BA.2.75 sub-variant has acquired more mutations (9) in spike protein and other genes of SARS-CoV-2 than any other variant. Thus, its chemical composition and thermodynamic properties have changed comparing to earlier variants. In this paper Gibbs energy of binding and antigen-receptor binding rate is reported for the BA.2.75 variant. Gibbs energy of binding (driving force of binding) of Omicron BA.2.75 variant is more negative than that of the competing variants BA.2 and BA.5.

Simulations based on Supernova (SN) observations predict several galactic SN explosions (SNe) occur every century. Unlike SNes within the Interstellar Medium (ISM) where ambient gas generally absorbs blast waves within a million years, SNes occurring in a rarified environment outside of the (ISM) generate blast waves which remain in a high velocity free expansion phase for more extended periods. The SN blast wave forms an expanding spherical shell and when multiple blast waves intersect, the overlapping region naturally takes the form of a ring, an arc, or an Einstein Cross structure. The analysis shows the high velocity plasma establishes a medium with permeability which drives the index of refraction greater than 1. As a result, when a shock discontinuity forms in the overlapping region, light is reflected from the host galaxy which exposes the intersecting blast wave regions. The expanding shells are shown to induce an achromatic redshift to the reflected light consistent with those measured for gravitational lenses. Further, it is shown that a Hubble equation for a blast wave around the Milky Way Galaxy can be parameterized to align with measured redshifts of extragalactic light fields over a wide range of distances.

This manuscript discusses a novel method to map pressure results from one 3D surface shell mesh onto another. This technique is especially important when transferring results from one numerical analysis to another. This method works independent of the actual pressures, and only focuses on ensuring the surface areas consistently match. By utilizing this approach, the cumulative forces consistently match for all input pressures. This method is demonstrated to work for pressure profiles with precipitous changes in pressures, and with small quadrangular source elements being applied to a mix of large quadrangular and triangular target elements, and the forces at all pressure profiles match remarkably.

This algorithm is designed to perform Discrete Fourier Transforms (DFT) to convert temporal data into spectral data. This algorithm obtains the Fourier Transforms by studying the Coefficient of Determination of a series of artificial sinusoidal functions with the temporal data, and normalizing the variance data into a high-resolution spectral representation of the time-domain data with a finite sampling rate. What is especially beneficial about this DFT algorithm is that it can produce spectral data at any user-defined resolution.

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the con-comitant release of granule contents that damage surrounding tissues into sharp focus. Neutro-phil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. In-terestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promote lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and increase the risk of allergic responses. Recent observations point to the fact that re-duced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19

The frequency of selected polymorphisms, one in each gene coding for proteins with antioxidative properties (CAT, SOD2, GPX1, NQO1) was compared between patients suffering from pain-related temporomandibular disorders (TMDp;n=85) and control subjects (CTR;n=85). According to the Oral Behaviours Checklist score participants were divided into high-frequency parafunction (HFP;n=98) and low-frequency parafunction (LFP;n=72) groups. In addition, we have investigated the association of selected polymorphisms with participants' psychological (anxiety, depression) and psychosomatic (hypervigilance, somatosensory amplification) characteristics. Polymorphisms rs1001179, rs4880, rs1050450, rs689452 were genotyped using the genomic DNA extracted from buccal mucosa swabs and real-time TaqMan genotyping assays. No differences in genotype distribution between TMDp patients and control subjects were found. Still, TMDp patients who were homozygous for minor allele A, related to the GPX1 polymorphism rs1050450 reported significantly more waking-state oral behaviours compared to GA+GG genotype carriers (score: 30 vs. 23, p=0.019). Frequency of genotype AA for rs1050450 polymorphism was higher in HFP compared to LFP participants (14.3% vs. 4.2%, p =0.030). Most important predictors of waking-state oral behaviours were depression, anxiety, AA genotype (rs1050450) and female sex. Explored genetic factors were not found to be significant risk factors for either TMDp or sleep-related oral behaviours. The association of waking-state oral behaviours with selected gene polymorphisms additionally supports previous assumptions that the daytime bruxism is more closely linked to various stress manifestations, which might also be reflected through the variability related to cellular antioxidative activity.

Pedigree data of 13 339 border collie dog was collected along with hip and elbow dysplasia records (1352 CHD and 524 CED), and an inbreeding-purging (IP) model was created to detect possible purging. Ancestral inbreeding coefficients were calculated by gene dropping simulation method (Ballou, 1997; Kalinowski, 2000) with GRain 2.0 (Baumung et al., 2015) software. GLMM models were created to the examined traits fitted with a log-link Poisson distribution, added to the estimated values of classical inbreeding coefficient (F_W), and the ancestral inbreeding (F_BAL, F_KAL, F_KAL_NEW) as covariates. The effective population size decreased in the examined period along with the increase of F_W however, slight differences were found as a consequence of breeding dog imports. CHD values were getting lower by the expansion of F_BAL as the alleles were inbred in the past. For CHD signs of purging were obtained. There was a positive trend regarding the breeding activity (both sire and dam of the future litters should be screened and certified free from CHD and CED), as years of selection increased the frequency of alleles with favorable hip and elbow conformation. Division of the ancestral inbreeding coefficient shows that alleles IBD for the first time (F_KAL_NEW) had a negative effect on both traits, while F_KAL shows favorable results for alleles IBD in the past generations. Some authors had proven this phenomenon in captive populations or experimental conditions however, no evidence of inbreeding purge has ever been described in dog populations. Despite the various breeding practices, it seems, that alleles of these polygenic disorders could be successfully purged out of the population with long term selection.

This study investigates the metabolic parallels between stimulated pancreatic beta cells and cancer cells, emphasizing glucose and glutamine metabolism. Addressing the significant public health challenges of Type 2 Diabetes Mellitus (T2DM) and cancer, we aim to deepen understanding of the mechanisms driving insulin secretion and cellular proliferation. Our analysis of anaplerotic cycles and NADPH's role in biosynthesis elucidates their vital functions in both processes. Additionally, we find that both cell types share an antioxidative response mediated by the Nrf2 signaling pathway, glutathione synthesis, and UCP2 upregulation. Notably, UCP2 facilitates the transfer of C4 metabolites, enhancing reductive TCA cycle metabolism. We also uncover that hypoxic responses are transient in beta cells post-stimulation but persistent in cancer cells. By synthesizing these insights, our research suggests novel therapeutic targets for T2DM, highlighting the shared metabolic strategies of stimulated beta cells and cancer cells. This comparative analysis not only illuminates the metabolic complexity of these conditions but also emphasizes the crucial role of metabolic pathways in cell function and survival, offering fresh perspectives for tackling T2DM and cancer challenges.

Membrane-based beverage dealcoholization is a successful process for producing low- and non-alcoholic beer and represents a fast-growing industry. Polyamide NF and RO membranes are commonly applied for this process. Polyelectrolyte multilayer (PEM) NF membranes are emerging as industrially relevant species and their unique properties (usually hollow fiber geometry, high and tunable selectivity, low fouling) underlines the importance of testing them in the food industry as well. To test PEM NF membranes for beer dealcoholization, at small pilot scale we dealcoholized filtered and unfiltered lager beer with the tightest available commercial polyelectrolyte multilayer NF membrane (NX Filtration dNF40), which has a MWCO=400Da which is quite high for these purposes. Dealcoholization is possible with a reasonable flux (10 LMH) at low pressures (5-8.6 bar) with a real extract loss of 16-18% and an alcohol passage of ~100%. Inorganic salt passage is high (which is typical for PEM NF membranes), which greatly affected beer flavor. During the dealcoholization process, the membrane underwent changes which substantially increased its salt rejection values (MgSO4 passage decreased 4-fold) while permeance loss was minimal (less than 10%). According to our sensory examination, the process yielded an acceptable flavored beer which could be greatly enhanced by the addition of the lost salts and glycerol.

Similarly to a phoenix, SARS-CoV-2 has appeared periodically in waves. The new variants that appeared through mutations have during the 4 years of the pandemic suppressed earlier variants, causing new waves of the pandemic. The Omicron BA.2.86 Pirola variant is the latest in the sequence of SARS-CoV-2 variants, which appeared in 2023. The BA.2.86 variant has started to spread rapidly and we are witnesses of a new epidemic wave. In this short period, an increased infectivity was noticed, which results in rapid spreading and decreased pathogenicity, which results in a lower number of severe cases. However, in the public there is a fear of further development of the epidemic. This analysis was made with the goal to assess the risks in the period of late 2023. Mutations that were developed by the BA.2.86 variant have led to a change in empirical formula and thermodynamic properties. It seems that there is no ground for fear of an extensive spreading of severe forms, but there are reasons for caution and monitoring of the spreading of the epidemic and potential appearance of new mutations.

Tribological testing of moving shaft/sealing pairs in complex environments is at the frontline of research. Machines working in abrasive conditions are subject to different wear effects. It is valid not only on the Earth but especially valid for rovers and future robots used in Mars and Moon missions. The aim of our joint research with the European Space Agency is to study the abrasion phenomena of moving machine elements on Mars and the Moon, by using artificial soil samples (“simulants”). This review detail the available simulant sources and recommend a selection of the most suitable ones for tribological testing. Moreover, the potential mating structural materials subjected to abrasive space applications are reviewed. The tribological tests are exploring the features of the rotary shaft/seal relationship that is subject to dry friction and intense abrasion. By using the simulants, measurements are performed under laboratory conditions with both a sample test and a real shaft/seal connection. Parameters of the selection criteria have been defined and classification of the simulant sources were made. It was found that simulant particle size distribution and chemical substance content is detailed enough only for a limited type of available artificial Moon and Mars soil samples. 4 simulants have been identified and applied later in the tribological testing. For the shaft materials, based on a detailed case study of polymers, steel and aluminium alloys, a high-strength aluminium alloy with a hard anodized surface and a stainless steel were selected for further abrasion tests.

Introduction. This retrospective study aimed to compare the risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Methods. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF23, fetuinA, sclerostin, and VC scores (Adragao method). Multivariable linear regression identified VC predictors. Results: The prevalence of VC was similar in both groups, but HD patients had more pronounced VC scores ≥6. Pre-HD patients were older, with higher prevalence of Balkan endemic nephropathy, hypertension, and less frequent use of calcium phosphate binders. Both groups exhibited similar patterns of hyperphosphatemia, low vitamin D, and iPTH levels. In HD group normal phosphate was significantly common in patients with VC, whereas hyperphosphatemia was significantly common in patients without VC. Fetuin-A levels were higher in pre-HD patients, while FGF23 was elevated in HD patients. In pre-HD patients, male gender was associated with reduced VC risk, while in HD patients, malignancies and serum phosphate levels were negative VC predictors. Conclusion: Effective monitoring and tailored treatment of VC in CKD are still focused on phosphate regulation. Besides, mineral disturbances, hormones and biomarkers regulation, and patient-specific variables need to be considered.

We discuss the issues with tentative generalisations of the process matrix formalism from finite-dimensional mechanical systems all the way to quantum field theory. We present a detailed overview of possible open problems that arise when one attempts to move from particle ontology into the realm of field ontology, i.e., when one transitions from mechanics to field theory framework. These issues need to be addressed, and problems solved, if one aims to expand the scope of applicability of the process matrix formalism, and therefore its usefulness. This is far from a trivial and straightforward endeavour, but rather a task for a whole future research programme.

As a consequence of applying advanced maintenance practices, the theoretical probability of failures is relatively low. However, observation of low market intelligence and maintenance management has been reported. The experimental investigation is supported by findings from a survey targeting asset-intensive companies applying hydraulic power systems. Next, the study incorporates multidimensional data analysis using CA-AHC (Correspondance Analysis with Agglomerative Hierarchical Clustering) approach. The non-parametric machine learning models are used from generated feature subspace to extract features affecting maintenance performance indicators. The results support empirical evidence that equipment age increases the probability of failures. However, the novel findings show that number of maintenance personnel, equipment size measured by nominal working energy consumption, and activities dedicated to maintaining fluid cleanliness impact regression results of companies utilising hydraulic applications.

Consumer behavior is unpredictable. The accelerated pace of life and daily changes in the desires and preferences of each individual require significant marketing efforts to fulfill needs. The impact of the COVID-19 pandemic has created significant disruptions in the market to which consumers have responded in a specific way. Our previous research on this topic [11], which included an analysis of various factors that influence consumer habits, was the basis for a new, more detailed analysis of the impact on individual consumption. The results of our previous research set psy-chological influence as a significant factor in consumer behavior. That is the main reason we put the impact of COVID-19 at the center of this research. The analysis was conducted on an existing sample of 559 respondents in the Republic of Croatia. The data obtained by the questionnaire were used to develop a hierarchical model. The Analytic Hierarchy Process (AHP) is a model based on deci-sion-making and was used to rank individual influences on consumer behavior due to the COVID-19 pandemic. These influences have had a significant impact on consumer buying habits.

The influence of numerous factors determines and changes the daily behavior of consumers. This paper aims to estimate and rank the weight of cultural, social, personal, and psychological factors that change the buying habits of individuals. The research was conducted on a sample of 559 re-spondents. Data from the survey were used to create a hierarchical model structure. The Analytic Hierarchy Process (AHP) as a decision-making method was used in the analysis to estimate and rank the factors that influence consumer habits. An analysis of results showed that the personal and psychological factors have the principal influence on consumer habits. Personal budget, as the dominant criterion in a group of set criteria, contributed to the fact that the personal factors have the dominant influence on consumer habits. The work showed that the choice of the method used is relevant to the results and that the analysis of the impact on consumer habits can be expanded by including several factors.

This study was based on the corresponding elemental abundances of carbonaceous - chondrites and the Solar photospheric elemental abundances [1]. The comparative analysis between the average magnesium, silicon and iron abundances of the Solar System and the abundances of these elements in potential nearby planetary systems was based on the Mg, Si and Fe abundances of host stars, which are in the Galactic thin disk within 25 parsecs distance from the Sun. The stellar abundance data had been taken from the Hypatia Catalog, which contains high precision data of chemical elements. We show that in general there are no significant differences between the molar Mg/Si and Fe/Si ratios of the most examined stars and the corresponding elemental ratios of the Solar System. However, the comparative study also shows that a significant fraction of the nearby extrasolar terrestrial planets may have higher bulk Mg/Si ratio than Solar, but the Solar Fe/Si ratio can relatively be frequent. We conclude that the medium - sized metallic cores can relatively be common in the rocky planetary interiors, while the mantle mineralogy for most of the rocky exoplanets in the Solar neighborhood may differ from that of Earth.

Campylobacter jejuni is a zoonotic bacterium, causing intestinal infection in humans. One characteristic feature of the pathogenicity process is the ability of this bacterium invading the epithelial cells. Several factors have been identified to contribute to this process and some recent analyses revealed changes in the bacterium cell on molecular level. However, our knowledge is still limited about responses of the host that accompany the bacterial internalisation and survival process. This study focused on molecular events on transcriptomic level detected between the 1st and the 3rd hour of internalisation in INT407 epithelial cells. From the 41.769 human genes tested, altogether 19,060 genes and 22,734 pseudogenes and introns were shown by whole transcriptome analysis to be affected in different extent. Most affected functions regulate transcription (28%), signal transduction (21%), apoptosis (15%), immune responses (9%), transmembrane transport (6%), cell-cell signaling (3%), cell-cell adhesions (3%) and carbohydrate metabolism (3%) and to a lesser extent other functions. Our results provide insight into a scenario where, the invaded cell focuses on survival, but, at the same time, flashing the possibility of pushing the process toward the death of the invaded and metabolically disrupted cell.

Physical activity is especially important of children's everyday life with chronic disease. The aim of the study was to show whether asthma is a barrier to physical activity in our society. The correlation between the severity of the disease, body mass index, and physical activity were analyzed, and, parents' opinion whether children should participate in active sports was assessed. Physical activity of children with asthma was analyzed by questionnaires and activity-measuring armbands. 93 parents and their children were involved in the survey, while 20 children were wearing the armband. The age of children was 12.6±3.5 years (mean±SD), 69.9% were boys, 30.1% were girls. 93.4% of the respondents participated in physical education program and 56.5% also attended sporting activities on a regular basis. 61.2% of the children had mild, 37.6% moderate, and 1.2% severe asthma. 6.5% of the respondents stated that their illness had been consistently or frequently limiting the performance concerning their school or home duties over the past 4 weeks. Twelve percent of parents felt that physical activity was not appropriate in the context of this disease. We conclude, that fear of the consequences of physical activity depends largely on education which should involve their parents, teachers and coaches.

Abstract: Green walls and green dams are increasingly being considered as part of many nation-al and international desertification initiatives. This paper studies the spatiotemporal evolution of the green dam in the Moudjbara region (Djelfa Province, Algeria) from 1972 to 2019 by using Landsat imagery, Land Change Modeler and Open Land package. The future evolution of pine plantations for the year 2029 was also forecasted, based on an anthropogenic scenario (i.e., an-thropogenic pressure is the main driver of the green dam destruction). Our findings revealed that the green dam project was successful for a few years, but after that, pine plantations deteri-orated significantly due to forest harvesting, livestock overgrazing, and the proliferation of the pine caterpillar processionary, which destroyed most of the reforestation. Land Change Modeler predicted a huge degradation of pine plantations for the year 2029, and if the deforestation con-tinues at the same rate, the green dam will disappear in the Moudjbara region during the next few decades. Aware of this threat, the Algerian authorities are now planning to reforest more than 1.2 million ha under the latest rural renewal policy by introducing new principles related to sustainable development, fighting desertification, and climate change adaptation

In preserving genetic diversity among domestic animal breeds, the strategies emphasizing be-tween-breed diversity may be not optimal by neglecting within-breed variation. The present study aimed to assess the extent of the population subdivision of Mangalica pigs and the contri-bution of migration intensity to their substructure. Genealogy analysis was performed for breeding animals born between 1981 and 2023 examining three colour variations (Blonde, Swal-low-Belly, and Red). The fixation index (FST) was calculated and evaluated by Multidimensional Scaling and Clustering to expose the population substructure. The average FST is 0.04 for the Blonde and 0.05 for the Swallow-Belly and the Red while in the active herds, these parameters are smaller being 0.03 and 0.04, respectively. The migration of individuals affected 61.63% of the Blonde, 75.53% of the Swallow-Belly, and 63.64% of the Red breed herds. No population sub-structure was found in any Mangalica breed which can be explained by the extensive within breed migration among the herds.

The study is devoted to analyzing the economic sustainability of the town of Amherst, MA. The city's top employer and core enterprise is the University of Massachusetts Amherst, with over 32,000 students and almost 2,000 staff members. Based on a literature review, a hypothesis was put forward that a university city should have a high level of economic sustainability. To assess economic sustainability, the USCESI Index was developed. It evaluates sustainability in three groups of parameters: society, economy, and ecology. The first group includes the level of racial diversity, the level of education of the population, and the access to medical services. The second group consists of the Gini coefficient by income level, the median cost of housing, and the unemployment rate. The environmental situation is assessed according to the Air Quality Index developed by the US Environmental Protection Agency. For comparison, the town of Braintree, MA, was taken. The USCESI was calculated for both locations. The analysis showed that both Amherst and Braintree have a high degree of economic sustainability. However, it was revealed that proximity to a significant economic center has a more powerful positive impact on economic sustainability than the location of a large university.

This study aimed to establish a predictive model for neoadjuvant chemoradiotherapy (nCRT) response in patients with locally advanced rectal carcinoma (LARC) using clinicopathological (CP) features along with radiomics from pretreatment Magnetic Resonance Imaging (MRI) 3D T2W contrast sequence scans. The study also assessed the impact of radiomic dimensionality on predictive performance. Seventy-five patients were prospectively enrolled with clinicopathologically confirmed LARC who underwent nCRT before surgery. Tumor properties were assessed by calculating 2142 shape, first-order, and second-order radiomics features. Least absolute shrinkage and selection operator (LASSO) and multivariate regression were used for feature selection. Two predictive models were constructed, one using 72 CP and 107 radiomics features, and the other using 72 CP and 1862 radiomics features. The models revealed moderately advantageous impact of increased dimensionality, while their predictive performance was in the range generally considered excellent, with respective AUCs of 0.86 and 0.90. A CP-only model (AUC=0.80) served as the benchmark for predictive performance without radiomics. The predictive models developed in this study using pretreatment MRI data, radiomics features, and clinicopathological parameters could potentially be used to routinely predict chemoradiotherapy responders, enabling clinicians to personalize treatment strategies for rectal carcinoma.

When discussing the gauge symmetries of any theory, the Henneaux-Teitelboim transformations are often underappreciated or even completely ignored, due to their on-shell triviality. Nevertheless, these gauge transformations play an important role in understanding the structure of the full gauge symmetry group of any theory, especially regarding the subgroup of diffeomorphisms. We give a review of the Henneaux-Teitelboim transformations and the resulting gauge group in the general case, and then discuss its role in the applications to the class of topological theories called nBF models, relevant for the constructions of higher gauge theories and quantum gravity.

Heusler Ni-Mn-Ga alloys with martensitic transformation being multiferroic materials are touted for magneto- and multi-caloric effect (MCE) and moreover, they exhibit magnetic shape memory (MSM) phenomena. MCE benefits from high saturation magnetization and also large variability and sensitivity of transformation temperatures on alloying. In contrast, MSM phenomena are limited by low temperatures of both ferromagnetic and ferroelastic transformations. In an attempt to increase the transformation temperatures and to understand the physical fundamentals beyond transformation variations and magnetic ordering, we experimentally investigate the magnetic and transformation properties in Ni2MnGa alloyed with transitional elements spanning from Cr to Cu. These elements are consecutively substituted on Ni, Mn, and Ga sites, to establish the effect of positional substitution and elemental evolution. The elemental dependence of saturation magnetization, magnetocrystalline anisotropy, Curie temperature, and martensitic transformation temperatures are compared with (non-)stoichiometric Ni-Mn-Ga Heusler compounds. The observed behavior is complex and there are no clear trends of transformation temperatures as a function of the number of valence (non-bonding) electrons per atom, however, the saturation magnetization at 10K and Curie temperature seems to follow the Pauli-Slater curve. Obtained results can serve as useful rectification for the theoretical prediction of new Ni-Mn-Ga-X Heusler alloys.

Nowadays, when milling complex parts or curved surfaces, we encounter several problems that must be taken into account in the production process. There are various factors that affect the quality and accuracy of production. The main objective of this paper was to analyze the size of the effective tool diameter when machining a shaped surface with respect to the selected position, namely at the perpendicular position of the tool. At the same time, the distribution of the engagement area on the tool surface was evaluated by extracting the area content and volume data at the point of contact. The experiment was also intended to highlight the importance of the choice of finishing strategy in a CAM system. The results showed that the tool engagement size corresponded to the extracted data describing the area and volume size for each tool position with respect to the curvature of the surface. The negative deviations obtained by the scanning method were due to machining close to the tool centre, which was affected by the changing effective tool diameter.

Robin sequence is a congenital anomaly characterized by a triad of features that include micrognathia, glossoptosis, and airway obstruction. This comprehensive historical review maps the evolution of approaches and appliances for its treatment from the past until current modern possibilities of interdisciplinary combination of modern engineering, medicine, materials, and computer science combined approach with emphasis to design appliances inspired by nature - individual human anatomy. Current biomimetic designs are clinically applied resulting in appliances that are more efficient, comfortable, sustainable, and safer than legacy traditional designs. Review maps the treatment modalities that have been used for patients with Robin sequence over the years. Early management of Robin sequence focused primarily on airway maintenance and feeding support, while current management strategies involve both nonsurgical and surgical interventions and biomimetic biocompatible personalized appliances. The goal of this paper was to provide a review of the evolution of management strategies for patients with Robin sequence that led to the current interdisciplinary biomimetic approaches impacting the future of Robin Sequence treatment with biomimetics at the forefront.

Aim of this research paper is to introduce a novel method of hybrid orthodontic tooth-borne distalizer treatment of class II malocclusion by using 3D printed biocompatible personalized distalizer. Explains 3D designing, printing and clinical application of individualized biocompatible medical device dedicated for orthodontic teeth distalization. Compares such distalizer manufactured from two different biocompatible photopolymers (white and transparent). Evaluates their clinical performance and also patients’ aesthetical perception. Clinical part includes comparison of treatment debonding on the set of 12 complete orthodontic treatments with uni-lateral class II malocclusion managed with hybrid approach (CAT-Invisalign with 3D printed distalizer). Paper offers an evaluation of the personalized distalizer functioning in regard to current publications and comparison to conventional prefabricated alternatives like Carriere® Distalizer™ appliance. Results showed no significance of material differences on clinical performance of such individualized distalizers. Research showed preference of patients towards transparent biocompatible photopolymer instead of white A2 shade.

Purpose: There is limited research on the reasons behind startup failure, and none of the available studies use a competency approach. In this study we applied Spencer’s competency model to identify the competencies in startups which, according to their CEOs, contributed to failure. Methodology: Three coders analyzed the stories of 50 startup failures published online using modified Critical Incident Technique. Findings: Two salient competencies were identified playing a fundamental role in startup failures if missing: Information seeking and Customer service orientation. A network pattern of 9 more prevalent competency deficits was created: Technical/professional/managerial expertise, Analytical thinking, Flexibility, Self-control, Concern for order, quality and accuracy, Interpersonal understanding, Self-confidence, Team leadership and Teamwork and cooperation. Besides startup-specific behavior descriptions were added to Spencer’s competencies. Research implications: Competency approach and Critical Incident Technique method proved to be feasible to identify competency deficits in failed startups. Practical implications: The identified competency deficits offer relevant focus areas for the assessment and development of startup teams. Originality: The study provided research evidence to describe the competency deficits of startup teams that are connected to their failure.

The few studies dealing with leaf phenological responses to elevated nutrients in forest trees have given ambiguous results, i.e., while some reported delayed leaf-out and autumn leaf senescence, others reported advanced leaf phenology caused by increased nutrition. This study aimed to determine the effects of experimentally increased phosphorus (+P) on the leaf phenologies of two juvenile provenances of common beech and sessile oak. Other objectives were to determine whether there are interspecies differences as well as intraspecies variations. Saplings were excavated in two mixed beech-oak stands and transplanted into four wooden boxes filled with a commercial soil substrate. Phosphorus fertilizer was added to two of the boxes, while the remaining boxes served as controls. Both species responded to +P treatment with advanced autumn leaf senescence in the first year of the experiment. Leaf senescence in common beech began significantly earlier, while in both species, the process was accelerated compared to that in the control. In the second year, the leaf senescence response to +P treatment was even more pronounced in both species. The +P effect on leafing phenology was absent in both common beech provenances and in an oak provenance. However, the other oak provenance showed advanced leafing, indicating the existence of intraspecies differences.

This research explores the transformation of learning methodologies from traditional to modern approaches, focusing on the development of a gamified educational application with an Artificial Intelligence (AI) mentor for secondary school graduates preparing for Croatian state graduation exams. Traditionally, education has been marked by a passive student role and teacher-centric transmission of knowledge. In contrast, modern learning tools, such as gamified applications, introduce interactive and engaging elements. The purpose of this study is to identify user-centric learning approaches through a comprehensive survey of graduating students, assessing their readiness for exams, learning styles, and preferences. The research explores issues such as financial burdens on parents for preparatory courses and copyright concerns with external educational materials. In summary, the learning application should prioritise sustained knowledge retention, motivation, and stress reduction, offering an alternative to external preparatory courses. Conclusions underscore the importance of fostering an engaging learning environment, incorporating teacher-like elements, and aligning with user expectations. As digital technology positively impacts the learning experience, understanding user preferences is crucial in designing educational apps that cater to learners' needs. The study provides insights for developing a gamified learning application that not only prepares students for exams but also enhances long-term knowledge acquisition and engagement.

Device-to-device (D2D) communication is an essential part of the future fifth generation (5G) system that can be seen as “network of networks”, consisting of multiple seamlessly integrated radio access technologies (RATs). Public safety communications, autonomous driving, social-aware networking, and infotainment services are example use cases of D2D technology. High data rate communications and use of several active air interfaces in the described network create energy consumption challenges for both base stations and the end user devices. In this paper, we review the status of 3GPP standardization and define a set of application scenarios. We use the recent models of 3GPP Long Term Evolution (LTE) and WiFi interfaces in analyzing the power consumption both from the infrastructure and user device perspectives. The results indicate that the number of active interfaces should be minimized.

(1) Background: Among the chronic complications of type 2 diabetes mellitus, cancer became the leading cause of death in several countries. Our objective was the determination of whether prevalent type 2 diabetes mellitus is associated with a higher incidence of cancer. (2) Methods: This study is a nationwide analysis performed in Hungary. Study population was divided into a group with type 2 diabetes mellitus and into a non-diabetic group. The primary outcome was the risk related to overall cancer incidence. A key secondary outcome was the overall incidence of cancer in distinct study years. Further outcomes were the annual percent changes. (3) Results: The odds ratio related to the overall incidence of cancer was 2.50 (95% confidence interval: 2.46-2.55, P<0.0001) in patients with diabetes as related to controls. The odds ratio was higher in males than in females. The highest risk was found in the 18-39-year-old subgroup. The annual cancer incidence rate declined in controls, but not in patients with diabetes. Several types of cancer showed a decreasing tendency in non-diabetic controls.; (4) Conclusions: type 2 diabetes is associated with a higher risk of cancer. High risk in young patients with type 2 diabetes suggests that these young individuals should be considered as a risk group.

(1) Background: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of cancer but how these two diseases associate is still debated. The goal was the assessment of the overall incidence of cancer among patients with newly diagnosed T2DM in Hungary. Summarizing, incident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months. (2) Methods: A nationwide, retrospective, longitudinal study was performed using a Hungarian database. The incident T2DM and diabetes free Hungarian population were included in the study. The primary endpoints were the overall and site-specific incidence and annual percentage change of the incidence of cancer in both populations. (3) Results: The overall incidence of cancer in patients amounted to 29.4/1000 and 6.6/1000 with or without T2DM, respectively, and the OR (95%CI) of cancer of the T2DM group was 4.32 (4.14-4.53), p<0.0001. The risk of having cancer was age-dependent, having the highest odd in the age group 18-39. The incidence of cancer was declining in the non-diabetic but was unchanged in T2DM population. The average lag time of diagnosing a cancer after the detection of T2DM was 3.86 months.; (4) Conclusions: Iincident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months.

This study explores the complexities of sport manager selection, investigating the impact of affirmative action, recruitment strategies, organizational culture, diversity initiatives in board selection, and career advancement insights from coaches' perspectives. To conduct this investigation, a purposive sampling technique was employed, selecting 65 prominent sports managers and coaches from Romania. Participants, aged between 35 to 58 years old, boasted an average of 10 to 20 years of sports experience and were chosen based on specific criteria, including academic qualifications. Data collection occurred over an extended period, spanning from fall 2022 to spring 2024, through semi-structured interviews with sport managers and coaches. The findings unveiled persistent challenges in effectively implementing affirmative action measures, as sport managers grapple with balancing the promotion of deserving candidates while maintaining continuity in board culture. Achieving meaningful diversity necessitates nuanced approaches that consider both candidate quality and cultural compatibility. Moreover, the study sheds light on coaches' perspectives when considering executive council positions, highlighting various pathways to career advancement. Recruitment practices prioritized informal methods, emphasizing board cohesion. Despite the recognized importance of diversity, challenges persist in selecting candidates solely based on demographic representation. The study provides valuable insights into promoting diversity and inclusivity within sports organizations' executive councils. Future research directions may include exploring longitudinal trends and delving into the qualitative experiences of underrepresented groups, with the aim of advancing understanding and promoting equity within sports organizations.

The research paper comprehensively and consistently addresses all relevant theoretical areas related to the topic and includes an extensive empirical analysis of the absorption of EU funds and their impact on the sustainable development of Croatia, Slovenia, Hungary, and Poland. The analysis aims to investigate the efficiency of the absorption of funds from the EU, the impact of these funds on regional development of countries, as well as the reasons for such impacts. The "Regional Development Model Based on EU Funds" was tested with the aim of applying the model to the Republic of Croatia, countries in the region, and other European countries to achieve a higher level of absorption of financial resources from the available EU funds. Data for the empirical analysis were collected using a highly structured survey questionnaire on a sample of 244 respondents involved in the preparation and implementation of EU-funded projects. The contribution of economic science in theoretical terms arises from the development of scientific knowledge and ideas about the importance of increasing the number of development projects that will increase the absorption of funds from the European Union, thereby increasing economic activities in Croatia and the region. The expected contribution of economic science in the applied sense is based on the formulation of the "Regional Development Model Based on EU Funds," which is based on the application of knowledge, good practices, and stakeholder experiences, considering relevant indicators from available sources. The greatest contribution is demonstrated through testing the "Regional Development Model Based on EU Funds," which is applicable to the Republic of Croatia, countries in the region, and other European countries over a longer period. Finally, research of the impact of EU funds on the regional development of recipient countries is considerably less represented and very modest, only in the "upswing" of systematic scientific research. The research aims to fill the gaps in research and encourage thinking of key stakeholders responsible for regional development, who should eventually realize the importance of defining a regional policy aimed at EU funds as a key to regional development and reducing regional disparities within countries.

In this study, we focus on an abstract form of summation equations, which can be regarded as a particular class of nonlinear difference equations. We investigate sufficient conditions for the existence of discrete almost automorphic solutions by appealing to the fixed point theory and establish a linkage between the existence of discrete almost automorphic solutions and the existence of bounded solutions for the nonlinear difference equations in the spotlight. Consequentially, we propose a discrete counterpart of the Bohr-Neugebauer theorem for the qualitative theory of difference equations.

Agricultural production needs technologies that assist the management of natural resources, for example, the collection of real-time data on soil, water, weather, crops, and biodiversity conditions. Sensor technology solutions and open-source software are appropriate for promoting more sustainable agricultural production. Among the advantages of using open-source technologies and software is its potential for extension, collaboration, customization, flexibility, maintenance cost, transparency, speed, and better security. Given the above, the objective of this research was to find, in different electronic databases, exclusively open-source software for precision agriculture, offering a systematic review, and addressing considerations and challenges. This survey considers up-to-date open-source software available in repositories such as GitHub and GitLab, to understand its characteristics and application formats.

The author demonstrates a stable Lagrangian solid modeling method, tracking the interactions of solid mass particles rather than using a meshed grid. This numerical method avoids the problem of tensile instability often seen with smooth particle applied mechanics by having the solid particles apply stresses expected with Hooke's law, as opposed to using a smoothing function for neighboring solid particles. This method has been tested successfully with a bar in tension, compression, and shear, as well as a disk compressed into a flat plate, and the numerical model consistently matched the analytical Hooke's law as well as Hertz contact theory for all examples. The solid modeling numerical method was then built into a 2-D model of a pressure vessel, which was tested with liquid water particles under pressure and simulated with smoothed particle hydrodynamics. This simulation was stable, and demonstrated the feasibility of Lagrangian specification modeling for fluid–solid interactions.

One in 12 babies is born with a rare genetic disease. Sadly, most cases are undetected until later age, missing time for early treatment and opportunity to prevent complications. Humanity has entered a new era where Big Data collected by governments, including 2D and 3D facial scans, are available. Many rare genetic diseases can be identified by artificial intelligence (AI) analysis of the facial photo. Phenotyping AI utilizations facilitate comprehensive and accurate genetic evaluations. AI processing of this Big Data to identify rare genetic diseases could bring unimaginable benefits to healthcare, although this would be a questionable step in terms of citizen privacy and could lead to future "Orwellian" ramifications with government abuse. Going forward, a balance must be found between protecting the privacy of citizens and the enticing use of AI for their health risks and cost savings through prevention. The unimaginable potential of AI early diagnostics from facial photos also raises various ethical and legal concerns. This paper presents concept, protentional methods and legal and other limitations within EU legal framework in contrast with potential benefits. This paper is focused on AI utilization to early diagnostic of rare genetic diseases. Shift of paradigm in the screening for rare genetic diseases in population with AI face analysis is expected to have a significant impact. The potential of AI algorithms utilizations similar to face2gene app in general population or systematically on Big governmental datasets recording facial traits changes in time can have significant impact on public health but at the same time give raise to profound concern as violation of one’s privacy.

Shaped surfaces are increasingly used in the field of mould making for casting or injection moulding, where future products include shapes with different curvatures. These are surfaces that form convex curves, concave curves, or a combination thereof. Given these machined surfaces, it is important to know the impact of the finishing strategies on these surfaces. This paper deals with the comparison of finishing milling strategies in the production of shaped surfaces and the analysis of different methods for the evaluation of surface topography, surface roughness and the evaluation of deviations. The material used for the experiments was AlCu4Mg aluminium alloy, and Constant Z, Spiral and Spiral circle strategies were chosen for the finishing strategies. The evaluation of surface topography and surface roughness was carried out at three different sample heights with respect to the tool contact with the machined surface. The results showed changes in the toolpaths due to the variation of the effective diameter of the tool cutter to the machined surface as well as the choice of strategy. To produce specimens with corresponding shapes in terms of topography, the Constant Z strategy was the most suitable, in which uniform toolpaths were obtained over the whole height of the sample.

Lake Rawa Besar is an urban lake surrounded by dense settlements and market area. Currently Lake Rawa Besar is experiencing physical and ecology strain. This research’s objectives are to determine the levels of sediment and nutrient, the distribution, also the relation to land use and human activities producing pollutant. Field surveys with 30 sample points and observations was needed scattered within the lake. Measuring the value of each parameter is carried out in national standardized laboratory. The result shows that sediment load of TDS is still below the standard limit for clean water, while TSS levels in the middle of lake exceed the standard limit. Nutrient loads, spesifically nitrate and phospate levels is below the standard limit. While turbidity and BOD levels have a uniform distribution pattern in the lake, exceed the standard limit for clean water, and have a positive correlation. High levels of turbidity and BOD are caused by household waste and human activities producing organic waste such as tofu factory, fowl manure, and garbage dump. Small sewage goes into the lake mediates pollutants inflow. Attention is needed by nearby people, also for the government, to sustain the ecological condition of the lake.

The incidence of articular injury, particularly osteochondral fractures (OCF), has seen a notable increase in recent years. Regardless of their location, fragments might be overlooked by plain radiographs which might lead to osteoarthritis in the long run. Diagnostic imaging has a pivotal role in the assessment and classification of the fracture severity, as well as the presence of any associated dislocations. These fractures require surgical intervention for the restoration of joint function and the reduction of long-term complications. The paper aims to present the surgical correction and post-operative treatment of osteochondral fractures with absorbable implants in three children. Affected areas are discussed as follows: lateral condyle of the femur, patella, and radial head. Utilising absorbable implants for the management of OCFs provides numerous advantages, including the elimination of the need for reanaesthesia and reoperation, reducing complications, and enabling early rehabilitation. This approach also minimises the period of hospitalisation and proved effective in pediatric OCF treatment.

Society considers wine as a special product among food and beverages because of its high gastronomical value and its positively distinctive quality. In recent years, philosophies of the agricultural techniques and development of the oenological technology have been focused on the reduction of wasteful, "polluting" elements, and trends are moving towards an environmental friendly approach. Due to the stricter regulations and rules (with the limited amount and selection of the permitted chemicals) resistant, also known as interspecific or innovative grape varieties can be the ideal basic materials of alternative cultivation technologies. In terms of variety selection, innovative varieties can be equivalent to international varieties, although organically their quality could not compete with them. These grapes are more resistant to various fungal diseases and infections than international varieties. Well-founded analytical and organoleptic results have to provide the scientific background of resistant varieties, as these cultivars with the environmental friendly cultivation techniques, could be the raw material of the future.

The maneuverability of ships is influenced by several factors, including ship design, size, propulsion system, hull shape, and external conditions such as wind, waves, and currents. The size, shape, and arrangement of the hull, rudder, and propeller are decisive for maneuverability. Hydrodynamic forces such as bank effect and squat significantly impact the maneuverability of large ships in narrow channels. With the increasing trend of building ever-larger ships, the demand to evaluate the maneuvering performance of the ship at the design stage has become more critical than ever. Both experimental and computational methods are used to obtain accurate maneuvering characteristics of vessels. In this study, the methods for predicting ship maneuvering characteristics are analyzed using a systematic review based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA). This article contributes to a deeper understanding of the hydrodynamic capabilities of ships and identifies possible future challenges in the field of ship hydrodynamics. The findings inform educators and the shipping industry about the importance of predicting the maneuvering performance of ships, with an emphasis on the education and training of seafarers needed to make timely decisions in critical situations.

Aim: This study aimed to evaluate the effectiveness of a plyometric training program designed to enhance agility, speed, and social interaction among boys with mild intellectual disability (ID) aged 10-12, within the Special Olympics framework. Participants: Thirty-two boys (mean age = 10.69 ± 0.8 years; mean IQ = 61 ± 7) from three inclusive education centers participated in the study. Methods: The intervention consisted of a 10-week plyometric training program, conducted twice a week. Pre- and post-intervention assessments included the Reaction Time Test, 4-Corner Agility Test, 10-Meter Speed Run, 4x5 Meter Relay Test, and the Friendship Activity Scale (FAS). Results: The study found significant improvements across all measures. Reaction time decreased by 0.83 seconds (t = 7.44, p < 0.001), 4-corner agility improved by 0.77 seconds (t = 11.93, p < 0.001), 4x5 meter speed improved by 0.61 m/s (t = 17.37, p < 0.001), and 10-meter run speed improved by 1.55 m/s (t = -12.76, p < 0.001). Additionally, the FAS score increased by 0.81 points (t = 9.59, p < 0.001), indicating enhanced social interactions. Conclusion: The plyometric training program significantly improved agility, speed, and social interaction in children with mild ID, demonstrating the effectiveness of inclusive, adaptive physical education strategies within the Special Olympics framework.

In this paper, a multirotor UAV platform based on the PX4 ecosystem was discussed, which in combination with the MATLAB Simulink programming environment enables utilization in various aspects of mechatronic engineering education. Extensive testing of the UAV platform control module was performed, in order to enable implementation in engineering education. In the design phase of the educational platform, take-off-the-shelf components were selected and tested, and airframe parts were manufactured using rapid prototyping technologies. The proposed educational platform with four rotors was presented and tested. The learning outcomes of the undergraduate mechatronics professional study program according to the Croatian Qualifications Framework and related to the considered platform are shown. A preliminary framework of laboratory exercises for the field of mechatronic systems control is investigated.

This work addresses the energy-based source localization problem in wireless sensors networks. Instead of circumventing the maximum likelihood (ML) problem by applying convex relaxations and approximations (like all existing approaches do), we here tackle it directly by the use of metaheuristics. To the best of our knowledge, this is the first time that metaheuristics is applied to this type of problems. More specifically an elephant herding optimization (EHO) algorithm is applied. Through extensive simulations, the key parameters of the EHO algorithm are optimized such that they match the energy decay model between two sensor nodes. A detailed analysis of the computational complexity is presented, as well as performance comparison between the proposed algorithm and existing non-metaheuristic ones. Simulation results show that the new approach significantly outperforms the existing solutions in noisy environments, encouraging further improvement and testing of metaheuristic methods.

This study analyses the short-run hydro generation scheduling for the wind power differences from the contracted schedule. The approach for construction of the joint short-run marginal cost curve for the hydro-wind coordinated generation is proposed and applied on the real example. This joint short-run marginal cost (SRMC) curve is important for its participation in the energy markets and for economic feasibility assessment of such coordination. The approach credibly describes the short-run marginal costs which this coordination bears in “real life”. The approach is based on the duality framework of a convex programming and as a novelty combines the shadow price of risk mitigation capability and the water shadow price. The proposed approach is formulated as a stochastic linear program and tested on the case of the Vinodol hydropower system and the wind farm Vrataruša in Croatia. The result of the case study is a family of 24 joint short-run marginal cost curves.

In this work, backscattering signatures of snow-covered lake ice and sea ice from X- and Ku-band synthetic aperture radar (SAR) data are investigated. The SAR data were acquired with the ESA airborne SnowSAR sensor in winter 2012 over Lake Orajärvi in northern Finland and over landfast ice in the Bay of Bothnia of the Baltic Sea. Co-incident with the SnowSAR acquisitions in-situ snow and ice data were measured. In addition, time series of TerraSAR-X images and ice mass balance buoy data were acquired for the Lake Orajärvi in 2011-12. The main objective of our study was to investigate relationships between SAR backscattering signatures and snow depth over lake and sea ice, with the ultimate objective of assessing the feasibility of retrieval of snow characteristics using X- and Ku-band dual-polarisation (VV and VH) SAR over freshwater or sea ice. This study constitutes the first comprehensive survey of snow backscattering signatures at these two combined frequencies over both lake and sea ice. For lake ice, we show that X-band VH-polarized backscattering coefficient (σo) and the Ku-band VV/VH-ratio exhibited the highest sensitivity to the snow depth. For sea ice, the highest sensitivity to the snow depth was found from the Ku-band VV-polarised σo and the Ku-band VV/VH-ratio. However, the observed relations were relatively weak, indicating that at least for the prevailing snow conditions, obtaining reliable estimates of snow depth over lake and sea ice would be challenging using only X- and Ku-band backscattering information.

Methods based on simulation pedagogy are widely used to practice hands on skills in safety environment. The usability of an EEG-simulator on clinical neurophysiology course was evaluated. Second year biomedical laboratory science students (N=35) on this course was included in the study. They were divided into three groups. Two groups used the EEG simulator with different feedback modes and one group without use of the simulator. Results was expected to reveal a correlation between user experience and learning outcomes. This study made used of a mixed method study design. During the study students were asked to keep a learning diary throughout the course on their experience. Diaries were analyzed qualitatively based on content analyses. Quantitative analyses based on an UX questionnaire that measures classical usability aspects (efficiency, perspicuity, dependability) and user experience aspects (novelty, stimulation) and the students’ feelings to use simulator. The quantitative data was analyzed using SPSSTM software. The quantitative and qualitative analyses showed that the use of EEG-simulator which was evaluating teaching-learning process have an extra benefit in clinical neurophysiology education and students felt that simulator is useful in learning. The simulation debriefing session should be followed by a full theoretical and practical session. Students compare their learning from the simulator with that of the actual placement which fosters the reflective practice of learning again deepening the understanding of the EEG electrode placement and different wave patterns.

This study aimed to evaluate the effect of convective and microwave drying on the content of bioactive compounds of blackberry (Rubus fruticosus), drying parameters and energy consumption. The fruit was dehydrated in a convective dehydrator at a temperature of 50 °C and 70 °C and a microwave oven at power levels of 90 V, 180 V and 240 V. The highest amount of anthocyanins, polyphenols and antioxidant capacity were obtained in microwave dried blackberry fruits at 90 V and 180 V. It turned out that microwave dehydration shortened the processing time and lower the energy consumption compared to the convective drying. Blackberry fruits dehydrated at 240 V showed the shortest dehydration time, minimal energy consumption and the most efficient diffusion.

Background: Studies exploring the possible protective effect of coffee and tea consumption on dementia showed inconsistent results so far. We aimed to investigate whether consumption of tea and different types of coffee at midlife are associated with dementia later in life and, whether sex or ApoE4 influence such association. Methods: We included 7381 participants from the Norwegian HUNT Study. Self-reported questionnaires assessed daily consumption of coffee and tea at baseline. After 22 years, individuals 70 years or older were screened on cognitive impairment. Results: General coffee consumption and tea consumption was not associated with dementia risk. Compared to daily consumption of 0-1 cups of coffee, daily consumption of ≥8 cups of boiled coffee was associated with increased dementia risk in women (OR:1.83, 95% CI: 1.10-3.04, p-value for trend=0.03) and daily consumption of 4-5 cups of other types of coffee was associated with a decrease in dementia risk in only men (OR 0.48, 95% CI: 0.32-0.72, p-value for trend =0.05). Furthermore, the association between boiled coffee and increased dementia risk was only found in ApoE4 non-carriers. Differences by sex or ApoE4 carrier status were not supported by strong statistical evidence for interaction. Conclusion: Type of coffee may play a role in the direction of the association between coffee-drinking habits and dementia later in life.

Mosquitoes are widespread arthropods that serve as vectors for a broad spectrum of viruses, many of which pose a substantial threat to humans. Conversely, some viruses may seemingly present with beneficial implications for the health of man whilst impinging on other domains of life, such as the fungi-infecting mycoviruses. This study is only the second one so far to describe the exceptionally scarcely identified Xanthi chryso-like virus (XCLV), member of the mycopathogenic Chrysoviridae family, in a new geographical area and a novel potential arthropod vector, the Culex pipiens mosquito. Interestingly, the XCLV was initially fortuitously detected by West Nile virus-specific primers directed at a conserved part of the NS5 gene, possibly indicative of a genetic resemblance and shared ancestry reflected in the NS5 evolutionary heritage. Detection and characterization of the virus and insect alike was done via PCR and Sanger sequencing. This investigation draws attention to our knowledge of viral pervasiveness – be it topographical or vectorial – and how humble it truly is. Additionally, we would propose that more attention be given to arthropod-borne viral pathogens that might prove advantageous to human health.

The aim of the study is to obtain a more complete picture of the blood plasma melatonin concentration in the donkey species. To this purpose sampling and statistical processing were carried out in such a way that allowed to establish the annual and daily rhythm. Based on human observations, according to the hypothesis of the authors, the blood plasma melatonin concentration of pregnant individuals rises during late gestational period, before parturition. To confirm this, the melatonin concentration of pregnant and non-pregnant mares was monitored and compared. In regard to the circannual rhythm, the significantly lowest midnight melatonin value (27.67 pg/ml) is typical for the summer solstice. Under consideration of circadian changes, a significantly strongest melatonin production (45.16 pg/ml) can be observed on the night of the winter solstice (p &lt; 0.001). Considering the gestational age, the blood plasma melatonin concentration (around 38 pg/ml) does not change as pregnancy progresses (p = 0.136). The results obtained in the study population of the domestic ass usefully expand the little knowledge previously gathered about the development of blood plasma melatonin concentration of this species.

(1) Teeth, represent in humans the most resilient tissues. However, exposure to concentrated acids might lead to their obliteration, thus making human identification difficult. Teeth often contain dental restorations from materials that are even more resilient to acid impact. This paper introduces novel method of 3D reconstruction of dental patterns as a crucial step for digital identification with dental records.; (2) With combination of modern methods of Micro-Computer Tomography, Cone Beam Computer Tomography, Attenuated Total Reflection in conjunction with Fourier-Transform Infrared Spectroscopy and Artificial Intelligence Convolutional Neural Network algorithms, the paper presents the way of 3D dental pattern reconstruction and human remains identification. Research studies morphology of teeth, bone, and dental materials (Amalgam, Composite, Glass-ionomer cement) under different periods of exposure to 75% sulfuric acid; (3) Results reveal significant volume loss in bone, enamel, dentine, and as well glass-ionomer cement. Results also reveal significant resistance of composite and amalgam dental materials to sulfuric acid impact, thus serving as strong parts in the dental pattern mosaic. Paper also introduces probably first successful artificial intelligence application in automated forensic CBCT segmentation.; (4) Interdisciplinary cooperation utilizing mentioned technologies can solve problem of human remains identification with 3D reconstruction of dental patterns and their 2D projections over existing ante-mortem records.

In future automated vehicles we will often engage in non-driving tasks and will not watch the road. This will affect postural stabilization and may elicit discomfort or even motion sickness in dynamic driving. Future vehicles shall accommodate this by properly designed seats and interiors whereas comfortable vehicle motion shall be achieved with smooth driving styles and well de-signed (active) suspensions. To support research and development in dynamic comfort, this paper presents validation of a multi-segment full body human model including visuo-vestibular and muscle spindle feedback for postural stabilization. Dynamic driving is evaluated using a “sicken-ing drive” including a 0.2 Hz 4 m/s2 slalom. Vibration transmission is evaluated with compliant automotive seats, applying 3D platform motion and evaluating 3D translation and rotation of pelvis, trunk and head. The model matches human motion in dynamic driving and reproduces fore-aft, lateral and vertical oscillations. Visuo-vestibular and muscle spindle feedback are shown to be essential in particular for head-neck stabilization. Active leg muscle control at the hips and knees is shown to be essential to stabilize the trunk in the high amplitude slalom condition but not in low amplitude horizontal vibrations. However, active leg muscle control can strongly affect 4-6 Hz vertical vibration transmission. Compared to the vibration tests, the dynamic driving tests show enlarged postural control gains to minimize trunk and head roll and pitch, and to align head yaw with the driving direction. Human modelling can create the required insights to achieve breakthrough comfort enhance-ments while enabling efficient development for a wide range of driving conditions, body sizes and other factors. Hence, modelling human postural control can accelerate innovation of seats and vehicle motion control strategies for (automated) vehicles.

Beta cells couple stimulation by glucose with insulin secretion and impairments in this coupling play a central role in diabetes mellitus. To clarify the effect of cAMP and the role of Epac2A in intracellular calcium signals and intercellular coupling, we performed functional multicellular calcium imaging in beta cells in mouse pancreas tissue slices after stimulation with glucose and forskolin in wild-type and Epac2A knock-out mice. Increased cAMP evoked calcium signals in otherwise sub-stimulatory glucose and beta cells from Epac2A knock-out mice displayed a faster activation. During the plateau phase, beta cells from Epac2A knock-out mice displayed a slightly higher active time in response to glucose compared with wild-type littermates, and increased cAMP increased the active time via a large increase in oscillation frequency and small decrease in oscillation duration in both Epac2A knock-out and wild-type mice. Functional network properties during stimulation with glucose did not differ in Epac2A knock-out mice, but the presence of Epac2A was crucial for the protective effect of increased cAMP in preventing a decline in beta cell functional connectivity with time. Finally, increased cAMP prolonged beta cell activity during deactivation in an Epac2A-independent manner.

In this paper, the experimental results of the thermal sub-system of a reliable and cost-effective polygeneration solar system are presented. This polygeneration system produces heating, cooling and electricity from solar energy, which are used in an existing test-building. Heat is generated in four evacuated tube solar collectors (ETC). The heat may be used for space cooling, through a variable geometry ejector (VGE) heat pump. In order to reduce the mismatches between generation and consumption, two thermal storage tanks were added. The performance of a new thermal storage, with 400 l, able to storage both sensible and latent heat, was tested. Heating performances of the test-building were assessed. Ejector cycle tests were also performed.

Fibromyalgia is a complex and often misunderstood chronic pain disorder. It is characterized by widespread musculoskeletal pain, fatigue, and heightened sensitivity, and has evolved in diag-nostic criteria and understanding over the years. Initially met with skepticism, fibromyalgia is now recognized as a global health concern affecting millions of people, with a prevalence trans-cending demographic boundaries. The clinical features and diagnosis of fibromyalgia encompass a range of symptoms beyond pain, including sleep disturbances and cognitive difficulties. The study emphasizes the importance of a comprehensive evaluation for accurate diagnosis, considering the shift from tender point reliance to a more holistic approach. Etiology and pathophysiology involve genetic predisposition, neurotransmitter dysregulation, central sensitization, and immune system involvement. Risk factors such as gender, age, family history, and comorbid conditions contribute to susceptibility. The impact on quality of life is profound, affecting physical and social aspects, often accompanied by mood disorders. Management approaches include pharmacological interventions, non-pharmacological therapies, lifestyle modifications, and alternative treatments. The study also delves into emerging research, exploring advances in neurobiological understanding, brain imaging, genetic markers, glutamate modulation, cannabinoids, gut microbiome, and digital health tools for fibromyalgia manage-ment. Overall, this study provides a nuanced and up-to-date overview of the complexities sur-rounding fibromyalgia, aiming to enhance understanding and support for individuals grappling with this challenging condition.

Research with deuterium-depleted water (DDW) in the last two decades proved that deuterium/hydrogen ratio has a key role in cell cycle regulation and cellular metabolism. The present study aimed to investigate the possible effect of deuterium-depleted organic compounds (DDOC) alone and in combination with DDW on cancer growth in two in vivo mouse models. To produce DDOC, drinking water of laying hens was replaced with DDW (25 ppm) for 6 weeks, resulting in 60 ppm D level in dried egg yolk that was used as deuterium-depleted food additive. In one model, 4T1, a cell line with high metastatic capacity to the lung, was inoculated in the mice’s mammary pad. After three weeks of treatment with DDW and/or DDOC, the tumor volume in the lungs was smaller in all treated groups vs. controls with natural D level. Tumor growth and survival in mice transplanted with MCF-7 breast cancer cell line showed that the anticancer effect of DDW was enhanced by food containing the deuterium-depleted yolk. The study confirmed the importance of D/H ratio not only in consumed water but also in metabolic water produced by the mitochondria while oxidizing nutrient molecules. This is in line with the concept that initiation of cell growth requires the cells to generate a higher D/H ratio, but DDW, DDOC, or the naturally low-D lipids in a ketogenic diet, have significant effect on tumor growth by preventing the cells from raising D/H ratio to the threshold.

The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics, contributes to cancer drug resistance and the development of gout. In this work we have analyzed the effects of selected variants, residing in a structurally unresolved cytoplasmic region (a.a. 354-367) of ABCG2, on the function and trafficking of this protein. A cluster of four lysines (K357-360) and the phosphorylation of a threonine (T362) residue in this region have been previously suggested to significantly affect the cellular fate of ABCG2. Here we report that the naturally occurring K360del variant in human cells increased ABCG2 plasma membrane expression and accelerated cellular trafficking. The variable alanine replacements of the neighboring lysines had no significant effect on transport function, and the apical localization of ABCG2 in polarized cells has not been altered by any of these mutations. Moreover, in contrast to previous reports, we found that the phosphorylation incompetent T362A, or the phosphorylation mimicking T362E variants in this loop, had no measurable effects on the function or expression of ABCG2. Molecular dynamics simulations indicated an increased mobility of the mutant variants with no major effects on the core structure of the protein. These results may help to decipher the potential role of this unstructured region within this transporter.

The present work proposed a low-cost portable device as an enabling technology for Smart Farms using multispectral imaging and Machine Learning in soil texture. Clay is an important factor for the verification and monitoring of soil use due to its fast reaction to chemical and surface changes. The system developed uses the analysis of reflectance in wavebands for clay prediction. The selection of each wavelength is performed through an LED lamp panel. A NoIR microcamera controlled by a Raspberry Pi device is employed to acquire the image and unfold it in RGB histograms. Results showed an good prediction performance with R2 of 0.96, RMSEC of 3.66% and RMSECV of 16.87%. The high portability allows the equipment to be used in a field providing strategic information related to soil sciences.

In recent years, the potential of insects has been explored as a sustainable protein alternative to sustain the growing world population. Differences in the way insects are processed can affect their proximate composition and digestibility. This work studies the effects of the combination of different types of slaughter methods and drying temperatures on the proximate composition, organic matter digestibility (OMd), hydrolysis degree (DH/NH2 and DH/100 g DM), total hydrolysis (TH) and hygienic sanitary study of BSFL (black soldier fly larvae). Four types of slaughter methods were used: frozen (F), blanched + frozen (B), Melacide® + frozen (M) and liquid nitrogen (N), each with three drying temperatures (50, 70 and 90 °C). A negative correlation between acid detergent fibre (ADF) and protein digestibility parameters was obtained. 70 °C was the most suitable drying temperature, as it reported higher values of protein digestibility (DH, TH), resulting in hygienic and sanitary conditions suitable for food use. Slaughtering with liquid nitrogen and blanching were more convenient than traditional freezing or the use of Melacide® to achieve higher protein digestibility results.

The therapeutic effectiveness of current neurodegenerative diseases treatments is still under debate because of problems with bioavailability and a range of side effects. Fungi, which are increasingly recognized as sources of natural antioxidants and AChE enzyme inhibitors, may thus serve as potent neuroprotective agents. Previous studies have associated the anti-AChE and antioxidant activities of fungi mostly with polysaccharides and phenolic compounds, while other secondary metabolites such as polyamines (PAs) have been neglected. This study aimed to investigate eight edible and medicinal fungi from Serbia, marking the initial investigation into the neuroprotective capabilities of Postia caesia, Clitocybe odora, Clitopilus prunulus, and Morchella elata. Neuroprotective activity was examined using Ellman assay, while antioxidant capacity was tested by conducting DPPH, NO, ABTS and FRAP tests. PAs levels were determined by HPLC coupled with fluorescent detection. Ganoderma applanatum and Lepista nuda exhibited the most robust anti-AChE (98.05 ± 0.83% and 99.94 ± 3.10%, respectively) and antioxidant activities attributed to the synergistic effects of total protein, total phenolic and PAs levels. Furthermore, P. caesia displayed significant AChE inhibition (88.21 ± 4.76%), primarily linked to elevated SPD (62.98 ± 3.19%) and PUT levels (55.87 ± 3.16%). Our results highlight the need of thorough research to comprehend the intricate relationships between distinct fungus species and AChE inhibition. However, it's important to recognize that more research is required to identify the precise substances causing the reported inhibitory effects.

The oncogenicity of the human cytomegalovirus (CMV) is debated to this day. In recent years, mounting evidence addresses an anti-cancer effect via T cell-mediated CMV-targeted tumor de-struction. However, the data mostly comes from single-center studies and in vitro experiments. Broad geographic coverage is required to offer a global perspective. This study examined the correlation between country-specific CMV seroprevalence (n=73) and age-standardized inci-dence rates for 34 tumors using data obtained from the International Agency for Research on Cancer of the World Health Organization. The association between CMV and cancer incidences in 10-year age increments was also analyzed. The study revealed a worldwide inverse correlation between CMV seroprevalence and incidences of 88.2% tumors. Notably, this inverse link persists for all cancers combined (Spearman’s ρ= -0.732, p= 0.001). An antithetical and significant correlation is also observed in particular age groups for the vast majority of tumors. Our results corroborate the conclusions of previous studies and indicate that this phenomenon holds true on a global scale. It applies to a wide spectrum of cancer histologies, suggesting a common under-lying mechanism – CMV-stimulated T cell tumor targeting. Although these results further advance the notion of CMV-based therapies, further in-depth investigation of host-virus interactions is warranted.

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The mo-lecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus-secretion coupling cascade, ranging from the proximal regula-tion of ion channel activity, to the central Ca2+ signal, and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the rele-vance for the whole organism and translation to humans.

Background Most of the Leber hereditary optic neuropathy (LHON) cases are bilateral and sequential, how-ever there are rare unilateral examples, or those in which the delay of onset of vision loss between one and the other eye is longer. In the case of presumed childhood amblyopia in one eye, the vision loss in the good eye may be the only symptom of bilateral disease, that was unnoticed in previ-ously amblyopic eye, or a preexisting episode of LHON on the “amblyopic” eye. Clinical decision in such cases may be difficult and suggestive for other forms of atypical optic neuropathy until confirmed by genetic testing. Case series We present three genetically confirmed (MT-ND1:m.3700G>A, MT-ND6:m14484 T>C, and MT-ND4:m.11778G>A) patients with subacute vision loss in previously good eye with the other eye believed to be amblyopic from the childhood, and their features different of what would be expected in true amblyopia. In all, electrophysiology testing showed bilaterally reduced ampli-tude of PERG with low VEP P100 wave amplitudes and prolonged peak time in both eyes, also unusual for amblyopia. During the follow-up, pallor of the optic discs progressed in all eyes. Significant thinning of the retinal nerve fiber layer around the optic disc (pRNFL) and ganglion cell complex (GCC) in the macular region was present. All three patients had peculiar history. First patient was treated for presumed hyperopic amblyopia that did not improve since child-hood and experienced visual loss on the good eye at the age of 17 and was negative for the three typical LHON mutations. Extended testing confirmed atypical pathogenic variant MT-ND1:m.3700G>A in homoplasmy. The second patient with presumed strabismic amblyopia had unusual presentation of vision loss only at the age of 61 and after exclusion of other causes, typical MT-ND4:m.11778G>A pathogenic variant was found in homoplasmy. The third case was peculiar as he had presumed strabismic amblyopia since childhood and had some degree of disc pallor in the amblyopic eye upon presenting with loss of vision on the good eye at the age of 21 and typical pathogenic variant m14484 T>C, p.Met64Val was subsequently confirmed. However, one year after the disease onset, he started to experience significant spontaneous functional im-provement in the non-amblyopic up to 1.0 Snellen, whilst improvement in the presumed amblyop-ic eye was modest, suggesting preexisting amblyopia. This interestingly extensive improvement was carefully followed by electrophysiology as well as visual acuity and fields. Conclusion This report shows three different scenarios of presentation of LHON in patients with presumed uniocular amblyopia from childhood. In such cases, the diagnosis may be difficult and detailed structural and functional evaluation of the optic nerve head is necessary to assess whether earlier LHON episode was misdiagnosed as amblyopia or whether LHON presented bilaterally on both eyes whilst only being noticed in the previously good eye.

The aim of this study was to determine the changes in chemical composition of the fresh red raspberry ‘Willamette’ fruits, caused by the presence of raspberry leaf blotch emaravirus (RLBV). In three experimental orchards of ‘Willamette’ raspberry, fruits were harvested from RLBV‒free and RLBV-infected plants in 2019 and 2020. Fruits were collected at appropriate maturity stages and further analyzed on total phenolics, total anthocyanins, and selected individual phenolics. In all three experimental orchards, the phenolic profiles of infected and uninfected fruit samples were considerably different during both studied years. Nonetheless, the intensity of the modifications varied greatly depending on location and harvest year. Statistical analysis revealed that the influence of RLBV infection on the studied features is undeniable, although the influences of weather conditions and soil composition outweigh the influence of RLBV. Taking into consideration all experimental and statistical data, it can be concluded that raspberry 'Willamette' fruits may be RLBV-tolerant, while sensitivity to environmental conditions and soil composition is emphasized.

Kinesiophobia (fear of movement) has been recognized as a significant barrier to recovery and rehabilitation in patients after total knee arthroplasty (TKA). Our goal was to identify predictors of kinesiophobia and examine its correlation with early functional outcomes in TKA recipients. On the first and fifth postoperative days (POD1 and POD5), we evaluated pain using the International Pain Outcomes Questionnaire (IPO-Q) and created multidimensional pain composite scores (PCS). Pain Composite Score-total (PCStotal) assesses the overall impact of pain, taking into account outcomes of pain intensity, pain-related interference with function, and emotions and side effects. Functional status on POD 5 was determined by the Barthel index, 6-minute walking test, and knee range of motion. Kinesiophobia was measured on POD5 using the Tampa Scale for Kinesiophobia (TSK) and multivariable logistic regression was used to assess factors associated with kinesiophobia. Among 75 TKA patients, 27% exhibited kinesiophobia. The final regression model highlighted PCStotal on POD5 (OR=6.2, CI=1.9-19.9), PCStotal (OR=2.1, CI=1.2-3.8) on POD1, and the intensity of chronic pain before surgery (OR=1.4, CI=1.1-2.1) as significant kinesiophobia predictors. On POD5, those with kinesiophobia showed increased dependency, slower gait, and poorer knee extension recovery. This study highlights the importance of identifying and addressing kinesiophobia in TKA patients to optimize functional outcomes and improve recovery. Also, it is important to assess not only pain intensity but also the physical and emotional interference caused by pain, which can contribute to the development of kinesiophobia.

Many relevant health social actors have voiced concerns about the danger of self-medication in times of growing use of over-the-counter medicines and, in some contexts, unregulated selling of them. Previous research has examined the incidence of parental self-medication as well as the use and abuse of antibiotics without professional advice. However, these studies have limited evidence on the role of family doctors and the perceived severity of self-medication in the case of parents. Based on Health Belief Model, our research tested the effects of exposure to medical information on the perceived level of self-treating the children without medical advice. Specifically, we aimed to assess whether exposure to information warning about the risks of treating children without a medical prescription influences parents' attitudes toward administering medicines to their children without medical advice. The results showed that our respondents evaluated the practices of self-medication negatively, especially when it came to treating their children without medical advice. However, their attitudes towards self-medication varied depending on their beliefs about administering certain medications. Additionally, the results showed that the perceived level of satisfaction with the family physician could be a significant factor in controlling and avoiding the treatment of children without professional advice.

This review paper deals with recently proposed algorithms for distributed blind macro-calibration of sensor networks based on consensus (synchronization), not requiring any fusion center. The basic algorithm, performing the estimation of the local calibration parameters, is derived commencing from appropriate local criteria, and developing the corresponding gradient descent scheme. It is shown that the estimated parameters of the calibration functions asymptotically converge, in the mean-square sense and with probability one (w.p.1), to such values that ensure consensus on calibrated sensor gains and calibrated sensor offsets. For the more realistic case in which additive measurement noise, communication dropouts and additive communication noise are present, two algorithm modifications are introduced: one using a simple compensation term, and a more robust one based on an instrumental variable. By utilizing stochastic approximation arguments it is shown that the modified algorithms also achieve asymptotic agreement for calibrated sensor gains and offsets, in the mean-square sense and w.p.1. Convergence rate is analyzed in terms of an upper bound of the mean-square error. It is also shown that the communications between nodes can be completely asynchronous, which is of substantial importance for real-world applications. Suggestions for design of \textit{a priori} adjustable weights are given. Finally, it is shown that, if there is a subset of (precalibrated) reference sensors with fixed calibration parameters, the calibrated sensor gains and offsets of the rest of the sensors do not achieve consensus - they converge to different points dictated by the reference sensors and the network characteristics. Wide applicability and efficacy of these algorithms are illustrated on several simulation examples.

Background: In rheumatoid arthritis (RA), anti-citrullinated protein/peptide antibodies (ACPAs) are responsible for disease onset and progression, however, our knowledge is limited on ligand binding affinities of autoantibodies with different citrulline-peptide specificity. Methods: Citrulline-peptide specific ACPA IgGs were affinity purified and tested by ELISA. Binding affinities of ACPA IgGs and serum antibodies were compared by surface plasmon resonance (SPR) analysis. Bifunctional nanoparticles harboring a multi-epitope citrulline-peptide and a complement activating peptide were used to induce selective depletion of ACPA producing B cells. Results: KD values of affinity purified ACPA IgGs varies between 10-6-10-8 M and inversely correlate with disease activity. Based on their cross-reaction with citrulline-peptides we designed a novel multi-epitope peptide, containing Cit-Gly and Ala-Cit motifs in two-two copies, separated with a short, neutral spacer. This peptide detects antibodies in RA sera with 66 % sensitivity and 98 % specificity in ELISA and is recognized by 90% of RA sera, while none of the healthy samples in SPR. When coupled to nanoparticles, the multi-epitope peptide specifically targets and depletes ACPA producing B cells ex vivo. Conclusions: The unique multi-epitope peptide designed on the basis of ACPA cross-reactivity might be suitable to develop better diagnostics and novel therapies for RA.

Background: Parathyroid imaging techniques are used in patients with biochemically confirmed primary hyperparathyroidism (pHPT) to detect the localization of enlarged parathyroid gland(s) (PTG) and thereby to allow more focused, unilateral or minimally invasive parathyreoidectomy (PTX), instead of classical bilateral neck exploration (BNE). Although the preferred sequence of imaging continues to evolve, ultrasonography (US) is usually the first line modality, followed by 99mTc sestamibi parathyroid scan (SPS). However, both tests may have suboptimal localizing accuracy with considerable rate of non-localized cases. Therefore, more accurate four-dimensional computed tomography scan (4D-CT) has been employed for PTG imaging. Currently, there is a paucity of data evaluating the utility of 4D-CT in low case-load settings. Aim: To evaluate the impact of PTG imaging, using 4D-CT in conjunction with it’s intraoperatively displayed results, on the outcomes of surgical PTX. Our primary outcome was sensitivity of 4D-CT in comparison to US and SPS for preoperative PTG adenoma localization. The secondary outcomes were the need for redo surgery and morbidity. Additionally, the characteristics of surgical PTX, i.e. operative time, number of removed parathyroid glands, and rate of simultaneous thyroid surgery, were assessed. Methods: A single-center retrospective analysis of surgically treated patients with pHPT from 01/2010 to 01/2021 was conducted. Evaluation of impact of the preoperative imaging modalities on the results of surgical treatment was carried out. Results: During the study period 290 PTX were performed, 45 cases were excluded due to surgery for secondary, tertiary or recurrent HPT, or due to use of alternative imaging techniques; the remaining 245 patients were included in the study. US was carried out for PTG imaging in 236 (96.3%), SPS in 93 (38.0%), and 4D-CT in 52 patients (21.2%). The use of 4D-CT was associated with a significantly higher rate of successful localization of enlarged PTG (49 cases, 94.2%) compared to US and SPS (74 cases, 31.4%, and 54 cases, 58.1%, respectively). We distinguished between three groups of patients based on preoperative imaging: 1) PTG lateralization via US or SPS in 106 (43.3%) cases, 2) precise localization of PTG via 4D-CT in 49 (20.0%) patients, and 3) in 90 cases (36.7%) PTG imaging failed to localize enlarged gland. The group of 4D-CT localization had significantly shorter operative time, lower rate of simultaneous thyroid resections, as well as lower rate of removal of ≥2 PTG, compared to the other groups. The 4D-CT imaging was also associated with the lowest perioperative morbidity and with the lowest median PTH in one month follow-up; however, compared to the other groups, these differences were statistically not significant. Implementation of 4D-CT (since 01/2018) decreased the need for redo surgery (from 11.5% to 7.3%), and significantly increased the annual case load of PTX at our institution (from 15.3 to 41.0), compared to the period before 4D-CT diagnostics. Conclusions: 4D-CT imaging enabled to precisely locate almost 95% of enlarged PTG in patients with pHPT. Accurate localization and intraoperatively displayed imaging results are useful guides for surgeons in making PTX a faster and safer procedure in a low volume center.

It is an utmost importance to characterize drug candidates as early in the development pipeline as possible. Appropriate application of the emerging high throughput analytical techniques unlocks the opportunities to obtain experimental data for in vitro absorption, distribution, metabolism and elimination (ADME) profiling of large compound libraries which is crucial for selection of lead compounds. In an usual scenario, only one drug candidate will be selected from thousands of early compounds based on several stability and screening results. A high to medium throughput screening approaches could significantly accelerates the subsequent research and production phases. Traditionally, the analysis of metabolic stability assays heavily relies on high throughput LC-MS/MS techniques to meet with the lead profiling demands. In this study presented an innovative experimental approach that can offer a refreshing alternative. Laser Assisted Rapid Evaporative Ionization Mass Spectrometry (LA-REIMS) is a quick and efficient method for characterizing complex biological samples without laborious sample preparation and chemical separation. Therefore, using an automated LA-REIMS well plate reader as fast as 8 seconds per sample, we assessed the oxidative metabolic stability of active agents using biomimetic metalloporphyrin-based oxidative model reactions at various pH for commercially available drug substances and compared stability measurements with traditional HPLC-DAD-MS results.

Although the frequency of myocarditis in the general population is very difficult to accurately determine due to the large number of asymptomatic cases, the incidence of this disease is increasing significantly due to better defined criteria for diagnosis and the development of modern diagnostic method. The multitude of different etiological factors, the diversity of the clinical picture and the variability of the diagnostic findings make this disease often demanding both for the selection of the diagnostic modality and for the proper therapeutic approach. The previously known most common viral etiology of this disease is today overshadowed by new findings based on immune-mediated processes, associated diseases that in their natural course can lead to myocardial involvement, but also the iatrogenic cause of myocarditis due to use of immune checkpoint inhibitors in the treatment of cancer patients. Suspecting that a patient with polymorphic and non-specific clinical signs and symptoms, changes in ECG and echocardiography has myocarditis is the starting point in the diagnostic algorithm. Cardio magnetic resonance imaging is non-invasive diagnostic gold standard for diagnosis and clinical follow-up of thses patients. Endomyocardial biopsy as an invasive method is the diagnostic choice in life-threatening patients with suspicion of fulminant myocarditis where the diagnosis has not yet established or there is no adequate response to the applied therapeutic regimen. The treatment of myocarditis is increasingly demanding and includes conservative methods of treating heart failure, immunomodulatory and immunospressive therapy, methods of mechanical circulatory support and heart transplantation. The goal of developing new diagnostic and therapeutic methods is to reduce mortality from this complex disease, which is still high.