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Abstract We study the main decomposition approaches (primal, dual and primal–dual) for a distributed optimization problem from a dynamical system perspective where the couplings among the variables of the optimization problem are described by an undirected, unweighted hypergraph. We conduct stability analysis for the respective dynamical systems of the decomposition cases by using non linear decentralized control theoretic techniques and spectral properties of the respective communication matrices, i.e., the incidence and the Laplacian matrices of the hypergraph. Finally, we provide numerical simulations under a specific coalitional setting that demonstrate the superiority of the hypergraph compared to its respective graph analogue, the clique expansion graph, for the given decomposition algorithms in terms of convergence rate and information transmission efficiency.

Abstract The aim of this study is to compare the diagnostic performance of magnetic resonance imaging (MRI) against computed tomography (CT) in various aspects of local staging in colon cancer patients. This study was a prospective single arm diagnostic accuracy study. All consecutive adult patients with confirmed colon cancer that met the current criteria for surgical resection were considered as eligible. Diagnostic performance assessment included T (T1/T2 vs T3/T4 and T3cd) and N (N positive) staging, serosa and retroperitoneal surgical margin (RSM) involvement and extramural vascular invasion (EMVI). Imaging was based on a 3 Tesla MRI system and the evaluation of all sequences (T1, T2 and diffusion-weighted imaging-DWI series) by two independent readers. CT scan was performed in a 128 row multidetector (MD) CT scanner (slice thickness: 1 mm) with intravenous contrast. Pathology report was considered as the gold standard for local staging. Sensitivity (SE), specificity (SP), and area under the curve (AUC) were calculated for both observers. MRI displayed a higher diagnostic performance over CT in terms of T1/T2 vs T3/T4 (SE: 100% vs 83.9%, SP: 96.6% vs 81%, AUC: 0.825 vs 0.983, p

Abstract Background In response to the global scope of forced displacement, international organizations highlight the need of scalable solutions to support individuals’ health and integration into host societies. Exposure to high mental and physical stress perceived before, during, and after displacement can impair functional capabilities, essential for adapting to a new environment. This secondary analysis examined the impact of an exercise and sport intervention on cognitive function and pain severity among individuals living in a refugee camp in Greece. Methods We implemented a randomized controlled trial involving n = 142 (52.8% women) forcibly displaced individuals from Southwest Asia and Sub-Saharan Africa. Participants were randomly assigned to a waitlist or a 10-week co-designed exercise and sport intervention with a 1:1 allocation rate between groups and sexes. Assessments at baseline and follow-up included the Flanker task, the Oddball paradigm, pain severity via visual analog scales, and the Åstrand-Rhyming indirect test of maximal oxygen uptake. We analyzed the intervention effects using structural equation modeling. Results Our findings did not indicate a direct intervention effect on cognitive function or pain (p ≥ .332). However, the intervention group significantly improved cardiorespiratory fitness, ß = .17, p = .010, which was associated with faster reaction times in cognitive tasks, ß = − .22, p = .004. Moreover, there was some evidence that adherence might be linked to reduced pain severity, ß = − .14, p = .065. Conclusions Exercise and sport did not directly impact cognitive function and pain severity among a sociodemographically diverse sample living in a refugee camp, suggesting the need for complementary measures. Nevertheless, our results indicate that improvements in cardiorespiratory fitness benefit aspects of attention. Trial registration The study was approved by the local ethics committee of the University of Thessaly (no. 39) and registered prospectively on February 8, 2021 at the ISRCTN registry (no. 16291983).

Abstract The primary objective of this manuscript is to investigate the existence and uniqueness of solutions for the Langevin ( k , φ ) $(\mathtt{k},\varphi )$ -Hilfer fractional differential equation of different orders with multipoint nonlocal fractional integral boundary conditions. We consider the generalized version of the Hilfer fractional diferential equation called as ( k , φ ) $(\mathtt{k},\varphi )$ -Hilfer fractional differential equation. We provide some significant outcomes about ( k , φ ) $(\mathtt{k},\varphi )$ -Hilfer fractional Langevin differential equation that requires deriving equivalent fractional integral equation to ( k , φ ) $(\mathtt{k},\varphi )$ -Hilfer Langevin fractional differential equation. The existence result is established using the Krasnoselskii’s fixed-point theorem, while the uniqueness is addressed with the help of Banach contraction principle. Additionally, we investigate the different forms of Ulam stability for the solution of the mentioned problem, under specific conditions. To validate our main outcomes, we present a detailed example at the end of the manuscript.

Abstract Background Dyslipidemia represents an important risk factor for cardiovascular diseases, although its optimal management after kidney transplantation remains unclear. The present meta-analysis aimed to shed light on the efficacy and safety of statins among kidney transplant recipients, evaluating their potential effects on the risk of cardiovascular events, mortality and graft survival. Methods Medline, Scopus, Web of Science, CENTRAL, Clinicaltrials.gov and Google Scholar were systematically searched from their inception through April 20, 2024. Both randomized controlled trials and observational studies evaluating the effects of statin administration after kidney transplantation were held eligible. Random-effects models were fitted using the maximum likelihood method, while the certainty of evidence was appraised following the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach. Results Overall, 27 studies (10 randomized controlled trials and 17 observational studies) were included. Statin use compared to no use was associated with a lower risk of major adverse cardiovascular events [Relative risk (RR): 0.87, 95% confidence interval (CI): 0.67–0.96, moderate certainty] and overall mortality (RR: 0.84, 95% CI: 0.74–0.94, low certainty). The risk of graft loss did not differ between the compared groups (RR: 0.72, 95% CI: 0.48–1.08, very low certainty). Regarding safety endpoints, statin use was associated with a lower risk of hepatotoxicity (RR: 0.81, 95% CI: 0.70–0.93, moderate certainty), but with a greater risk of rhabdomyolysis (RR: 1.37, 95% CI: 1.10–1.70, low certainty) and cataract (RR: 1.22, 95% CI: 1.14–1.31, moderate certainty). No statistically significant differences between the compared groups with and without statin use were observed concerning the risk of creatine kinase elevation, post-transplant diabetes mellitus, hip fracture, venous thromboembolism, or cancer. Conclusions Among kidney transplant recipients, statin use is associated with a lower risk of cardiovascular events and better patient survival, presenting an acceptable safety profile. Further large-scale studies are needed to determine the optimal statin dosing strategy and lipid-lowering goals, depending on comorbidities and immunosuppression regimens. Registration https://doi.org/10.17504/protocols.io.5qpvok3yzl4o/v1 .

Abstract The generation of laser pulses with controlled optical waveforms, and their measurement, lie at the heart of both time-domain and frequency-domain precision metrology. Here, we obtain mid-infrared waves via intra-pulse difference-frequency generation (IPDFG) driven by 16-femtosecond near-infrared pulses, and characterise the jitter of sub-cycle fractions of these waves relative to the gate pulses using electro-optic sampling (EOS). We demonstrate sub-attosecond temporal jitter at individual zero-crossings and sub-0.1%-level relative amplitude fluctuations in the 10-kHz–0.625-MHz band. Chirping the nearly-octave-spanning mid-infrared pulses uncovers wavelength-dependent attosecond-scale waveform jitter. Our study validates EOS as a broadband (both in the radio-frequency and the optical domains), highly sensitive measurement technique for the jitter dynamics of optical waveforms. This sensitivity reveals outstanding stability of the waveforms obtained via IPDFG and EOS, directly benefiting precision measurements including linear and nonlinear (infrared) field-resolved spectroscopy. Furthermore, these results form the basis toward EOS-based active waveform stabilisation and sub-attosecond multi-oscillator synchronisation/delay tracking.

Abstract Objectives To analyse clinical outcomes of a non-medical switch from originator adalimumab (ADA) to its ABP501 biosimilar (ABP) over 6 months in patients with inflammatory rheumatic musculoskeletal diseases (RMD) in relation to comorbidity as a risk factor for therapy discontinuation. Methods RMD patients switching from originator ADA to ABP were identified from a large routine database from October 2018 onwards. Documented clinical data at the time of non-medical switching (baseline), and at 3 and 6 months were collected. Comorbidities were represented by the Charlson Comorbidity Index (CCI) at baseline and patients were categorized based on CCI > 0. Differences in the ABP retention rate over 6 months between patients with CCI = 0 and patients with CCI > 0 were analysed using Bayesian exponential regression. Results A total of 111 patients with axial spondyloarthritis (n = 68), rheumatoid arthritis (n = 23) and psoriatic arthritis (n = 15), were identified, 74.8% of whom had continued treatment with ABP after 6 months, while a smaller proportion had either switched to another ADA biosimilar (10.8%), switched back to originator ADA (7.2%), switched to a different biologic (3.6%), or dropped out (3.6%). At baseline, a CCI > 0 was found in 38% of patients. Cardiovascular comorbidities (40%) were most prevalent followed by diseases of the skin (33%), the gastrointestinal tract (20%) and the eye (20%). ABP treatment was continued after 6 months in 74% of patients with CCI = 0 and in 76% with CCI > 0. Bayesian analysis showed only a small difference (months) in the APB continuation rate between groups (estimate 0.0012, 95% credible interval (CrI) -0.0337 to 0.0361). Adjusting for age, sex, and disease subtype revealed somewhat shorter retention rates for patients with CCI > 0, but the distribution of the difference included 0 (estimate -0.0689, 95% CrI -0.2246 to 0.0234). Conclusion In a non-medical switch scenario of RMD patients, there was no evidence for a considerable difference in ABP retention rates over 6 months between comorbidity groups.

Abstract Affectivism is a research trend dedicated to the study of emotions and their role in cognition and human behavior. Affectivism both complements and competes with cognitivism, which typically neglects affect in explaining behavior. By the nature of their subject, both affectivism and cognitivism constitute fertile grounds for studying the confluence of conceptual knowledge from diverse disciplines, which is often credited with major breakthroughs and is known as convergence science. Analyzing over half a million relevant publications from PubMed, selected according to psychologist chosen MeSH terms, we find that affectivism yields higher impact than cognitivism, as measured through normalized citations. Importantly, this higher impact is strongly associated with higher multidisciplinarity in the citations of affectivism publications but lower multidisciplinarity in the papers themselves. Hence, the case of affectivism suggests that research content of low topical diversity but broad value can generate strong and wide-ranging scholarly impact, feeding downstream convergence.

Abstract Background The effectiveness of crisis response can be influenced by various structural, cultural, and functional aspects within a social system. This study uses a configurational approach to identify combinations of sociopolitical conditions that lead to a high case fatality rate (CFR) of COVID-19 in OECD countries. Methods A Fuzzy set qualitative comparative analysis (QCA) is conducted on a sample of 38 OECD countries. The outcome to be explained is high COVID-19 CFR. The five potentially causal conditions are level of democracy, state capacity, trust in government, health expenditure per capita, and the median age of population. A comprehensive QCA robustness test protocol is applied, which includes sensitivity ranges, fit-oriented robustness, and case-oriented robustness tests. Results None of the causal conditions in both the presence and negation form were found to be necessary for high or low levels of COVID-19 CFR. Two different combinations of sociopolitical conditions were usually sufficient for the occurrence of a high CFR of COVID-19 in OECD countries. Low state capacity and low trust in government are part of both recipes. The entire solution formula covers 84 percent of the outcome. Some countries have been identified as contradictory cases. The explanations for their COVID-19 CFR require more in-depth case studies. Conclusions From a governance perspective, the weakness of government in effectively implementing policies, and the citizens’ lack of confidence in their government, combined with other structural conditions, serve as barriers to mounting an effective response to COVID-19. These findings can support the idea that the effects of social determinants of COVID-19 outcomes are interconnected and reinforcing.

Introduction: Clear cell sarcoma (CCS) of soft tissue is a rare type of soft tissue sarcoma affecting usually lower extremities in young adults. The main challenges in the management of this disease include difficulties in diagnosis, aggressiveness of the cancer with rapid progression, and inadequate treatment, especially in small centers with few cases. Case Presentation: We present a case of a young woman diagnosed with CCS of soft tissue, stage IV. The patient benefited from a multidisciplinary approach including radiation therapy, surgery, chemotherapy, and targeted therapy with disease progression regardless of the therapeutic act. Despite all the efforts, the patient died from complications overlapping progression of the disease. Conclusion: The rarity of this sarcoma limits the amount of information available on the diagnosis and treatment process. The particularity of this case is the difficulty met in maintaining the disease under control using all the resources available due to lack of compliance of the patient in carrying out amputation at diagnosis, thus modifying the entire treatment algorithm. Targeted therapy showed promising results in the literature, however in our case resulted in an unexpected, rare adverse event aggravating the patient’s condition. In conclusion, patients with CCS should be referred to specialized centers for adequate multidisciplinary management and, if available, inclusion in clinical trials. New agents are needed to improve the survival of these patients.

Abstract We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

In the context of rapid urbanization and in­creasing population density, the livability of cities has become a major topic of interest for authorities and researchers. This paper explores the concept of livability, highlighting its historical evolution and its interaction with notions such as quality of life and sustainability.Using the PRISMA methodology for a system­atic literature review, the paper identifies the deter­minants of livability and analyzes the various defi­nitions and measurements associated with it. Addi­tionally, case studies from Vienna and Copenhagen are presented as examples of best practices in enhancing urban livability. The paper emphasiz­es the importance of an integrated approach that combines objective and subjective factors to create sustainable and pleasant urban environments for residents.

The insurance contract is a voluntary agreement between the insured and the insurer whereby the latter offers the former the value of the damages, within the limit of the insured amount, in the event of the occurrence of the (insured) risk, in exchange for the payment of the insurance premium made by the insured. The degree of technicality of the insurance contract results from its content, which is why specific legislation is intended for this type of contract. The elements of the insurance contract that we analyze in this paper are the insurance premium, the insurance indemnity, the interest in the insurance, the insured risk, the insured event (casualty), the damage or loss, the insured amount, the franchize, and the duration of the insurance.

Abstract Background Neuroblastoma (NB) is a heterogeneous embryonal malignancy and the deadliest tumor of infancy. It is a complex disease that can result in diverse clinical outcomes. In some children, tumors regress spontaneously. Others respond well to existing treatments. But for the high-risk group, which constitutes approximately 40% of all patients, the prognosis remains dire despite collaborative efforts in basic and clinical research. While its exact cellular origin is still under debate, NB is assumed to arise from the neural crest cell lineage including multipotent Schwann cell precursors (SCPs), which differentiate into sympatho-adrenal cell states eventually producing chromaffin cells and sympathoblasts. Methods To investigate clonal development of neuroblastoma cell states, we performed haplotype-specific analysis of human tumor samples using single-cell multi-omics, including joint DNA/RNA sequencing of sorted single cells (DNTR-seq). Samples were also assessed using immunofluorescence stainings and fluorescence in-situ hybridization (FISH). Results Beyond adrenergic tumor cells, we identify subpopulations of aneuploid SCP-like cells, characterized by clonal expansion, whole-chromosome 17 gains, as well as expression programs of proliferation, apoptosis, and a non-immunomodulatory phenotype. Conclusion Aneuploid pre-malignant SCP-like cells represent a novel feature of NB. Genetic evidence and tumor phylogeny suggest that these clones and malignant adrenergic populations originate from aneuploidy-prone cells of migrating neural crest or SCP origin, before lineage commitment to sympatho-adrenal cell states. Our findings expand the phenotypic spectrum of NB cell states. Considering the multipotency of SCPs in development, we suggest that the transformation of fetal SCPs may represent one possible mechanism of tumor initiation in NB with chromosome 17 aberrations as a characteristic element.

Abstract Scandinavian electronic health-care registers provide a unique setting to investigate potential unidentified side effects of drugs. We analysed the association between prescription drugs dispensed in Norway and Sweden and the short-term risk of developing pulmonary embolism. A total of 12,104 pulmonary embolism cases were identified from patient- and cause-of-death registries in Norway (2004–2014) and 36,088 in Sweden (2005–2014). A case-crossover design was used to compare individual drugs dispensed 1–30 days before the date of pulmonary embolism diagnosis with dispensation in a 61–90 day time-window, while controlling for the receipt of other drugs. A BOLASSO approach was used to select drugs that were associated with short-term risk of pulmonary embolism. Thirty-eight drugs were associated with pulmonary embolism in the combined analysis of the Norwegian and Swedish data. Drugs associated with increased risk of pulmonary embolism included certain proton-pump inhibitors, antibiotics, antithrombotics, vasodilators, furosemide, anti-varicose medications, corticosteroids, immunostimulants (pegfilgrastim), opioids, analgesics, anxiolytics, antidepressants, antiprotozoals, and drugs for cough and colds. Mineral supplements, hydrochlorothiazide and potassium-sparing agents, beta-blockers, angiotensin 2 receptor blockers, statins, and methotrexate were associated with lower risk. Most associations persisted, and several additional drugs were associated, with pulmonary embolism when using a longer time window of 90 days instead of 30 days. These results provide exploratory, pharmacopeia-wide evidence of medications that may increase or decrease the risk of pulmonary embolism. Some of these findings were expected based on the drugs' indications, while others are novel and require further study as potentially modifiable precipitants of pulmonary embolism.

Abstract Basal Cell Adhesion Molecule (BCAM), a receptor for laminin subunit α5, plays a crucial role in the pathogenesis of various malignancies. Notably, evidence of hypermethylation at multiple immune checkpoints in patients with low BCAM expression suggests these individuals may respond favorably to immunotherapy using ICIs (immune checkpoint inhibitors). This finding lays the foundation for the hypothesis that BCAM may serve as an important biomarker in cancer patients. To investigate this potential, we evaluated BCAM expression patterns in 3114 patients from both discovery and validation cohorts, spanning seven cancer types, using quantitative immunofluorescence (QIF). We also explored the correlation between BCAM and PD-L1 expressions within these cohorts, aiming to establish its potential predictive value for immunotherapy response. Our findings indicate that BCAM was highly expressed in ovarian (79.2%) and lung (78.5%) tumors, with lower yet significant expression in breast (37.7%), head and neck (31.3%), and bladder-urothelial tumors (27.6%). Notably, high BCAM expression was associated with better OS in NSCLC. More importantly, BCAM expression did not correlate with PD-L1 protein expression in any of these tumors, highlighting its independent predictive potential. The widespread expression of BCAM across multiple tumor types, coupled with its lack of correlation with PD-L1 expression, highlights its potential as a predictive novel biomarker across various cancer types.

Abstract Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)−2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.

Radioactivity in the marine environment, although present since the Earth’s formation, is comparatively understudied in contrast to aerial and terrestrial environments. A thorough examination of the radioactivity levels in aquatic environments can establish a robust foundation for comprehending various geochemical processes and phenomena within the water column and near the seabed, and as a result estimate the impact of radioactivity on local ecosystems. To achieve this objective, in-situ, long-term, and continuous monitoring is required. The present part I of the white paper highlights the fundamentals of marine radioactivity, describes the main objectives of an ambitious EU-funded project (RAMONES: Radioactivity Monitoring in Ocean Ecosystems) and introduces the innovative aspects of the technology developed as novel solutions to open problems.

Acromegaly is a rare endocrine disorder characterized by the excessive production of growth hormone (GH) in adulthood. Currently, it is understood that certain pituitary neuroendocrine tumors (PitNETs) exhibit a hereditary predisposition. These tumors’ genetic patterns fall into two categories: isolated and syndromic tumors. The isolated forms are characterized by molecular defects that predispose exclusively to PitNETs, including familial isolated pituitary adenomas (FIPAs) and sporadic genetic defects not characterized by hereditary predisposition. All the categories involve either germline or somatic mutations, or both, each associated with varying levels of penetrance and different phenotypes. This highlights the importance of genetic testing and the need for a more comprehensive view of the whole disease. Despite the availability of multiple treatment options, diagnosis often occurs after several years, and management is still difficult. Early detection and intervention are crucial for preventing complications and enhancing the quality of life for affected individuals. This review aims to elucidate the molecular, clinical, and histological characteristics of GH-secreting PitNETs, providing insights into their prevalence, treatment nuances, and the benefits of genetic testing for each type of genetic disorder associated with acromegaly.

Fibroblast growth factor 21 (FGF21) is a hormone involved in regulating the metabolism, energy balance, and glucose homeostasis, with new studies demonstrating its beneficial effects on the heart. This study investigated the relationship between FGF21 levels and clinical, biochemical, and echocardiographic parameters in patients with acute coronary syndromes (ACSs). This study included 80 patients diagnosed with ACS between May and July 2023, categorized into four groups based on body mass index (BMI): Group 1 (BMI 18.5–24.9 kg/m2), Group 2 (BMI 25–29.9 kg/m2), Group 3 (BMI 30–34.9 kg/m2), and Group 4 (BMI ≥ 35 kg/m2). Serum FGF21 levels were measured by ELISA (Abclonal Catalog NO.: RK00084). Serum FGF21 levels were quantifiable in 55 samples (mean ± SD: 342.42 ± 430.17 pg/mL). Group-specific mean FGF21 levels were 238.98 pg/mL ± SD in Group 1 (n = 14), 296.78 pg/mL ± SD in Group 2 (n = 13), 373.77 pg/mL ± SD in Group 3 (n = 12), and 449.94 pg/mL ± SD in Group 4 (n = 16), with no statistically significant differences between groups (p = 0.47). Based on ACS diagnoses, mean FGF21 levels were 245.72 pg/mL for STEMI (n = 21), 257.89 pg/mL for NSTEMI (n = 9), and 456.28 pg/mL for unstable angina (n = 25), with no significant differences observed between these diagnostic categories. Significant correlations were identified between FGF21 levels and BMI, diastolic blood pressure, and serum chloride. Regression analyses revealed correlations with uric acid, chloride, and creatinine kinase MB. This study highlights the complex interplay between FGF21, BMI, and acute coronary syndromes. While no significant differences were found in FGF21 levels between the different BMI and ACS diagnostic groups, correlations with clinical and biochemical parameters suggest a multifaceted role of FGF21 in cardiovascular health. Further research with a larger sample size is warranted to elucidate these relationships.

Children’s mental health symptoms’ development can be characterized by both continuity and discontinuity. However, existing studies ignore the potential discontinuity in children’s internalizing symptoms’ development. Hence, the current study examines continuous and discontinuous developmental trajectories using representative data from a sample of 2792 children (49.10% females) from the Growing Up in Australia cohort assessed seven times (ages 4, 6, 8, 10, 12, 14, 16). Longitudinal measurement invariance analyses revealed that internalizing symptoms were comparable over time. Linear, quadratic, and piecewise latent growth curve models were deployed to estimate the trajectory of internalizing symptoms from early childhood to late adolescence. The analyses showed that internalizing symptoms were characterized by a quadratic-quadratic piecewise growth curve comprising two distinct phases of upward concave growth. Internalizing scores reduced steadily between ages 4 and 8 years but exhibited a slight upward curvature between ages 8 and 10 years. By age 14 years, the trajectory remained relatively stable but spiked between age 14 and 16 years. The two phases of internalizing symptoms’ development were largely unrelated. Overall, the study adds to the knowledge about the development of internalizing mental health from early childhood to late adolescence and highlights the need for additional support in late adolescence.

In contemporary narratives, rural landscapes and identities, as judged by the inhabitants’ sense of belonging, continue to be important points that need to be (re)considered when discussing places as instruments for local development. This paper pushes forward these debates and explores the construction of rural and regional identity in Romania with the help of a case study that focuses on perceptions of rural landscapes as cultural heritage in two rural communities situated on opposite sides of the river Mureș. Based on participant and ethnographic observation and making use of a survey and a qualitative analysis, this paper highlights the most significant features of the local cultural identities and their rural landscape heritage expressed by the two sets of people, which often coincide with the most important characteristics attributed to the regions separated by the river Mureș. The results of this study underline the dividing role of the river in the preservation of rural identity and cultural heritage. They also demonstrate that rural landscapes and the construction of identities along the river have generated both development opportunities and various risks.

To ensure resource security, to have access to resources for a sufficiently long period of time, it is necessary to take action to diversify the sources of raw and secondary materials, to reduce dependence on particular sources and to increase resource efficiency and circularity. It is generally valid for all raw materials, including basic raw materials, but especially for critical raw materials. In this paper we analyse what are the critical raw material resources at global and European level, the legislation in this field and the main challenges countries are facing at the moment.

The analysis of data concerning non-bank financial institutions in Romania reveals a consistent increase in loan issuance over the past 11 years, especially in the context of the pandemic. The excessive growth in the number of loans has generated an elevated risk of non-repayment, necessitating careful debtor management. Warning signs, such as decreasing available funds and payment delays, represent critical points for assessing credit risk. National-level analysis underscores the importance of implementing preventive measures to avoid the risk of bankruptcy. Non-bank financial institutions must adopt proactive and adaptable strategies to efficiently manage the loan portfolio and ensure the long-term stability of the financial sector.

Non-banking financial institutions (NBFI), including microfinance institutions (MFIs), pawnshops, leasing companies, and insurance corporations, have become essential for financing the Romanian economy, contributing to the diversification of funding sources and supporting economic growth. NBFI have demonstrated their ability to provide flexible and accessible financing solutions, particularly during crises. As of the end of 2022, lending activities constituted the majority of NBFI portfolios, with consumer loans being the primary source of household financing. Loans extended to non-financial corporations experienced significant growth, with many denominated in euros. Additionally, there has been an increase in loans granted to non-residents. Between 2019 and 2023, outstanding balances decreased as a percentage of total amounts owed, while the number of debtors with arrears saw a slight increase. In the European context, NBFI have become increasingly important for financing non-financial corporations, indicating a significant rise in the proportion of loans provided by these institutions. These developments underscore the pivotal role of NBFI both domestically and globally.

In this study, we investigated the performance improvement caused by the addition of copper (Cu) nanoparticles to high-density polyethylene (HDPE) matrix material. Composite materials, with filler percentages of 0.0, 2.0, 4.0, 6.0, 8.0, and 10.0 wt% were synthesized through the material extrusion (MEX) 3D printing technique. The synthesized nanocomposite filaments were utilized for the manufacturing of specimens suitable for the experimental procedure that followed. Hence, we were able to systematically investigate their tensile, flexural, impact, and microhardness properties through various mechanical tests that were conducted according to the corresponding standards. Broadband Dielectric Spectroscopy was used to investigate the electrical/dielectric properties of the composites. Moreover, by employing means of Raman spectroscopy and thermogravimetric analysis (TGA) we were also able to further investigate their vibrational, structural, and thermal properties. Concomitantly, means of scanning electron microscopy (SEM), as well as atomic force microscopy (AFM), were used for the examination of the morphological and structural characteristics of the synthesized specimens, while energy-dispersive X-ray spectroscopy (EDS) was also performed in order to receive a more detailed picture on the structural characteristics of the various synthesized composites. The corresponding nanomaterials were also assessed for their antibacterial properties regarding Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) with the assistance of a method named screening agar well diffusion. The results showed that the mechanical properties of HDPE benefited from the utilization of Cu as a filler, as they showed a notable improvement. The specimen of HDPE/Cu 4.0 wt% was the one that presented the highest levels of reinforcement in four out of the seven tested mechanical properties (for example, it exhibited a 36.7% improvement in the flexural strength, compared to the pure matrix). At the same time, the nanocomposites were efficient against the S. aureus bacterium and less efficient against the E. coli bacterium. The use of such multi-functional, robust nanocomposites in MEX 3D printing is positively impacting applications in various fields, most notably in the defense and security sectors. The latter becomes increasingly important if one takes into account that most firearms encompass various polymeric parts that require robustness and improved mechanical properties, while at the same time keeping the risk of spreading various infectious microorganisms at a bare minimum.

Abstract Several non‐coding RNAs are known to be associated with the pathobiology and progression of multiple myeloma (MM). ciRS‐7 (also known as CDR1‐AS), a key oncogenic circular RNA (circRNA) that sponges miR‐7‐5p and other cancer‐related microRNAs, was recently found to be downregulated in malignant plasma cells resistant to immunomodulatory drugs. Considering that various circRNAs have a strong potential as molecular biomarkers, we aimed to investigate the expression of ciRS‐7 in plasma cell disorders, assess its prognostic importance in MM, and compare these findings with those of individuals with smoldering MM (SMM) and monoclonal gammopathy of unknown significance (MGUS). This study included 171 patients (110 newly diagnosed MM, 34 SMM, and 27 MGUS cases), from which bone marrow aspirate samples were collected for CD138+ plasma cell selection. Total RNA was reversely transcribed using random hexamer primers, and the expression levels of ciRS‐7 were quantified using an in‐house‐developed protocol that includes pre‐amplification and real‐time quantitative polymerase chain reaction. ciRS‐7 levels were found to significantly differ among CD138+ plasma cells of MM, SMM, and MGUS patients. ROC analysis indicated that ciRS‐7 expression effectively distinguishes between MM and SMM patients. Moreover, high levels of ciRS‐7 were associated with unfavorable prognosis in MM, independently of MM patients’ age and Revised International Staging System stage. Additionally, in silico analysis predicted the binding of 85 microRNAs to ciRS‐7. In conclusion, this study provides novel insights into the role of ciRS‐7 as a promising molecular marker able to distinguish MM from SMM and predict prognosis in MM.

Abstract Background Age-related macular degeneration (AMD) is a prevalent ocular pathology affecting mostly the elderly population. AMD is characterized by a progressive retinal pigment epithelial (RPE) cell degeneration, mainly caused by an impaired antioxidative defense. One of the AMD therapeutic procedures involves injecting healthy RPE cells into the subretinal space, necessitating pure, healthy RPE cell suspensions. This study aims to electrically characterize RPE cells to demonstrate a possibility using simulations to separate healthy RPE cells from a mixture of healthy/oxidized cells by dielectrophoresis. Methods BPEI-1 rat RPE cells were exposed to hydrogen peroxide to create an in-vitro AMD cellular model. Cell viability was evaluated using various methods, including microscopic imaging, impedance-based real-time cell analysis, and the MTS assay. Healthy and oxidized cells were characterized by recording their dielectrophoretic spectra, and electric cell parameters (crossover frequency, membrane conductivity and permittivity, and cytoplasm conductivity) were computed. A COMSOL simulation was performed on a theoretical microfluidic-based dielectrophoretic separation chip using these parameters. Results Increasing the hydrogen peroxide concentration shifted the first crossover frequency toward lower values, and the cell membrane permittivity progressively increased. These changes were attributed to progressive membrane peroxidation, as they were diminished when measured on cells treated with the antioxidant N-acetylcysteine. The changes in the crossover frequency were sufficient for the efficient separation of healthy cells, as demonstrated by simulations. Conclusions The study demonstrates that dielectrophoresis can be used to separate healthy RPE cells from oxidized ones based on their electrical properties. This method could be a viable approach for obtaining pure, healthy RPE cell suspensions for AMD therapeutic procedures.

Abstract Standardized assessment of the gastroesophageal valve during endoscopy, attainable via the Hill classification, is important for clinical assessment and therapeutic decision making. The Hill classification is associated with the presence of hiatal hernia (HH), a common endoscopic finding connected to gastro-esophageal reflux disease. A novel efficient medical artificial intelligence (AI) training pipeline using active learning (AL) is designed. We identified 21,970 gastroscopic images as training data and used our AL to train a model for predicting the Hill classification and detecting HH. Performance of the AL and traditionally trained models were evaluated on an external expert-annotated image collection. The AL model achieved accuracy of 76%. A traditionally trained model with 125% more training data achieved 77% accuracy. Furthermore, the AL model achieved higher precision than the traditional one for rare classes, with 0.54 versus 0.39 (p

Abstract Aesthetic preference is intricately linked to learning and creativity. Previous studies have largely examined the perception of novelty in terms of pleasantness and the generation of novelty via creativity separately. The current study examines the connection between perception and generation of novelty in music; specifically, we investigated how pleasantness judgements and brain responses to musical notes of varying probability (estimated by a computational model of auditory expectation) are linked to learning and creativity. To facilitate learning de novo, 40 non-musicians were trained on an unfamiliar artificial music grammar. After learning, participants evaluated the pleasantness of the final notes of melodies, which varied in probability, while their EEG was recorded. They also composed their own musical pieces using the learned grammar which were subsequently assessed by experts. As expected, there was an inverted U-shaped relationship between liking and probability: participants were more likely to rate the notes with intermediate probabilities as pleasant. Further, intermediate probability notes elicited larger N100 and P200 at posterior and frontal sites, respectively, associated with prediction error processing. Crucially, individuals who produced less creative compositions preferred higher probability notes, whereas individuals who composed more creative pieces preferred notes with intermediate probability. Finally, evoked brain responses to note probability were relatively independent of learning and creativity, suggesting that these higher-level processes are not mediated by brain responses related to performance monitoring. Overall, our findings shed light on the relationship between perception and generation of novelty, offering new insights into aesthetic preference and its neural correlates.

Abstract HMGA1 is an abundant non-histone chromatin protein that has been implicated in embryonic development, cancer, and cellular senescence, but its specific role remains elusive. Here, we combine functional genomics approaches with graph theory to investigate how HMGA1 genomic deposition controls high-order chromatin networks in an oncogene-induced senescence model. While the direct role of HMGA1 in gene activation has been described previously, we find little evidence to support this. Instead, we show that the heterogeneous linear distribution of HMGA1 drives a specific 3D chromatin organization. HMGA1-dense loci form highly interactive networks, similar to, but independent of, constitutive heterochromatic loci. This, coupled with the exclusion of HMGA1-poor chromatin regions, leads to coordinated gene regulation through the repositioning of genes. In the absence of HMGA1, the whole process is largely reversed, but many regulatory interactions also emerge, amplifying the inflammatory senescence-associated secretory phenotype. Such HMGA1-mediated fine-tuning of gene expression contributes to the heterogeneous nature of senescence at the single-cell level. A similar ‘buffer’ effect of HMGA1 on inflammatory signalling is also detected in lung cancer cells. Our study reveals a mechanism through which HMGA1 modulates chromatin compartmentalization and gene regulation in senescence and beyond.

Abstract Formalin-fixed paraffin-embedded (FFPE) tissue represents a valuable source for translational cancer research. However, the widespread application of various downstream methods remains challenging. Here, we aimed to assess the feasibility of a genomic and gene expression analysis workflow using FFPE breast cancer (BC) tissue. We conducted a systematic literature review for the assessment of concordance between FFPE and fresh-frozen matched tissue samples derived from patients with BC for DNA and RNA downstream applications. The analytical performance of three different nucleic acid extraction kits on FFPE BC clinical samples was compared. We also applied a newly developed targeted DNA Next-Generation Sequencing (NGS) 370-gene panel and the nCounter BC360® platform on simultaneously extracted DNA and RNA, respectively, using FFPE tissue from a phase II clinical trial. Of the 3701 initial search results, 40 articles were included in the systematic review. High degree of concordance was observed in various downstream application platforms. Moreover, the performance of simultaneous DNA/RNA extraction kit was demonstrated with targeted DNA NGS and gene expression profiling. Exclusion of variants below 5% variant allele frequency was essential to overcome FFPE-induced artefacts. Targeted genomic analyses were feasible in simultaneously extracted DNA/RNA from FFPE material, providing insights for their implementation in clinical trials/cohorts.

Abstract Background Structural genomic variants (SVs) are prevalent in plant genomes and have played an important role in evolution and domestication, as they constitute a significant source of genomic and phenotypic variability. Nevertheless, most methods in quantitative genetics focusing on crop improvement, such as genomic prediction, consider only Single Nucleotide Polymorphisms (SNPs). Deep Learning (DL) is a promising strategy for genomic prediction, but its performance using SVs and SNPs as genetic markers remains unknown. Results We used rice to investigate whether combining SVs and SNPs can result in better trait prediction over SNPs alone and examine the potential advantage of Deep Learning (DL) networks over Bayesian Linear models. Specifically, the performances of BayesC (considering additive effects) and a Bayesian Reproducible Kernel Hilbert space (RKHS) regression (considering both additive and non-additive effects) were compared to those of two different DL architectures, the Multilayer Perceptron, and the Convolution Neural Network, to explore their prediction ability by using various marker input strategies. We found that exploiting structural and nucleotide variation slightly improved prediction ability on complex traits in 87% of the cases. DL models outperformed Bayesian models in 75% of the studied cases, considering the four traits and the two validation strategies used. Finally, DL systematically improved prediction ability of binary traits against the Bayesian models. Conclusions Our study reveals that the use of structural genomic variants can improve trait prediction in rice, independently of the methodology used. Also, our results suggest that Deep Learning (DL) networks can perform better than Bayesian models in the prediction of binary traits, and in quantitative traits when the training and target sets are not closely related. This highlights the potential of DL to enhance crop improvement in specific scenarios and the importance to consider SVs in addition to SNPs in genomic selection.

Abstract Background Cupriavidus gilardii is an aerobic, gram-negative, motile, glucose-nonfermenting bacillus, first described in 1999. Typically, it exhibits low pathogenicity in humans, causing opportunistic infections primarily in individuals with compromised immune systems. This bacterium has been also found in various environmental sources such as plants and contaminated soils. Notably, there have been no documented cases of C. gilardii infections in animals. Case presentation This case report outlines a bovine neonatal diarrhea outbreak that occurred in Northern Greece, during which C. gilardii was isolated. Faecal samples from 5-day-old calves were collected and transported to the laboratory for further examination. Bacterial culture and next generation sequencing techniques were employed to confirm the presence of this bacterium in the samples. Following the isolation and identification of C. gilardii from the samples, an autogenous vaccine was produced and administered to the cows within the farm. Subsequent to vaccination, a progressive reduction in calf diarrhea and deaths was observed, leading to their eventual complete resolution. To the best of our knowledge, this represents the first documentation of C. gilardii isolation from cases of bovine neonatal diarrhea. Conclusion This case report presents the first isolation case of C. gilardii from animal samples and more specifically from calf faecal samples. It represents an important observation, providing evidence that this opportunistic human pathogen could contribute to clinical symptoms in animals.

Abstract To survive extreme desiccation, seeds enter a period of quiescence that can last millennia. Seed quiescence involves the accumulation of protective storage proteins and lipids through unknown adjustments in protein homeostasis (proteostasis). Here, we show that mutation of all six type–II metacaspase (MCA–II) proteases in Arabidopsis thaliana disturbs proteostasis in seeds. MCA–II mutant seeds fail to restrict the AAA ATPase CELL DIVISION CYCLE 48 (CDC48) at the endoplasmic reticulum to discard misfolded proteins, compromising seed storability. Endoplasmic reticulum (ER) localization of CDC48 relies on the MCA–IIs-dependent cleavage of PUX10 (ubiquitination regulatory X domain–containing 10), the adaptor protein responsible for titrating CDC48 to lipid droplets. PUX10 cleavage enables the shuttling of CDC48 between lipid droplets and the ER, providing an important regulatory mechanism sustaining spatiotemporal proteolysis, lipid droplet dynamics, and protein homeostasis. In turn, the removal of the PUX10 adaptor in MCA–II mutant seeds partially restores proteostasis, CDC48 localization, and lipid droplet dynamics prolonging seed lifespan. Taken together, we uncover a proteolytic module conferring seed longevity.

Abstract Self-sufficiency, climate change and increasing geopolitical risks have driven energy policies to make renewable energy sources dominant in the power production portfolios. The initial boom in the mid-2000s of global photovoltaic installations demonstrated the feasibility of the ambitious renewable energy targets. However, this rapid scale-up has introduced challenges, including price volatility and system integration issues. This communication calls the attention to these emerging challenges and offers quantitative insights on how rapid adoption of a more diversified photovoltaics deployment strategies can mitigate price volatilities, reduce fossil fuel dependence and steer Europe towards a forward-thinking sustainable energy pathway. The analysis reveals that as innovative bifacial photovoltaic systems are incorporated on a large-scale disruptive scenario, four main patterns emerge: economic value of solar production increases, base-load electricity price decreases, sun-rich countries expand their solar contributions, whereas nations with ample grid interconnections enhance their energy imports from neighbouring countries. It also underscores the importance of maintaining photovoltaics an attractive option for energy investors and traders in the future. Establishing this groundwork is critical since a successful integration of large-scale solar systems contributing to decrease price volatilities in Europe and US will carry significant repercussions for global energy policy formulation.

Abstract Purpose Convolutional Neural Networks (CNNs) have emerged as transformative tools in the field of radiation oncology, significantly advancing the precision of contouring practices. However, the adaptability of these algorithms across diverse scanners, institutions, and imaging protocols remains a considerable obstacle. This study aims to investigate the effects of incorporating institution-specific datasets into the training regimen of CNNs to assess their generalization ability in real-world clinical environments. Focusing on a data-centric analysis, the influence of varying multi- and single center training approaches on algorithm performance is conducted. Methods nnU-Net is trained using a dataset comprising 161 18F-PSMA-1007 PET images collected from four distinct institutions (Freiburg: n = 96, Munich: n = 19, Cyprus: n = 32, Dresden: n = 14). The dataset is partitioned such that data from each center are systematically excluded from training and used solely for testing to assess the model's generalizability and adaptability to data from unfamiliar sources. Performance is compared through a 5-Fold Cross-Validation, providing a detailed comparison between models trained on datasets from single centers to those trained on aggregated multi-center datasets. Dice Similarity Score, Hausdorff distance and volumetric analysis are used as primary evaluation metrics. Results The mixed training approach yielded a median DSC of 0.76 (IQR: 0.64–0.84) in a five-fold cross-validation, showing no significant differences (p = 0.18) compared to models trained with data exclusion from each center, which performed with a median DSC of 0.74 (IQR: 0.56–0.86). Significant performance improvements regarding multi-center training were observed for the Dresden cohort (multi-center median DSC 0.71, IQR: 0.58–0.80 vs. single-center 0.68, IQR: 0.50–0.80, p 0.05; Freiburg: multi-center 0.78, IQR: 0.53–0.87 vs. single-center 0.71, IQR: 0.53–0.83, p = 0.23). Conclusion CNNs trained for auto contouring intraprostatic GTV in 18F-PSMA-1007 PET on a diverse dataset from multiple centers mostly generalize well to unseen data from other centers. Training on a multicentric dataset can improve performance compared to training exclusively with a single-center dataset regarding intraprostatic 18F-PSMA-1007 PET GTV segmentation. The segmentation performance of the same CNN can vary depending on the dataset employed for training and testing.

Abstract Accurate survival prediction for Non-Small Cell Lung Cancer (NSCLC) patients remains a significant challenge for the scientific and clinical community despite decades of advanced analytics. Addressing this challenge not only helps inform the critical aspects of clinical study design and biomarker discovery but also ensures that the ‘right patient’ receives the ‘right treatment’. However, survival prediction is a highly complex task, given the large number of ‘omics; and clinical features, as well as the high degree of freedom that drive patient survival. Prior knowledge could play a critical role in uncovering the complexity of a disease and understanding the driving factors affecting a patient’s survival. We introduce a methodology for incorporating prior knowledge into machine learning–based models for prediction of patient survival through Knowledge Graphs, demonstrating the advantage of such an approach for NSCLC patients. Using data from patients treated with immuno-oncologic therapies in the POPLAR (NCT01903993) and OAK (NCT02008227) clinical trials, we found that the use of knowledge graphs yielded significantly improved hazard ratios, including in the POPLAR cohort, for models based on biomarker tumor mutation burden compared with those based on knowledge graphs. Use of a model-defined mutational 10-gene signature led to significant overall survival differentiation for both trials. We provide parameterized code for incorporating knowledge graphs into survival analyses for use by the wider scientific community.

Abstract Background Type 1 diabetes mellitus (T1DM) is characterized by immune and metabolic dysregulation. Apo1/Fas is implicated in maintaining homeostasis of the immune system. Cytokeratin-18 (cCK-18) is a predictive marker of liver disorders in T2DM. Intercellular adhesion molecule-1 (ICAM-1) is considered to increase susceptibility to diabetes mellitus. All three markers are associated with endothelial function, apoptosis and diabetes-related complications. The possible role of Apo1/Fas, cCK-18 and ICAM-1 was investigated in children and adolescents with T1DM. Method Forty-nine (49) children and adolescents with T1DM and 49 controls were included in the study. Somatometric measurements were obtained and the Body Mass Index (BMI) of the participants was calculated. Biochemical parameters were measured by standard laboratory methods and Apo1/Fas, cCK-18 and ICAM-1 were measured using appropriate ELISA kits. The statistical analysis was performed using the IBM SPSS Statistics 23 program. Results Apo1/Fas (p = 0.001), cCK-18 (p

In this article, we improve the behavior of nonparametric Shewhart-type control charts, which employ order statistics and multiple runs-type rules. The proposed class of monitoring schemes includes some existing control charts. In addition, new distribution-free monitoring schemes that pertain to the class, are set up and examined extensively. Explicit expressions for determining the variability and the mean of the run length distribution for the enhanced control charts are additionally delivered. As an example, a real-life managerial application is considered, where the proposed framework is implemented in order to enhance the provided services of a company under a supply chain management environment. Based on numerical comparisons, we draw the conclusion that the new charts outperform their competitors in identifying potential changes in the fundamental distribution in almost all cases considered.

This article delves into the structure of Iupiter Dolichenus temples, focusing on its sanctuaries in the Danubian Provinces of Dacia, Pannonia Inferior, Pannonia Superior, Raetia, and Noricum. It emphasizes the need for a nuanced understanding of the cult’s role in the religious landscape, cautioning against oversimplified theoretical approaches. Eight Dolichenus cult structures had archaeologically been identified in these provinces (Mehadia, Porolissum, Brigetio, Vetus Salina, Carnuntum I, Carnuntum II, Virunum, Vetoniana), showcasing the cult’s manifestation on a broader scale. The study focuses on analyzing these temples’ architectural features and functionalities, highlighting both differences and similarities. The article aims to provide a detailed examination of each sanctuary, considering phases of construction, alterations, and factors contributing to variations, through the analysis of archaeological finds and architectural characteristics related to the sanctuaries, it seeks to establish patterns and understand the role of specific chambers within these sacred precincts.

Along with several other pre-Roman centers of power along the Lower Danube’s final section, such as Troesmis, Noviodunum, or Aegyssus, Axiopolis (Hinog Hill, Cernavoda, Constanța county) was one of the longest and most intensively occupied archaeological sites on the territory of Dobrudja in ancient times. It was initially a Hellenistic emporium, then an attested strategia of the client Odrysian kings, and later an important military and naval, commercial and religious center in Roman and Middle Byzantine times. During the Principate, the nautae universi Danuvii had their headquarters (collegium) there and it is very likely that a statio portorii of the publicum portorium Illyrici utriusque ripae Thraciae was in place at Axiopolis during the 2nd-3rd centuries AD. During the Dominate, the city with Christian martyrs mentioned by the martyrologies was chosen seat for the pedatura superior of the Scythian legio II Herculia and subsequently raised to the rank of bishopric in the 6th century. Its chronology begins with the hypothetical foundation by Lysimachus and continues to the mid 11th century, under Constantine IX (1042-1055), at the time when the last known coin from Cernavoda dates. The Axiopolis site is located approx. 3 km S of the dobrudjan end of the “King Carol I” bridge at Cernavodă, next to Hinog island, more precisely on a triangular plateau on the right bank of the Danube, at the entrance to a deep valley. It was archaeologically investigated by Pamfil Polonic in 1898-1899 and the results of the excavations were briefly published by Grigore Tocilescu in 1903. Given its importance in ancient times, with its remarkable position on the Danube line and at the mouth of the Carasu valley, Axiopolis remained, unjustly, little known for well over a century. The article aims to systematize the available information and outline the most important moments in the history of the site, based upon the known archaeological data. It includes a systematic description and interpretation of the sequence of the three enclosures of the edifices and artifacts found here, including the numismatic evidence, but also of the limestone quarry that provided building material for the erection of defensive system in the Roman and Middle-Byzantine times.

Ion beam figuring (IBF) is a powerful technique for figure correction of X-ray mirrors to a high accuracy. Here, recent technical advancements in the IBF instrument developed at Diamond Light Source are presented and experimental results for figuring of X-ray mirrors are given. The IBF system is equipped with a stable DC gridded ion source (120 mm diameter), a four-axis motion stage to manipulate the optic, a Faraday cup to monitor the ion-beam current, and a camera for alignment. A novel laser speckle angular measurement instrument also provides on-board metrology. To demonstrate the IBF system's capabilities, two silicon X-ray mirrors were processed. For 1D correction, a height error of 0.08 nm r.m.s. and a slope error of 44 nrad r.m.s. were achieved. For 2D correction over a 67 mm × 17 mm clear aperture, a height error of 0.8 nm r.m.s. and a slope error of 230 nrad r.m.s. were obtained. For the 1D case, this optical quality is comparable with the highest-grade, commercially available, X-ray optics.

Synchrotron light sources require X-ray optics with extremely demanding accuracy for the surface profile, with less than 100 nrad slope errors and sub-nanometre height errors. Such errors are challenging to achieve for aspheres using traditional polishing methods. However, post-polishing error correction can be performed using techniques such as ion beam figuring (IBF) to improve optics to the desired quality. This work presents a brief overview of the history of IBF, introduces some of the challenges for obtaining such demanding figure errors, and highlights the work done at several in-house IBF facilities at synchrotron light sources worldwide to obtain state-of-the-art optical quality.

Capsaicin, the most prominent pungent compound of chilli peppers, has been used in traditional medicine systems for centuries; it already has a number of established clinical and industrial applications. Capsaicin is known to act through the TRPV1 receptor, which exists in various tissues; capsaicin is hepatically metabolised, having a half-life correlated with the method of application. Research on various applications of capsaicin in different formulations is still ongoing. Thus, local capsaicin applications have a pronounced anti-inflammatory effect, while systemic applications have a multitude of different effects because their increased lipophilic character ensures their augmented bioavailability. Furthermore, various teams have documented capsaicin’s anti-cancer effects, proven both in vivo and in vitro designs. A notable constraint in the therapeutic effects of capsaicin is its increased toxicity, especially in sensitive tissues. Regarding the traditional applications of capsaicin, apart from all the effects recorded as medicinal effects, the application of capsaicin in acupuncture points has been demonstrated to be effective and the combination of acupuncture and capsaicin warrants further research. Finally, capsaicin has demonstrated antimicrobial effects, which can supplement its anti-inflammatory and anti-carcinogenic actions.

Introduction: Parkinson’s disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Methods: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. Results: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152–1810) in PRKN carriers and 765 ± 96.6 (range 660–850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. Conclusions: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Whether it is about literature, music, painting, graphic design, advertising, or other creative domains, Artificial Intelligence (AI) finds its way in. The present study aims to offer a pre-generative AI overview on AI creativity perception. It serves as a benchmark that enables future researchers to compare earlier and recent AI advances so to explore the profound technological shifts currently occurring. Focusing on domain comparative empirical dimension, the paper exploratory investigates perceptions on AI creativity, on AI-human co-creation potential, and AI creativity’s ethical and authorship considerations. A set of comparative semi-structured expert interviews with Romanian computer scientists and artists (N=33) is conducted. The data is analyzed using Atlas.ti software. As common grounds for computer scientists and artists, the results show that AI can provide original artworks due to its capacity to manage large amounts of data. However, it is deeply dependent on them. Within the creation process, AI is perceived as a partner or a tool that can augment human abilities. Ethical aspects should be considered both before and after the creation process. Artists, in comparison with computer scientists, emphasize more on the trivialization of the AI creation act and on the unfair and threatening competition. Although they believe that machines should not create, they also agree on machine-centric authorship.

Based on the definition of the γ-order generalized normal, the γ-order generalized standard normal is obtained, and applications are referred. We proceed on the definition of the γ-order generalized chi-square, [Formula: see text] and the probability density function (pdf) is evaluated. Moreover, the moment generating function (mgf) of the [Formula: see text] is evaluated and in the case of γ = 2 the mgf of the well known [Formula: see text] is obtained. The same procedure is followed for the moments of the [Formula: see text] One step forward is the evaluation of the convolution of two [Formula: see text] and therefore [Formula: see text] is obtained eventually and the corresponding pdf is evaluated. Finally examples and applications of [Formula: see text] are discussed.

The supply operation is widely used among professionals, which is why it has imposed the regulation of the relations between them. The supply contract complements the provisions of the sales contract, concerning the effects of the contract, specifically the obligations of the parties: those of the supplier, namely the transfer of ownership of the supplied goods, delivery of goods and provision of services, bearing the risk of loss of the goods up until they are handed over, the warranty obligation for eviction, and the warranty obligation for the defects of the supplied goods, as well as those of the beneficiary, namely taking over the goods and paying the price of the products or services. An aspect that adds specificity to the supply contract is the possibility of subcontracting the supply, which, we believe, raises issues due to the lack of regulation regarding the possibility of changing the price by conventional means.

The traditional perspective on education, teaching, and learning is no longer sufficient in fluid societies exposed to dramatic and rapid changes. The need for continuous educational reform is evident. However, recent paradigmatic societal shifts, extreme events, and extraordinary scientific and technological advances underscore the urgency of these changes. These developments highlight the necessity for innovation and the reduction of intergenerational gaps in educating new generations. By embracing these changes, we can create a more inclusive, adaptable, and innovative educational environment for all. While the Romanian educational system, like many traditional systems, is extensive in its spatial coverage, material resources, human resources, and the number of beneficiaries served, it also presents an opportunity for positive change. Its highly centralized, over-normative, and strictly structured nature, with a top-down control approach, has fostered systemic inertia and resistance to change. However, this also means that with the right strategies, the system can be transformed into a more dynamic and adaptable one. Effective and sustainable reforms are not just the responsibility of policymakers and educational leaders. They require initial assessments of the status quo to identify genuine needs for change and to determine possible obstacles and available resources. Real change and innovation are promoted and supported by a clear definition and understanding of the factors that generate and maintain inertia and resistance to change. Identifying and understanding these complex mechanisms at both the organizational and individual levels should precede any change plan, emphasizing the crucial role of each individual in the process. To identify individual motivations that can generate opposition or resistance to potential change requests within the educational system, we conducted a study involving 293 in-service and pre-service teachers from the Department of Educational Sciences at the West University of Timisoara. The study utilized the Resistance to Change Scale developed by Oreg (2003), a widely recognized and validated tool, which evaluates the primary factors determining resistance to change: routine seeking, emotional reaction, short-term focus, and cognitive rigidity. This scale was administered through a structured questionnaire and the data was analyzed using statistical methods. This study revealed notable variations in attitudes toward change based on gender, residency, and professional status (in-service and pre-service teachers). These findings underscore the importance of addressing both systemic and individual factors to facilitate meaningful and lasting reforms in education. By understanding and mitigating the sources of resistance, educational leaders can implement strategies such as fostering a culture of innovation, providing professional development opportunities, and involving stakeholders in decision-making, that foster a more adaptable and innovative educational environment.