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Abstract Estimation of the energy of quantum many-body systems is a paradigmatic task in various research fields. In particular, efficient energy estimation may be crucial in achieving a quantum advantage for a practically relevant problem. For instance, the measurement effort poses a critical bottleneck for variational quantum algorithms. We aim to find the optimal strategy with single-qubit measurements that yields the highest provable accuracy given a total measurement budget. As a central tool, we establish tail bounds for empirical estimators of the energy. They are helpful for identifying measurement settings that improve the energy estimate the most. This task constitutes an NP-hard problem. However, we are able to circumvent this bottleneck and use the tail bounds to develop a practical, efficient estimation strategy, which we call ShadowGrouping. As the name indicates, it combines shadow estimation methods with grouping strategies for Pauli strings. In numerical experiments, we demonstrate that ShadowGrouping improves upon state-of-the-art methods in estimating the electronic ground-state energies of various small molecules, both in provable and practical accuracy benchmarks. Hence, this work provides a promising way, e.g., to tackle the measurement bottleneck associated with quantum many-body Hamiltonians.

ObjectivesPromoting resilience, the ability to withstand and overcome challenging situations, is crucial for maintaining the performance of healthcare systems. Unique challenges faced by healthcare facilities in border regions render them particularly vulnerable during crises, emphasizing the need to promote resilience in these areas. The current study evaluated the state and needs of resilience in healthcare professionals in a representative European border region.MethodsAll hospitals and emergency medical care services in the Euregio Meuse-Rhine (Germany, Belgium, the Netherlands) were approached to participate via an online-survey. Behavioral data on psychological distress (Patient Health Questionnaire-4), work-related stressors, individual resilience (Brief Resilience Scale, Resilience at Work scale), and organizational resilience (Benchmark Resilience Tool-short) were collected.Results2233 participants initiated the survey with 500 responses included in the analysis. 46% of the participants indicated clinically significant psychological distress. Most challenging stressors were staff availability, available time, and workload. On average, individual resilience was in the normal range, yet 15.6% showed below average resilience. At the organizational level, healthcare institutions can particularly enhance resilience in the domains of Internal resources, Situation Awareness, and Unity of purpose. Compared to their neighbor countries, German healthcare professionals indicated higher levels of depressive symptoms, were more burdened by work-related stressors, and reported lower levels of organizational resilience.ConclusionFindings highlight that healthcare institutions not only need to promote the resilience of the individual employee particularly in border regions, healthcare institutions, must also act to be better prepared for potential threats and crises while considering each country's unique needs.

Background and objectiveOverweight and obesity affects millions of individuals worldwide and consequently represents a major public health concern. Individuals living with overweight and obesity have difficulty maintaining a low body weight due to known physiological mechanisms which prevent further weight loss and drive weight regain. In contrast, mechanisms which promote low body weight maintenance receive less attention and are largely unknown. To uncover these intrinsic mechanisms, we investigated a human cohort of constitutionally thin (CT) individuals which maintain a low body weight and are resistant to weight gain despite exposure to an obesogenic environment.MethodsTo identify novel genes that contribute to low body weight maintenance, we performed transcriptomics on adipose tissue biopsies collected from CT and normal body weight (NBW) individuals and identified sulfotransferase 1A1 (SULT1A1) as a target for further investigation in mice. Sult1a1 knockout (KO) mice were fed a standard diet to assess the impact of Sult1a1 deletion on metabolic traits. To determine if high-fat feeding recapitulated the CT weight gain resistance phenotype, Sult1a1 KO mice were fed a high-fat diet for 13-weeks. A subset of wild-type and Sult1a1 KO mice from the standard diet were further analyzed for characterization of adipose tissue respiratory capacity.ResultsIn comparison to NBW controls, adipose tissue from CT individuals expresses less SULT1A1. Sult1a1 KO mice weigh 10% less at the end of the study period and on a high-fat diet, Sult1a1 KO mice tended to gain less weight and had reduced fat mass at 14-weeks of age. These changes were associated with reduced fasting insulin and lessened adipose tissue inflammation and fibrosis. Subcutaneous adipose tissue from Sult1a1 KO mice on a standard chow diet had elevated leak respiration, uncoupling protein 1 (UCP1) expression and increased expression of a mitochondrial marker, VDAC, associating Sult1a1 deletion to adipose tissue browning.ConclusionsOur results associate Sult1a1 deletion with a tendency for lower body weight through remodeling of white adipose tissue towards a brown phenotype. The presence of UCP1, the expression of an additional mitochondrial protein and increased respiratory capacity suggest browning of the subcutaneous adipose tissue depot of Sult1a1 KO mice.

Nsp14 is an RNA methyltransferase (MTase) encoded by all coronaviruses. In fact, many viral families, including DNA viruses, encode MTases that catalyze the methylation of the RNA precap structure, resulting in fully capped viral RNA. This capping is crucial for efficient viral RNA translation, stability, and immune evasion. Our previous research identified nsp14 inhibitors based on the chemical scaffold of its methyl donor − the S-adenosyl methionine (SAM) − featuring a modified adenine base and a substituted arylsulfonamide. However, the binding mode of these inhibitors was based only on docking experiments. To uncover atomic details of nsp14 inhibition we solved the crystal structure of nsp14 bound to STM957. The structure revealed the atomic details of nsp14 inhibition such that the 7-deaza-adenine moiety of STM957 forms specific interactions with Tyr368, Ala353, and Phe367, while the arylsulfonamide moiety engages with Asn388 and Phe506. The large aromatic substituent at the 7-deaza position displaces a network of water molecules near the adenine base. Surprisingly, this was recently observed in the case of an unrelated monkeypox MTase VP39, where the 7-deaza modified SAH analogs also displaced water molecules from the vicinity of the active site.

Introduction Cardiopulmonary resuscitation (CPR) is among the most important skills in clinical practice. Errors can happen here, just like everywhere, and potentially have severe consequences. Two common error handling strategies known from practice are Error Management (EM) and Error Avoidance (EA). However, its effects on medical performance outcomes remain unclear. This study aimed to examine the role of error framing in basic life support (BLS) training for future healthcare professionals.Materials and Methods In an equivalence trial (N = 430), first-year medical, dentistry, physiotherapy, and midwifery students underwent BLS training. In the three study arms, participants received either (1) instructions framing errors positively (EM), (2) instructions framing errors to be avoided (EA), or (3) no further instructions (Control). CPR performance was assessed using a resuscitation manikin measuring compression depth (CD) and compression rate (CR). The self-confidence ratings were assessed using a questionnaire. Equivalence margins for the outcome parameters and sample size calculations were based on previous standard BLS studies, using two-sided 95% confidence intervals to determine significance of equivalence.Results The results regarding CD revealed equivalence with a trend toward superiority of EM over EA (proportional difference 23.3%-points; 95% CI 11.4%–34.2%) and EM over control (proportional difference 23.4%-points; 95% CI 11.5%–34.2%.) and significant equivalence of EA and control (proportional difference 0.1%-points; 95% CI −11.6%–11.7%). Significant equivalence was determined for all study arms with respect to CR and self-confidence.Conclusion Our study revealed that EM was not detrimental to learners’ CPR performance. Given existing research on long-term beneficial effects of EM on patient safety, coupled with the proven equivalence of EM and EA concerning short-term performance, we argue that EM is a promising approach for future medical education purposes. Raising awareness of error framing and teaching error-handling strategies is expected to benefit ongoing safety management efforts in medical education and beyond.

Abstract The traditional nomenclature of enteroendocrine cells (EECs), established in 1977, applied the “one cell - one hormone” dogma, which distinguishes subpopulations based on the secretion of a specific hormone. These hormone-specific subpopulations included S cells for secretin (SCT), K cells for glucose-dependent insulinotropic polypeptide (GIP), N cells producing neurotensin (NTS), I cells producing cholecystokinin (CCK), D cells producing somatostatin (SST), and others. In the past 15 years, reinvestigations into murine and human organoid-derived EECs, however, strongly questioned this dogma and established that certain EECs coexpress multiple hormones. Using the Gut Cell Atlas, the largest available single-cell transcriptome dataset of human intestinal cells, this study consolidates that the original dogma is outdated not only for murine and human organoid-derived EECs, but also for primary human EECs, showing that the expression of certain hormones is not restricted to their designated cell type. Moreover, specific analyses into SCT-expressing cells reject the presence of any cell population that exhibits significantly elevated secretin expression compared to other cell populations, previously referred to as S cells. Instead, this investigation indicates that secretin production is realized jointly by other enteroendocrine subpopulations, validating corresponding observations in murine EECs also for human EECs. Furthermore, our findings corroborate that SCT expression peaks in mature EECs, in contrast, progenitor EECs exhibit markedly lower expression levels, supporting the hypothesis that SCT expression is a hallmark of EEC maturation.

One of the critical processes in human reproduction that is still poorly understood is implantation. The implantation of an early human embryo is considered a significant limitation of successful pregnancy. Therefore, researchers are trying to develop an ideal model of endometrium in vitro that can mimic the endometrial micro-environment in vivo as much as possible. The ultimate goal of endometrial modeling is to study the molecular interactions at the embryo-maternal interface and to use this model as an in vitro diagnostic tool for infertility. Significant progress has been made over the years in generating such models. The first experiments of endometrial modeling involved animal models, which are undoubtedly valuable, but at the same time, their dissimilarities with human tissue represent a significant obstacle to further research. This fact led researchers to develop basic monolayer coculture systems using uterine cells obtained from biopsies and, later on, complex and multilayer coculture models. With successful tissue engineering methods and various cultivation systems, it is possible to form endometrial two-dimensional (2D) models to three-dimensional (3D) organoids and novel assembloids that can recapitulate many aspects of endometrial tissue architecture and cell composition. These organoids have already helped to provide new insight into the embryo-endometrium interplay. The main aim of this paper is a comprehensive review of past and current approaches to endometrial model generation, their feasibility, and potential clinical application for infertility treatment.

"Factual narrative in the 17th century: On the narrative structure of the minutes of the Estonian corporation of nobility". To date, there has been hardly any scholarly consideration of minutes (Protokoll) and reports (Bericht) as narrative texts with poetic potential, especially in 17th-century literature. In preparation for an edition of the minutes, this article is dedicated to an initial analysis of the minutes written by Caspar Meyer, secretary of the corporation of Estonian nobility (Estländische Ritterschaft) from 1634 to 1653. The analysis comprises several aspects: a preliminary look at definitions is followed by a discussion of the emergence of minutes as a combination of different text forms (e.g., records of meetings, travel reports, court verdicts, letters) in the presumably immediate draft transcript and the subsequent carefully crafted fair copy. It then outlines the narrative means and structures used to construct the lifeworld of the corporation of Estonian nobility in the protocol as a factual narrative. Particular attention is paid to the author of the protocol and his representation in the narrative. The strict requirements of brevity, neutrality, and reliability in representing reality severely limited the author’s options, but allow an illuminating insight into the means of constructing self-narratives, as the author is also a protagonist in the Baltic lifeworld (baltische Lebenswelt) of his time.

Abstract Datasets consist of measurement data and metadata. Metadata provides context, essential for understanding and (re-)using data. Various metadata standards exist for different methods, systems and contexts. However, relevant information resides at differing stages across the data-lifecycle. Often, this information is defined and standardized only at publication stage, which can lead to data loss and workload increase. In this study, we developed Metadatasheet, a metadata standard based on interviews with members of two biomedical consortia and systematic screening of data repositories. It aligns with the data-lifecycle allowing synchronous metadata recording within Microsoft Excel, a widespread data recording software. Additionally, we provide an implementation, the Metadata Workbook, that offers user-friendly features like automation, dynamic adaption, metadata integrity checks, and export options for various metadata standards. By design and due to its extensive documentation, the proposed metadata standard simplifies recording and structuring of metadata for biomedical scientists, promoting practicality and convenience in data management. This framework can accelerate scientific progress by enhancing collaboration and knowledge transfer throughout the intermediate steps of data creation.

This study aims to address the issue by providing valuable insights into the factors contributing to the wellbore instability and proposing effective measures to mitigate the problem in the southern part of the Rumaila oil field. A comprehensive one-dimensional mechanical earth model (1D MEM) was developed by utilizing various logs data from 4 wells across the south part of this field, including gamma ray, bit size, caliper, bulk density, and sonic compression and shear logs. The model was validated with laboratory tests, including Brazilin and Triaxial tests, as well as repeated formation tests. To analyze the wellbore stability, three different failure criteria, namely Mohr-Coulomb, Mogi-Coulomb, and Modified lade, were employed. The results indicated that the Mogi-Coulomb criterion was the most accurate failure criterion in predicting rock failure. Wellbore instability problems had been observed across the shale sections throughout the Rumaila oil field, particularly through Tanuma, Khasib, top and bottom of Ahmadi, Nahr Umr, and Upper Shale members and Middle Shale members of Zubair formations. The 1D MEM results indicated that Shaly formations exhibited low stiffness rocks (low Young's Modulus (YME)), low rock strength, and high Poisson's ratio (PR), suggesting potential challenges related to wellbore instability in the Tanuma, top and bottom of Ahmadi, Nahr-Umr, and Zubair formations. A sensitivity analysis was performed to determine the safest mud weight and the optimum well trajectory for future drilling operations. According to the updated mud window of this field in 2023, the pressure in the Mishrif and Zubair formations was reinforced by injection wells, as it was noted that the pressure behavior shifted from depletion (2000 Psi). Based on the findings of this study, the good inclination of (0-25°) can be drilled with the mud weight of 1.24-1.26 sg, while the good inclination of (25-40°) can be drilled with the mud weight of 1.28-1.30 sg in all directions (i.e., all azimuths). The stress regime in most of the formations was found to be a strike-slip to a normal fault regime. The findings of this study can significantly benefit the oil industry and enhance overall productivity.

Abstract Background Cognitive impairment occurs in up to 65% of people with multiple sclerosis (PwMS), negatively affecting daily functioning and health-related quality of life. In general, neuropsychological testing is not part of standard MS-care due to insufficient time and trained personnel. Consequently, a baseline assessment of cognitive functioning is often lacking, hampering early identification of cognitive decline and change within a person over time. To assess cognitive functioning in PwMS in a time-efficient manner, a BICAMS-based self-explanatory digital screening tool called the Multiple Screener©, has recently been developed. The aim of the current study is to validate the Multiple Screener© in a representative sample of PwMS in the Netherlands. Additionally, we aim to investigate how cognitive functioning is related to psychological factors, and both work and societal participation. Methods In this cross-sectional multicentre study, 750 PwMS (aged 18–67 years) are included. To obtain a representative sample, PwMS are recruited via 12 hospitals across the Netherlands. They undergo assessment with the Minimal Assessment of Cognitive Functioning in MS (MACFIMS; reference-standard) and the Multiple Screener©. Sensitivity, specificity, and predictive values for identifying (mild) cognitive impairment are determined in a subset of 300 participants. In a second step, the identified cut-off values are tested in an independent subset of at least 150 PwMS. Moreover, test–retest reliability for the Multiple Screener© is determined in 30 PwMS. Information on psychological and work-related factors is assessed with questionnaires. Discussion Validating the Multiple Screener© in PwMS and investigating cognition and its determinants will further facilitate early identification and adequate monitoring of cognitive decline in PwMS.

Abstract Background Up to 65% of people with multiple sclerosis (PwMS) develop cognitive deficits, which hampers their ability to work, participating in day-to-day life and ultimately reducing quality of life (QoL). Early cognitive symptoms are often less tangible to PwMS and their direct environment and are noticed only when symptoms and work functioning problems become more advanced, i.e., when (brain) damage is already advanced. Treatment of symptoms at a late stage can lead to cognitive impairment and unemployment, highlighting the need for preventative interventions in PwMS. Aims This study aims to evaluate the (cost-) effectiveness of two innovative preventative interventions, aimed at postponing cognitive decline and work functioning problems, compared to enhanced usual care in improving health-related QoL (HRQoL). Methods Randomised controlled trial including 270 PwMS with mild cognitive impairment, who have paid employment ≥ 12 h per week and are able to participate in physical exercise (Expanded Disability Status Scale

The article emphasizes the need to develop entrepreneurship in the academic environment to commercialize the scientific research results as one of the possible directions. The problems that prevent Ukrainian and Slovak scientists from commercializing their scientific developments are highlighted, classified, and described in detail, and recommendations are proposed for solving these problems. The commercialization of scientific research is based on transforming scientific developments into profitable commercial products or services that can be successfully introduced to the market. The study examines various aspects of commercialization, including evaluating the commercial potential of scientific research, developing business models, finding investors and partners, intellectual property, marketing innovations, and sales. The elements of innovative ecosystems of different countries and Ukraine are described. Various algorithms for commercializing scientific research are suggested and scrutinized, including specific steps scientists must perform to introduce their developments to the market successfully. The difference in commercialization processes in Ukraine and economically developed countries is demonstrated. A business commercialization algorithm is proposed, which assumes that the first step is to analyse the demand for innovation. It has been proven that projects developed under the market's needs today and in the future are more effective for commercial use. Hence, this approach provides better opportunities for attracting investments, creating strategic alliances with the industrial sector, and increasing effective commercial projects. Recommendations suggested by the authors can help Ukrainian and Slovak scientists commercialize their scientific works more effectively, which will positively impact economic development.

Background: Adjunctive treatment of periodontitis lacks solutions which allow for enough time for wound healing in the periodontal pockets by avoiding fast re-colonization. Such a solution might be an antibiotic-containing formulation with a controlled release over a period of weeks. Here, a recently described minocycline-containing approach is qualified for further clinical development by focusing on proof-of-concept, systemic burden, resistance development, and degradation studies. Methods: Animal studies were done in two different (mouse-chamber, rat Porphyromonas gingivalis challenging) models, including effects on inflammation markers, bone loss, and bone structure. Also, serum concentrations of minocycline after local application were determined by HPLC-MS/MS. The resistance status of bacterial clinical isolates against minocycline was investigated and the degradation of the formulation was characterized by laser scanning and scanning electron microscopy. Results: Animal studies clearly demonstrated the applicability of the new formulation in the investigated models. Inflammation markers decreased in a dose-dependent manner and reduced bone loss compared to non-treated group was observed. Therefore, the systemic burden of the antibiotic was neglectable. Minocycline is still effective against oral pathogens; resistance development was not seen. The biodegradable thread was first swollen and subsequently degraded over a period of weeks. Conclusions: The results support the continued clinical development of this new formulation. A phase I clinical trial is planned to further evaluate its safety and efficacy.

The acute levodopa challenge is widely used to distinguish Parkinson’s disease (PD) from atypical parkinsonian syndromes (APSs) such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). In APSs, very few patients present a clinically relevant response to levodopa. The aim of this study was to determine whether patients with atypical parkinsonism benefit from levodopa in any aspect of their multiple motor deficits despite the generally poor response. This retrospective study analyzed individual motor responses to the acute levodopa challenge using the MDS-UPDRS III in 47 PSP, 26 MSA, and 71 PD patients at Hannover Medical School. Despite the generally poor levodopa response in both PSP and MSA patients, bradykinesia and rigidity were the symptoms most notably affected by levodopa in PSP patients, while MSA patients experienced significant improvements in bradykinesia and action tremor. These findings underscore the variability in levodopa response among PSP and MSA patients and highlight the need for personalized treatment approaches in atypical parkinsonism.

Since antiquity, the phenomenon of friendship has attracted the attention of philosophers, theologians and, most recently, also of the representatives of many others scientific disciplines. At the beginning of this study, which interconnects the findings of sociology, philosophy and anthropology with the historiographical approaches, the problems going with the attempt to define the concept of “friendship” are presented in a systematic way. Afterward, the article deals with the question in which way a long-term correspondence can be used for the analysis of the relationship between two historical protagonists who have been considered as friends. The interpretation problems and the possible methodological approaches in researching the friendship of two correspondents are illustrated on the large complex of the letters between Tomáš Garrigue Masaryk and Josef Svatopluk Machar. These letters come from 1893 to 1932 and are widely unknown for large public.

Abstract Rationale Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood. Objectives To assess whether BT affects gene signatures in bronchial epithelial cells (BECs). Methods In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment. Measurements and main results Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33. Conclusions These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.

Abstract Background Providing optimal care for critically ill patients is an extremely important but also highly demanding task, both emotionally and physically. The “ICU Support” team meeting concept aims to support intensive care unit (ICU) teams by promoting interprofessional communication, peer support, and patient safety by providing a structure for daily team meetings. This protocol describes a study to explore the effectiveness of “ICU Support” for patient- and staff-centered outcomes. Methods ICU Support will be implemented at nine university hospitals located in Germany, following a two-arm randomized parallel group design with an intervention and a control condition and three data collection periods. In the intervention arm, leading ICU personnel (physicians and nurses) will be trained in ICU Support and implement the ICU Support elements into the daily work routine of their units upon completion of data collection period T0 (baseline). In the control arm, ICU Support will not be implemented until the completion of the data collection period T1 (1 month after study start). Until then, the regular daily schedule of the ICU teams will be maintained. The final data collection period (T2) will take place 4 months after the start of the study. Primary outcomes include the number of intensive care complications per patient during their ICU stay during T1 and the sick-related absence of ICU staff during T1. Secondary outcomes include, among others, the average severity of intensive care complications per patient and employee self-reported data regarding their teamwork and patient safety behaviors. Discussion The need for healthy and well-trained ICU staff is omnipresent; thus, structured and evidence-based interventions aimed at supporting ICU teams and facilitating patient safety are required. This multicenter study aims to explore the effectiveness of ICU Support for patient- and staff-centered outcomes. The insights derived from this study have the potential to significantly improve ICU patient safety, staff communication, and connectedness and decrease sickness-related expenses and social costs associated with high work demands among ICU staff. Trial registration German Clinical Trials Register DRKS00028642 . Registered on 4 April 2022.

Transitional cell carcinoma (TCC) of the ovary is a rare subtype of epithelial ovarian tumours defined as a tumour composed of epithelial elements, histologically resembling urothelium and its neoplasms. Ovarian metastases from primary urinary tract carcinomas are rare. The differential diagnosis of primary TCC of the ovary versus metastatic bladder TCC is challenging because of histological similarity. We present the case of a 49-year-old premenopausal woman who was initially diagnosed with non-invasive papillary urothelial carcinoma of bladder (NIPUC) and after 2 years with a synchronous TCC of the ovary while being investigated for suspected relapse. She underwent a radical cystectomy, total hysterectomy, bilateral salpingo-oopharectomy, and pelvic lymph node dissection. The final diagnosis of synchronous NIPUC of the bladder and TCC of the ovary was made by histopathology and immunohistochemical studies.

This study examines the relationship between antecedents of Individual Entrepreneurial Orientation (IEO) in female students. The study uses locus of control, Machiavellianism, resilience, and mindfulness as independent variables. Data for the study was collected using standardized self-rating questionnaires on 854 female students as a unit of analysis. Exploratory and Confirmatory Factor Analysis (EFA and CFA) have been used to examine the reliability and validity of the measurement. Consequently, Structural Equation Modeling (SEM) was conducted using Python after validating the measurement model. The final model describes the relationship of Individual Entrepreneurial Orientation with the internal dimension of locus of control together with Machiavellianism, resilience, and mindfulness. All mentioned constructs had a significant positive influence on the dependent variable. Simultaneously, mindfulness was found to have a positive effect on resilience and internal locus of control on Machiavellianism. This study has expanded the dynamic research boundary and resonates with the recent developments in IEO conceptualizations. Moreover, this work is one of the few studies conducted exclusively among female students.

In Estonia, the Generations and Gender Survey 2020 (GGS-II) is the third large-scale demographic survey that collects data on family and fertility dynamics. As the country participates in the Survey of Health, Ageing and Retirement in Europe, the GGS-II opted for a shorter age range of the sample (18–59). The questionnaire in the GGS-II in Estonia follows the GGS-II wave 1 baseline questionnaire. The questionnaire also includes the Global Uncertainties’ module developed by the Nordic countries, a battery of questions on the perceived impact of COVID-19, and several country-specific items. The GGS-II in Estonia was implemented using only computer-assisted web interviewing (CAWI). In this article, we present a concise overview of the sampling and data collection process, analyse representativeness and response rates, and briefly assess the data quality. We conclude that despite low response rates, the GGS-II provides a good basis for the analysis of fertility and family dynamics.

Eighteen short- to medium-chain monounsaturated fatty acids were screened for hydroxylation and epoxidation using eleven different peroxygenase preparations. Most of these unspecific peroxygenases (UPOs) are secreted by fungal species of the dark-spored basidiomycetous families Psathyrellaceae and Strophariaceae, two belonged to the white-spored genus Marasmius (Marasmiaceae), and one belonged to the ascomycetous family Chaetomiaceae. The fatty acids (FAs) studied were categorized into three groups based on the position of the double bond: (i) terminal unsaturated FAs (between ω and ω-1), (ii) α-β-unsaturated FAs (between C2 and C3), and (iii) β-γ-unsaturated FAs (between C3 and C4). Their chain lengths ranged from three to nine carbon atoms. FAs with a terminal double bond were significantly oxidized by only two UPOs, namely CglUPO and CraUPO (peroxygenases from Chaetomium globosum and Coprinellus radians, respectively), producing different products. FAs with internal double bonds were converted by all tested UPOs. While epoxides were observed as products in the case of α-β-unsaturated fatty acids, only CglUPO formed β-γ-epoxides from the corresponding FAs. The product pattern of the other UPOs for β-γ-unsaturated FAs was quite similar. On the other hand, the product pattern for oxidized α-β-unsaturated FAs was more variable and, in some cases, specific to a particular UPO. For example, in the reaction with trans-2-nonenoic acid, the enzymes clustered into six groups based on the formed products.

Abstract Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.

Background: Anticholinergic adverse effects pose a relevant threat to patients, in particular elderly and cognitively impaired patients. Patients with Parkinsonian syndromes are especially at risk from anticholinergic adverse effects due to the often-required complex drug therapy. Aims: The aim of this study was to evaluate the potential effect of the anticholinergic burden on motor and non-motor symptoms in Parkinson’s disease and atypical Parkinsonian syndromes. Methods: This cross-sectional, monocentric retrospective data analysis included 151 patients with Parkinson’s disease (PD), 63 with progressive supranuclear palsy (PSP), and 36 with multiple system atrophy (MSA). The anticholinergic burden of patients’ medications was determined using two established scores: the Anticholinergic Drug Scale (ADS) and the German Anticholinergic Burden Scale (GABS). These scores were compared between the different diseases and correlated with several disease-specific scores. Results: Anticholinergic burden was higher in patients with PD, in particular, compared to PSP. In the PD group, anticholinergic burden showed a weak correlation with almost all analyzed clinical scores and the number of administered drugs. The UMSARS I and II showed a significant correlation with the anticholinergic burden in MSA patients. In general, the GABS-measured anticholinergic burden was significantly higher compared to the ADS-measured. Conclusions: The calculated anticholinergic burden affected motor and non-motor symptoms in patients with various Parkinsonian syndromes poorly. Since the GABS also contains basic anti-parkinsonian drugs, this score tended to overestimate the anticholinergic burden in patients with Parkinsonian syndromes and, therefore, seemed less appropriate for this application.

In this randomized, placebo-controlled cross-over trial we aimed to investigate if radon spa therapy exerts more pain relief than exposure to warm water alone. In addition, immunological parameters were assessed in both treatment groups. In the RAD-ON02 trial, 116 patients suffering from musculoskeletal disorders (MSDs) received either serial radon spa or solely warm water baths. Pain intensity was assessed by determination of different pain parameters on a visual analogue scale and by pressure point dolorimetry at baseline and at weeks 4, 12 and 24. The longitudinal immune status of the patients was analyzed by a flow cytometry-based assay from peripheral blood at the time points of pain assessments. There were no side effects attributable to radon exposure observed. However, radon spa was superior to warm water applications at week 4 in terms of pain reduction. Pain and morning stiffness at the time of assessment were significantly reduced after radon spa (p

This paper presents the development and validation of a custom MATLAB library, designed to facilitate seamless and efficient real-time communication between the Siemens S7-PLCSIM Advanced simulator and MATLAB/Simulink. The library uses Siemens.Simulation.Runtime.API to enable this integration and its architecture is structured into three classes—PLCSimAdv, PLCSR, and PLCSW. To demonstrate the library’s capabilities, we have chosen the validation parameters and conducted functional experiments including real-time communication at the millisecond level, integration and control of a simulated industrial process, and simultaneous operation with multiple virtual controllers. One of the library’s preliminary conditions was to avoid the requests for regenerating of any version of control program or Simulink model as it is presently by S-functions in TIA portal. The results suggest that the proposed library provides a robust tool for various applications in industrial automation, from the digital twin modelling or simulation of advanced technologies to the operation of traditional control systems. This work has the potential to significantly streamline the simulation, control, and validation of automated processes and opens new ways for research and development in automation and control systems.

BackgroundRegulatory T cells (Tregs) contribute to the maintenance of immunological tolerance. There is evidence of impaired function of these cells in people with asthma and allergy. In this study, we evaluated and compared the function of Tregs in allergic asthmatic and allergic non-asthmatic patients, both before and after low-dose allergen challenges.MethodsThree groups of subjects were recruited for a baseline evaluation: healthy controls without allergy or asthma, allergic asthmatic subjects, and allergic non-asthmatic subjects. All of them were subjected to expiratory flow measurements, sputum induction, and blood sampling. In addition, both groups of allergic subjects underwent low-dose allergen challenges. Tregs were isolated from whole blood using CD4+CD25high and CD127low staining. The suppression function was measured by flow cytometry. The levels of IL-10, IFN-γ, IgG4, IgA, and TGF-β were measured using ELISA, and sputum Foxp3 was evaluated using qRT-PCR.ResultsThe suppressive function of Tregs in healthy controls was significantly higher than in allergic asthmatic or allergic non-asthmatic subjects. Repeated exposure to low doses of allergen increased the suppressor function of Tregs in allergic non-asthmatic subjects but decreased it in allergic asthmatic subjects. Foxp3 gene expression was increased in induced sputum in allergic non-asthmatic subjects, whereas it did not change in asthmatic subjects. Serum IL-10 level was decreased in allergic asthmatic subjects after allergen challenge but not in allergic non-asthmatic subjects. IFN-γ level increased upon allergen challenge in allergic non-asthmatic subjects. IgG4 level was higher in allergic non-asthmatic subjects than in allergic asthmatic subjects.ConclusionsLow-dose allergen challenges stimulate the suppressor function of Tregs in non-asthmatic allergic subjects but not in allergic asthmatic subjects.

Abstract Background Medical research is increasingly interdisciplinary. However, not all projects are successful and cooperation is not always sustained beyond the end of funding. This study empirically assesses the effect of control and trust on the sustainability of interdisciplinary medical research in terms of its performance and satisfaction. Methods The sample consists of 100 German publicly funded medical research collaborations with scientists from medicine, natural and social sciences (N = 364). We develop a system model to analyze the influence of trust and control on performance and satisfaction of the cooperation. Findings Both control and trust are important prerequisites for sustainability, control mainly for the performance of the collaboration, and trust primarily for its satisfaction. While the level of interdisciplinarity is a positive moderator for performance, expectation of continuity is a negative intervening variable for the effect of trust and control on satisfaction. Moreover, trust principally adds to the positive impact of control on sustainability. Conclusions Interdisciplinary medical research requires a participative but systematic management of the respective consortium.

(1) Background: Applications using touch screens are increasingly deployed in medical facilities, as well as in public areas. When touching the display with fingers, potentially pathogenic microorganisms such as methicillin-resistant Staphylococcus aureus (MRSA) can be transmitted. An automated process to decontaminate the device in between users would be highly useful. (2) Methods: Thin glass plates were superficially contaminated with the non-pathogenic Staphylococcus carnosus in a controlled manner. Subsequently, UVA radiation of 400 or 380 nm was laterally coupled into the glass plate, which acted as a light guide. Contact agar plates recorded the change in the staphylococci concentration over time. Additionally, the UVA radiation emitted by the glass plates was measured and the potential risk to humans assessed. (3) Results: Staphylococci concentration decreased as a result of UVA radiation for both wavelengths. At 400 nm, it took about 7.5 h and at 380 nm about 1 h until a reduction of 90% was reached. To meet higher disinfection requirements, disproportionately longer irradiation times were necessary. The potential UVA irradiation of humans in front of the glass pane was about 35 µW/cm2 or less and posed no risk to humans. (4) Conclusions: Side-coupled UVA radiation is in principle capable of safely automatically disinfecting microorganisms on touch screens. However, the required irradiation times are still in the hour range, so that a rapid disinfection within a minute or less is not yet possible with the presented setup. However, higher UVA intensities might reduce the current disinfection durations.

Abstract Background The COVID-19 pandemic affected everyone around the globe. Depending on the country, there have been different restrictive epidemiologic measures and also different long-term repercussions. Morbidity and mortality of COVID-19 affected the mental state of every human being. However, social separation and isolation due to the restrictive measures considerably increased this impact. According to the World Health Organization (WHO), anxiety and depression prevalence increased by 25% globally. In this study, we aimed to examine the lasting effects of the COVID-19 pandemic on the general population. Methods A cross-sectional study using an anonymous online-based 45-question online survey was conducted at Comenius University in Bratislava. The questionnaire comprised five general questions and two assessment tools the Zung Self-Rating Anxiety Scale (SAS) and the Zung Self-Rating Depression Scale (SDS). The results of the Self-Rating Scales were statistically examined in association with sex, age, and level of education. Results A total of 205 anonymous subjects participated in this study, and no responses were excluded. In the study group, 78 (38.05%) participants were male, and 127 (61.69%) were female. A higher tendency to anxiety was exhibited by female participants (p = 0.012) and the age group under 30 years of age (p = 0.042). The level of education has been identified as a significant factor for changes in mental state, as participants with higher levels of education tended to be in a worse mental state (p = 0.006). Conclusions Summarizing two years of the COVID-19 pandemic, the mental state of people with higher levels of education tended to feel worse, while females and younger adults felt more anxiety.

Abstract Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2′-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2′-O-RNA MTase with enzymes from unrelated single-stranded RNA viruses (SARS-CoV-2 and Zika) reveals a conserved sinefungin binding mode, implicating that a single inhibitor could be used against unrelated viral families. Indeed, several of our inhibitors such as TO507 also inhibit the coronaviral nsp14 MTase.

Objectives: C-C-chemokine receptors (CCRs) are expressed on a variety of immune cells and play an important role in many immune processes, particularly leukocyte migration. Comprehensive preclinical research demonstrated CCR2/CCR5-dependent pathways as pivotal for the pathophysiology of severe COVID-19. Here we report human data on use of a chemokine receptor inhibitor in patients with COVID-19. Methods: Interim results of a 2:1 randomised, placebo-controlled, investigator-initiated trial on the CCR2/CCR5-inhibitor Cenicriviroc (CVC) 150 mg BID orally for 28 d in hospitalised patients with moderate to severe COVID-19 are reported. The primary endpoint is the subject's responder status defined by achieving grade 1 or 2 on the 7-point ordinal scale of clinical improvement on day 15. Results: Of the 30 patients randomised, 18 were assigned to receive CVC and 12 to placebo. Efficient CCR2- and CCR5 inhibition was demonstrated through CCL2 and CCL4 elevation in CVC-treated patients (485% and 80% increase on day 3 compared to the baseline, respectively). In the modified intention-to-treat population, 82.4% of patients (14/17) in the CVC group met the primary endpoint, as did 91.7% (11/12) in the placebo group (OR = 0.5, 95% CI = 0.04–3.41). One patient treated with CVC died of progressive acute respiratory distress syndrome, and the remaining had a favourable outcome. Overall, treatment with CVC was well tolerated, with most adverse events being grade I or II and resolving spontaneously. Conclusions: Our interim analysis provides proof-of-concept data on CVC for COVID-19 patients as an intervention to inhibit CCR2/CCR5. Further studies are warranted to assess its clinical efficacy.

Gestational choriocarcinoma is a rare aggressive form of gestational trophoblastic neoplasia. In cases of intraplacental choriocarcinoma, the tumour is confined to the placenta. Intraplacental choriocarcinoma in twin pregnancies is a very rare occurrence with less than 5 previously reported cases in the literature. In this case, a 34-year-old primiparous woman, pregnant with dichorionic diamniotic twins, underwent an emergency caesarean section for fetal distress at 35 weeks gestation after presenting in preterm labour. Twin A was delivered with no signs of life. The demise was attributed to fetomaternal haemorrhage (FMH) secondary to intraplacental choriocarcinoma. The mother’s HCG normalised quickly postpartum with no radiological signs of metastatic disease. She has been managed conservatively with monthly HCG surveillance with no signs of recurrence. Twin B remains well with negative HCG surveillance. Although gestational choriocarcinoma can be aggressive and associated with poor obstetric outcomes, it has a good prognosis when diagnosed and treated early. The importance of detailed histopathological placental examination and clinical suspicion for choriocarcinoma following FMH is highlighted by this case.

Abstract As Mongolia is considered one of the most resource extraction-dependent countries globally, significant mining-related environmental and human health risks are expected. The aim of this study was to (I) assess the impacts of mining on soil pollution with metals in Mongolia's key coal mining towns (Baganuur, Nalaikh and Sharyn Gol) and (II) review the current knowledge on soil pollution with metal(loid)s and related health risks in Mongolia. The results showed predominantly low soil contents of Cd, Cu, Pb and Zn and a related absence of severe pollution and potential health risk in the coal mining towns. Urban design, rather than the presence of mines, controlled the pollution distribution. Despite the methodological shortcomings of several studies on soil pollution in Mongolia, their results suggest a similarly low threat in the three largest cities (Ulaanbaatar, Darkhan, Erdenet) and several mining areas. While the generally highlighted risk of As seems like an artificially escalated issue, the content of Cr in urban soil may be a neglected threat. Further pollution research in Mongolia should focus on street dust and drinking water pollution.

Humans have rich experience applying linear models and logical thinking, but only experts understand the behaviour of non-linear systems. However, the deep neural network (DNN) implementation of text non-linear systems outperforms optimal linear models. Therefore, the forward DNN (the pattern recognition system in this paper) attracts attention to the necessity of interpreting the results obtained by DNN. To preserve the high performance of DNN, we focus on a post-hoc explanation; this approach means building an explainable model for the decision obtained by the black box. To avoid the interpretation of a set of millions of non-linear functions, we divide DNN into two parts: the feature extractor and the classifier. Following that, we argue for a specific interpretation of each of them. While for classifiers, we have several suitable explainable models (and we decided on the fuzzy logical function), we believe that feature interpretation is a creative scientific activity corresponding to the usual research. The paper presents a tool to help researchers and users understand extracted features not necessarily known in the specific application domain. Explaining the new features offers a way to learn from computers.

Summary: Background: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM. Methods: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or –associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules. Findings: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup. Interpretation: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features. Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.

Summary: Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD+), but limited knowledge of NAD+ metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD+ salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD+ biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD+ biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD+ metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues.

Pattern recognition systems always misclassify anomalies, which can be dangerous for uninformed users. Therefore, anomalies must be filtered out from each classification. The main challenge for the anomaly filter design is the huge number of possible anomaly samples compared with the number of samples in the training set. Tailoring the filter for the given classifier is just the first step in this reduction. Paper tests the hypothesis that the filter trained in avoiding “near” anomalies will also refuse the “far” anomalies, and the anomaly detector is then just a classifier distinguishing between “far real” and “near anomaly” samples. As a “far real” samples generator was used, a Generative Adversarial Network (GAN) fake generator that transforms normally distributed random seeds into fakes similar to the training samples. The paper proves the assumption that seeds unused in fake training will generate anomalies. These seeds are distinguished according to their Chebyshev norms. While the fakes have seeds within the hypersphere with a given radius, the near anomalies have seeds within the sphere near cover. Experiments with various anomaly test sets have shown that GAN-based anomaly detectors create a reliable anti-anomaly shield using the abovementioned assumptions. The proposed anomaly detector is tailored to the given classifier, but its limitation is due to the need for the availability of the database on which the classifier was trained.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin–creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

Multi-qubit entangling interactions arise naturally in several quantum computing platforms and promise advantages over traditional two-qubit gates. In particular, a fixed multi-qubit Ising-type interaction together with single-qubit X-gates can be used to synthesize global ZZ-gates (GZZ gates). In this work, we first show that the synthesis of such quantum gates that are time-optimal is NP-hard. Second, we provide explicit constructions of special time-optimal multi-qubit gates. They have constant gate times and can be implemented with linearly many X-gate layers. Third, we develop a heuristic algorithm with polynomial runtime for synthesizing fast multi-qubit gates. Fourth, we derive lower and upper bounds on the optimal GZZ gate-time. Based on explicit constructions of GZZ gates and numerical studies, we conjecture that any GZZ gate can be executed in a time O($n$) for $n$ qubits. Our heuristic synthesis algorithm leads to GZZ gate-times with a similar scaling, which is optimal in this sense. We expect that our efficient synthesis of fast multi-qubit gates allows for faster and, hence, also more error-robust execution of quantum algorithms.

Lifespan can be affected by both physiological ageing and specific sets of pathologies associated with old age. Here the authors report a resource of large-scale cross-sectional phenotyping of aging male mice at different time points to analyse a large set of phenotypes and molecular markers, including during genetic and diet interventions affecting lifespan.

Abstract The European Spallation Source ERIC (ESS), currently under construction in Lund, Sweden is a facility established to deliver the highest integrated neutron flux originating from a pulsed source with the aim of supporting an initial fifteen neutron instruments for cutting edge science experiments. This in turn requires reliable monitoring at complex neutron beam lines: in particular, linearity, timing capability, adaptability of the design for various flux ranges (dynamic range) and sensitivity to neutrons within the range of 0.6-10Å are expected from the neutron beam monitors to be installed at the ESS beam lines. Additionally, operational stability and low attenuation are also desirable characteristics for such neutron beam monitoring. A prototype neutron beam monitor based on the ionisation chamber principle and a boron converter, designed by CDT CASCADE Detector Technologies GmbH and ESS, has been investigated at the BER-II research reactor of Helmholtz Zentrum Berlin (HZB). The effort to design and investigate a thermal neutron ionisation beam monitor was initiated by adapting the concept of ionisation chambers previously known elsewhere. So far all the characterised neutron beam monitors discriminate neutron hits on a discrete event basis (pulse mode), whereas the beam monitor prototype introduced in this paper estimates the total flux as a function of current (current mode). While most other neutron beam monitoring devices and detectors rely upon a signal amplifying gain stage, the ionisation chamber operates without any gain and is consequently robust against typical detector ageing effects that compromise the sensitivity over time. The initial tests were performed at the ESS V20 test beam line under realistic conditions resembling those of the future pulses of ESS. The linearity is demonstrated for 3Å pulses in the flux range of 2-3 × 105 n/s/cm2 and for white pulses (0.6-10Å) in the range of 1-5 × 106 n/s/cm2. The timing behaviour resembles the data previously recorded at the V20 beam lines. This novel implementation of a neutron sensitive ionisation chamber shows great promise for beam monitoring and diagnostics at ESS. As the ionisation beam monitor itself is an entirely passive device, it is adequately robust to be employed in areas of high irradiation where no regular servicing or maintenance can be provided.

BackgroundThe NLRP3 inflammasome integrates several danger signals into the activation of innate immunity and inflammation by secreting IL-1β and IL-18. Most published data relate to the NLRP3 inflammasome in immune cells, but some reports claim similar roles in parenchymal, namely epithelial, cells. For example, podocytes, epithelial cells critical for the maintenance of kidney filtration, have been reported to express NLRP3 and to release IL-β in diabetic kidney disease, contributing to filtration barrier dysfunction and kidney injury. We questioned this and hence performed independent verification experiments.MethodsWe studied the expression of inflammasome components in human and mouse kidneys and human podocytes using single-cell transcriptome analysis. Human podocytes were exposed to NLRP3 inflammasome agonists in vitro and we induced diabetes in mice with a podocyte-specific expression of the Muckle-Wells variant of NLRP3, leading to overactivation of the Nlrp3 inflammasome (Nphs2Cre;Nlrp3A350V) versus wildtype controls. Phenotype analysis included deep learning-based glomerular and podocyte morphometry, tissue clearing, and STED microscopy of the glomerular filtration barrier. The Nlrp3 inflammasome was blocked by feeding ß-hydroxy-butyrate.ResultsSingle-cell transcriptome analysis did not support relevant NLRP3 expression in parenchymal cells of the kidney. The same applied to primary human podocytes in which NLRP3 agonists did not induce IL-1β or IL-18 secretion. Diabetes induced identical glomerulomegaly in wildtype and Nphs2Cre;Nlrp3A350V mice but hyperfiltration-induced podocyte loss was attenuated and podocytes were larger in Nphs2Cre;Nlrp3A350V mice, an effect reversible with feeding the NLRP3 inflammasome antagonist ß-hydroxy-butyrate. Ultrastructural analysis of the slit diaphragm was genotype-independent hence albuminuria was identical.ConclusionPodocytes express low amounts of the NLRP3 inflammasome, if at all, and do not produce IL-1β and IL-18, not even upon introduction of the A350V Muckle-Wells NLRP3 variant and upon induction of podocyte stress. NLRP3-mediated glomerular inflammation is limited to immune cells.

Delta-like homolog 1 (Dlk1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Experimental data presented here identify two independent regulatory mechanisms, transcriptional and translational, by which Ifrd1 (TIS7) and its orthologue Ifrd2 (SKMc15) regulate Dlk1 levels. Mice deficient in both Ifrd1 and Ifrd2 (dKO) had severely reduced adipose tissue and were resistant to high-fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation, was significantly upregulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk1 inhibited the expression of adipogenesis regulators Pparg and Cebpa, and fatty acid transporter Cd36. Although both Ifrd1 and Ifrd2 contributed to this phenotype, they utilized two different mechanisms. Ifrd1 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk1. On the other hand, distinctive experimental evidence showed that Ifrd2 acts as a general translational inhibitor significantly affecting Dlk1 protein levels. Novel mechanisms of Dlk1 regulation in adipocyte differentiation involving Ifrd1 and Ifrd2 are based on experimental data presented here.

BackgroundAsthma is a chronic inflammatory airway disease characterized by a prevailing type 2 inflammation, airway hyperresponsiveness, and mucus hypersecretion and is driven by various factors among which oxidative molecules, called reactive oxygen species (ROS), play a major role. Superoxide dismutases (SODs) are enzymes that constitute the first line of defense against ROS. Melon SOD-gliadin, which is known as GliSODin®, is commonly used as a nutritional supplement that has proven antioxidant properties.ObjectivesIn this study, we evaluated the efficacy and mechanism of action GliSODin® in the treatment of allergic asthma.MethodsHouse dust mite (HDM)-induced asthmatic mice were orally exposed to GliSODin®, and airway hyperresponsiveness, lung inflammation, in vitro T-cell polarization, in vivo T-cell reactivation, and blood immunoglobulin were investigated.ResultsGliSODin® reduced airway hyperresponsiveness, lung innate and adaptive immune response, and HDM-specific IgE production. Coculturing CD4+ T-cell with HDM-sensitized dendritic cells and GliSODin® reduced T-cell polarization into Th2 and Th17 cells. Moreover, adoptively transferred CD4+ T cells from asthmatic mice exhibited a reduced reactivation of Th2 and Th17 cells following stimulation with HDM plus GliSODin®.ConclusionGliSODin® abrogates asthma features and reduces CD4+ T-cell polarization and reactivation. Taken together, these data suggest that GliSODin® could be used for the management of asthma symptoms.