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Abstract We present a comprehensive and user-friendly framework built upon the pyiron integrated development environment (IDE), enabling researchers to perform the entire Machine Learning Potential (MLP) development cycle consisting of (i) creating systematic DFT databases, (ii) fitting the Density Functional Theory (DFT) data to empirical potentials or MLPs, and (iii) validating the potentials in a largely automatic approach. The power and performance of this framework are demonstrated for three conceptually very different classes of interatomic potentials: an empirical potential (embedded atom method - EAM), neural networks (high-dimensional neural network potentials - HDNNP) and expansions in basis sets (atomic cluster expansion - ACE). As an advanced example for validation and application, we show the computation of a binary composition-temperature phase diagram for Al-Li, a technologically important lightweight alloy system with applications in the aerospace industry.

Abstract Background Helicopter hoist operations (HHO) are an important option for rescue operations in rugged and challenging terrain. German mid-range mountains are characterized by the versatility of ground conditions, few urban structures, and frequent use for local leisure activities, including the practice of more or less high-risk outdoor sports. This retrospective analysis aims to investigate the incidence of rescue missions in German mid-range mountains requiring HHO. The contributing air rescue bases' operational tactics and the underlying medical characteristics, such as injury patterns and the provided medical care, are also reported. Methods This study is a retrospective analysis of the documentation of HHO missions carried out at the air rescue bases in Freiburg, Nuremberg, and Bautzen staffed by emergency physicians between 01/2020 and 07/2022. Data was extracted from the German Air Rescue database. To assess the topics of interest, we conducted basic descriptive statistics. Results Data selection retrieved 410 HHO-associated rescue missions. A total of 304 datasets, including HHO, were suitable for further statistical processing. Air rescue base Freiburg contributed 152, Nuremberg 63, and Bautzen 89 missions. HHO missions showed an increased frequency in the summer season and from Friday to Sunday. In this collective, 75% of the underlying diagnoses were trauma-associated; in 33% of all patients, traumatic injury of the pelvis or lower limb occurred. 28% of the patients were in a potential or actual life-threatening condition and were scored NACA 4 or higher. The rates of invasive medical treatment, such as endotracheal intubation (5%) or venous access (79%), were considerably higher than in overall emergency missions. In terms of mission tactics and cooperation with mountain rescue services, different approaches of the three air bases resulted in differences regarding first-on-scene rates and time spans. Conclusion The results show a relevant year-round need to deploy emergency medical expertise to inaccessible terrain in the three regions examined. Detailed analysis showed relevant differences in operational tactics between the three bases and potential for optimization. Simultaneous alerting of the hoist helicopter and reliable and precise coordination with other rescue organizations involved, especially the local mountain rescue service and the rescue coordination center, can help to shorten both the treatment-free interval and the prehospital time for patients in inaccessible terrain. Trial registration: The study is registered at DRKS (DRKS00033493).

Abstract Synaptic mechanisms that contribute to human memory consolidation remain largely unexplored. Consolidation critically relies on sleep. During slow wave sleep, neurons exhibit characteristic membrane potential oscillations known as UP and DOWN states. Coupling of memory reactivation to these slow oscillations promotes consolidation, though the underlying mechanisms remain elusive. Here, we performed axonal and multineuron patch-clamp recordings in acute human brain slices, obtained from neurosurgeries, to show that sleep-like UP and DOWN states modulate axonal action potentials and temporarily enhance synaptic transmission between neocortical pyramidal neurons. Synaptic enhancement by UP and DOWN state sequences facilitates recruitment of postsynaptic action potentials, which in turn results in long-term stabilization of synaptic strength. In contrast, synapses undergo lasting depression if presynaptic neurons fail to recruit postsynaptic action potentials. Our study offers a mechanistic explanation for how coupling of neural activity to slow waves can cause synaptic consolidation, with potential implications for brain stimulation strategies targeting memory performance.

Abstract Background Salmonella is widespread in pig husbandry and pork is an important source for human salmonellosis. Surveillance programmes are conducted in many European countries and various management measures are implemented on farm level to control Salmonella. Piglet or maternal vaccination can reduce Salmonella shedding and lower the likelihood of piglet infection. Proper management of risk factors can help to maintain low infection pressure. The aim of the study was to evaluate the effect of sow vaccination and piglet vaccination on Salmonella seroprevalence at slaughter. Results Different vaccination strategies were evaluated for their effect on seroprevalences in nursery (serum) and slaughter pigs (meat juice) in a farrow-to-finish production chain tested positive for Salmonella Typhimurium (ST). Antibody levels of four piglet groups from one rearing farm and of pigs from four downstream fattening farms were measured by Salmonella LPS-ELISA in a longitudinal study (UNVAC: no vaccination against Salmonella; PIGVAC: piglets vaccinated twice with an attenuated Salmonella Cholerasuis (SC) live vaccine; SOWVAC-1: piglets born from sows vaccinated twice before farrowing with attenuated ST live vaccine; SOWVAC-2: Piglets from vaccinated sows (ST) which had been vaccinated twice already as a piglet (ST). Results revealed significantly lower ELISA optical density (OD) values (p 40) from groups PIGVAC, SOWVAC-1 and SOWVAC-2 compared to group UNVAC at the end of rearing period. Summarizing results from pigs of all fattening farms revealed that pigs from group PIGVAC had significantly lower ELISA OD values in meat juice samples than all other groups (p

Self-cleaving ribozymes are versatile tools for synthetic biologists when it comes to controlling gene expression. Up to date, 12 different classes are known, and over the past decades more and more details about their structure, cleavage mechanisms and natural environments have been uncovered. However, when these motifs are applied to mammalian gene expression constructs, the outcome can often be unexpected. A variety of factors, such as surrounding sequences and positioning of the ribozyme influences the activity and hence performance of catalytic RNAs. While some information about the efficiency of individual ribozymes (each tested in specific contexts) is known, general trends obtained from standardized, comparable experiments are lacking, complicating decisions such as which ribozyme to choose and where to insert it into the target mRNA. In many cases, application-specific optimization is required, which can be very laborious. Here, we systematically compared different classes of ribozymes within the 3’-UTR of a given reporter gene. We then examined position-dependent effects of the best-performing ribozymes. Moreover, we tested additional variants of already widely used hammerhead ribozymes originating from various organisms. We were able to identify functional structures suited for aptazyme design and generated highly efficient hammerhead ribozyme variants originating from the human genome. The present dataset will aide decisions about how to apply ribozymes for affecting gene expression as well as for developing ribozyme-based switches for controlling gene expression in human cells.

Abstract Background Unicompartmental knee arthroplasty (UKA) is a surgical procedure for managing osteoarthritis of one joint compartment, most commonly the medial side. This systematic review investigates the causes of UKA revision. The outcomes of interest were establishing the revision rate, time to revision, and the most common causes of revision in the long- and midterm follow-up. Methods This study was conducted according to the 2020 PRISMA statement. In October 2024, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Embase. All the clinical studies investigating the rate and causes of revision in UKA were accessed. Only studies with a minimum of 10 years of follow-up were considered. Results Data from 56 studies (13,540 patients) were collected. Of them, 65.6% were women. The mean length of the follow-up was 13.1 ± 3.0 years. The mean age of the patients was 65.6 ± 5.6 years, and the mean BMI was 28.5 ± 2.2 kg/m2. Revisions were performed in 8.8% (2641 of 30,140) of implanted UKAs. The mean time to revision was 6.5 ± 2.6 (range, 2.5 to 13.0) years. Conclusion 8.8% (2641 of 30,140) of UKAs were revised at a mean time of 6.5 ± 2.6 years. Level of evidence Level IV, systematic review.

Abstract In the past decades studies investigating the dendritic cell (DC) activation have been conducted almost exclusively in animal models. However, due to species-specific differences in the DC subsets, there is an urgent need for alternative in vitro models allowing the investigation of Langerhans cell (LC) and dermal dendritic cell (DDC) activation in human tissue. We have engineered a full-thickness (FT) human skin tissue equivalent with incorporated LC surrogates derived from the human myeloid leukemia-derived cell line Mutz-3, and DDC surrogates generated from the human leukemia monocytic cell line THP-1. Topical treatment of the skin models encompassing Mutz-LCs only with nickel sulfate (NiSO4) or 1-chloro-2,4-dinitrobenzene (DNCB) for 24 h resulted in significant higher numbers of CD1a positive cells in the dermal compartment, suggesting a sensitizer-induced migration of LCs. Remarkably, exposure of the skin models encompassing both, LC and DDC surrogates, revealed an early sensitizer-induced response reflected by increased numbers of CD1a positive cells in the epidermis and dermis after 8 h of treatment. Our human skin tissue equivalent encompassing incorporated LC and DDC surrogates allows the investigation of DC activation, subsequent sensitizer identification and drug discovery according to the principles of 3R.

Abstract Over the last 30 years, group-IV semiconductors have been intensely investigated in the quest for a fundamental direct bandgap semiconductor that could yield the last missing piece of the Si Photonics toolbox: a continuous-wave Si-based laser. Along this path, it has been demonstrated that the electronic band structure of the GeSn/SiGeSn heterostructures can be tuned into a direct bandgap quantum structure providing optical gain for lasing. In this paper, we present a versatile electrically pumped, continuous-wave laser emitting at a near-infrared wavelength of 2.32 µm with a low threshold current of 4 mA. It is based on a 6-periods SiGeSn/GeSn multiple quantum-well heterostructure. Operation of the micro-disk laser at liquid nitrogen temperature is possible by changing to pulsed operation and reducing the heat load. The demonstration of a continuous-wave, electrically pumped, all-group-IV laser is a major breakthrough towards a complete group-IV photonics technology platform.

Abstract Sustainable and resilient crop production is facing many challenges. The restoration of natural reactive silicon cycles offers an opportunity to improve sustainability through reducing phosphorus fertilizer use and to increase crops’ resilience to drought stress and pests. We therefore call upon farmers, agri-food-researchers, and policymakers to pave the road for transforming agriculture to a silicon-improved sustainable crop production, which represents a promising approach to achieve food security under global change.

Abstract Background Specialized outpatient palliative care (SAPV) is a component of palliative care in Germany, which assists approximately 10% of palliative patients. The majority of these patients have a malignant disease and are at increased risk of complications or severe infection. Antibiotic stewardship (ABS) measures are implemented to optimize antibiotic administration; however, there is little data available in this area, particularly for SAPV. Therefore, we examined the extent to which ABS measures can be meaningfully used or implemented in SAPV. Methods After establishing a corresponding interview guide, 15 experts from specialized areas were interviewed on this subject by the Institute for Market Research in Healthcare Munich (IMIG) through audio-registered individual interviews. The interviews were analyzed using the qualitative content analysis method according to Mayring. Results All 15 experts participated. The primary benefits cited were greater safety in the prescription and decision-making process for antibiotics in the areas of SAPV and improved quality of life. The implementation of continuous ABS measures for SAPV was considered difficult in some cases and linked to certain prerequisites, such as supportive advice from existing systems. The possibility of further training for SAPV members in the area of ABS was considered particularly advantageous. Conclusions The implementation of ABS measures in SAPV is feasible in principle; however, it is difficult to implement under the current conditions. Close cooperation with an existing external ABS expert/team will be helpful. This will provide more security for a small, but relevant proportion of SAPV patients, and for the SAPV team treating them.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the best curative treatment modality for many malignant hematologic disorders. In the absence of a matched related donor, matched unrelated donors (MUDs) and haploidentical donors are the most important stem cell sources. In this registry-based retrospective study, we compared the outcomes of allo-HSCTs from 10/10 MUDs with antithymocyte globulin (ATG)–based regimens (n = 7050) vs haploidentical transplants (Haplo-Tx) using posttransplant cyclophosphamide (PT-CY Haplo; n = 487) in adult patients with hematologic malignancies between 2010 and 2020. Cox proportional hazard-and competing risks regression models were formed to compare the outcomes. Overall survival (OS), Disease-free survival (DFS), and graft-versus-host disease (GVHD)–free and relapse-free survival (GRFS) were superior for 10/10 MUDs (OS [hazard ratio (HR), 1.27; 95% confidence interval (CI), 1.10-1.47; P = .001]; DFS [HR, 1.17; CI, 1.02-1.34; P = .022]; GRFS [HR, 1.34; CI, 1.19-1.50; P

ABSTRACT: In this study, possible reasons for an increased level of free fatty acids (FFA) in UHT-treated full-fat (3.5% wt/wt) milk and its effect on the frothing properties of milk were investigated. Lipolysis of raw milk from 2 different breeds of cattle (Holstein and Jersey) was induced by mechanical stress and kinetics of lipolysis were compared. Frothing capacity and foam stability of shelf-stable milk with different concentrations of FFA were determined, with a good to medium initial foam volume for up to 4 mEq FFA·(100 g of fat)−1 fat and poor foam stability with >2 mEq FFA·(100 g of fat)−1. A combination of mechanical stress and initial condition of fresh raw milk was found to trigger lipolysis and potential sources of mechanical stress during milk processing were identified.

Background: In medical education various non-digital teaching methods are established. However, studies have proven that the immersive character of virtual reality (VR) applications positively impact the understanding of spatial relationships.This study outlines the development and pilot testing of a novel system for collaborative, case-based VR teaching, utilizing real-time volume rendered computed tomography (CT) data of thoracic cases among graduate students. Methods: A system was configured and deployed to provide real-time volume rendered CT data in a collaborative, multiuser VR environment. A thoracic surgery VR course was implemented into the surgical graduate curriculum, which has subsequently been evaluated with questionnaires. Results: Seventy students assessed the curriculum through a questionnaire. Usability was rated intuitive (77.14 %) while few students (5.71 %) reported cyber sickness.A vast majority (98.57 %) agreed VR improved their understanding of anatomy compared to traditional methods and most students found learning more effective. (88.57 %) and joy during participation was rated high (97,14 %). A majority of the students (61.43 %) believed VR could partly replace traditional methods. They supported integrating VR into preclinical (81.43 %) and clinical teaching (94.29 %) as well as taking VR courses from home (78.57 %). Most participants (90,72 %) encouraged the expansion of VR infrastructure. Conclusion: The concept of a collaborative real-time VR-based educational program in medical graduate teaching has proven its technical feasibility and positive acceptance with a desire for more VR integration in surgical curricula. A two-armed study will be conducted to evaluate the objective impact as the expansion of VR environments for teaching continues.

Introduction Tick-borne encephalitis (TBE) is rapidly spreading to new areas in many parts of Europe. While vaccination remains the most effective method of protection against the disease, vaccine uptake is low in many endemic countries.Areas covered We conducted a literature search of the MEDLINE database to identify articles published from 2018 to 2023 that evaluated the immunogenicity and effectiveness of TBE vaccines, particularly Encepur, when booster doses were administered up to 10 years apart. We searched PubMed with the MeSH terms ‘Encephalitis, Tick-Borne/prevention and control’ and ‘Vaccination’ for articles published in the English language.Expert opinion Long-term immunogenicity data for Encepur and real-world data on vaccine effectiveness and breakthrough infections following the two European TBE vaccines, Encepur and FSME-Immun, have shown that extending the booster interval from 3–5 years to 10 years does not negatively impact protection against TBE, regardless of age. Such extension not only streamlines the vaccination schedules but may also increase vaccine uptake and compliance among those living in endemic regions.

Abstract The hair follicle stem cell niche is an immune-privileged microenvironment, characterized by reduced antigen presentation, thus shielding against permanent immune-mediated tissue damage. In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1/2 or STAT1 or therapeutic inhibition of JAK1/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.

(Series Information) European Papers - A Journal on Law and Integration, 2024 9(2), 729-744 | Article | (Table of Contents) I. Introduction. – II. Guiding principles. – III. Proceedings before the European Court of Human Rights. – III.1. The co-respondent mechanism. – III.2. The “prior involvement” of the Court of Justice. – III.3. Operation of inter-party applications and ECHR advisory opinions. – III.4. The principle of mutual trust between EU Member States and relationship between the two articles 53. – IV. Participation of the EU in the Committee of Ministers. – V. Election of judges. – VI. Conclusion. | (Abstract) The Article discusses the European Union’s accession to the European Convention on Human Rights (ECHR) from the Council of Europe’s perspective, focusing on the renegotiations between June 2020 and March 2023, which led to 10–20 formal amendments to the Draft Accession Agreement (DAA). It examines whether the guiding principles agreed upon in 2010 have been upheld and addresses the EU’s accession in terms of the co-respondent mechanism, the principle of mutual trust, and the EU’s participation in the Committee of Ministers, among other aspects. The document emphasises the balance between respecting the EU’s constitutional requirements and maintaining the integrity of the Convention system, concluding that the revised DAA represents a collaborative effort to address the challenges posed by the Court of Justice of the European Union’s (CJEU) Opinion 2/13 and to ensure coherent human rights protection in Europe.

Abstract Recent research in patients with functionally univentricular hearts (UVH) is focusing on pathologies of the lymphatic vessels. Morphology of the abdominal lymphatic vessels was analyzed by MRI in patients with UVH following total cavopulmonary connection (TCPC) and it was examined, if clinical and laboratory parameters correlate with changes after TCPC. We prospectively examined 33 patients at the age of 19.8 (14.6;30.2) years [median (Q1;Q3)] after TCPC (follow-up 14.3 years (9.7;24.9) with a heavily T2-weighted MRI sequence on a 3.0 T scanner. Examinations in coronal orientation were performed with respiratory gating, slice thickness 0.6 mm, TR 2400 ms, TE 692 ms, FoV 460 mm (covering thoracic and abdominal regions), scan time 14:41 min (13:18;16:30) after a solid meal and a cup of pineapple juice. The findings were classified according to delineation of abdominal lymphatic vessels. Type 1: 6 av and/or oedematous changes or ascites. The results were correlated with parameters obtained at the annual routine check-up. Statistical analysis was performed using U-test and Chi-square test. Fifteen patients (group 1) showed type 3 lymphatic morphologies, two of which had ascites. Eighteen patients (group 2) showed lower grade morphologies (type 1–2). Image quality was rated considering the delineation of the common hepatic duct and did not differ between groups (p = 0.134). “Lymphatic burden” was automatically examined and was indexed to the number of delineated abdominal vessels and showed quantification according to the chosen categories type 1–3. Patients in group 1 were younger at MRI examination (17.4;14.3/18.9 vs. 26.2;18.2/32.3 years, p = 0.03). Superior cavopulmonary connection (SCPC) had been performed earlier in group 1 (9.9;7.9/25.5 vs. 29.2;13.7/66.6 months, p = 0.018). Laboratory examinations in group 1 showed lower levels for Immunoglobulin G (IgG), Lipase, α-Antitrypsin, Cystatin C and TSH. There were no significant differences for total protein, NTproBNP, lymphocytes or platelets. A history of chylothorax was present in 7/15 versus 2/18 p = 0.022. Protein-losing enteropathy (PLE) occurred in 4/15 versus 1/18 (p = 0.092). T2 weighted MRI is feasible for noninvasive delineation of abdominal lymphatic vessel in patients following TCPC. In the long-term follow-up, patients with more pronounced changes of the abdominal lymphatic vessels were younger at SCPC and were more likely to show a history of chylothorax and lower IgG values.

Abstract Background The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results. Methods Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study. Results For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively. Conclusions These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development. Trial registration This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.

Abstract Microbial growth is central to soil carbon cycling. However, how microbial communities grow under climate change is still largely unexplored. Here we use a unique field experiment simulating future climate conditions (increased atmospheric CO2 and temperature) and drought concomitantly and investigate impacts on soil microbial activity. We trace 2H or 18O applied via water-vapor exchange into membrane (and storage) fatty acids or DNA, respectively, to assess community- and group-level adjustments in soil microbial physiology (replication, storage product synthesis, and carbon use efficiency). We show that, while bacterial growth decreases by half during drought, fungal growth remains stable, demonstrating a remarkable resistance against soil moisture changes. In addition, fungal investment into storage triglycerides increases more than five-fold under drought. Community-level carbon use efficiency (the balance between anabolism and catabolism) is unaffected by drought but decreases in future climate conditions, favoring catabolism. Our results highlight that accounting for different microbial growth strategies can foster our understanding of soil microbial contributions to carbon cycling and feedback on the climate system.

Abstract Individual dietary specialization, where individuals occupy a subset of a population’s wider dietary niche, is a key factor determining a species resilience against environmental change. However, the ontogeny of individual specialization, as well as associated underlying social learning, genetic, and environmental drivers, remain poorly understood. Using a multigenerational dataset of female European brown bears (Ursus arctos) followed since birth, we discerned the relative contributions of environmental similarity, genetic heritability, maternal effects, and offspring social learning from the mother to individual specialization. Individual specialization accounted for 43% of phenotypic variation and spanned half a trophic position, with individual diets ranging from omnivorous to carnivorous. The main determinants of dietary specialization were social learning during rearing (13%), environmental similarity (5%), maternal effects (11%), and permanent between-individual effects (9%), whereas the contribution of genetic heritability (3%) was negligible. The trophic position of offspring closely resembled the trophic position of their mothers during the first 3–4 years of independence, but waned with increasing time since separation. Our study shows that social learning and maternal effects were more important for individual dietary specialization than environmental composition. We propose a tighter integration of social effects into studies of range expansion and habitat selection under global change.

Abstract Time-resolved serial crystallography at X-ray Free Electron Lasers offers the opportunity to observe ultrafast photochemical reactions at the atomic level. The technique has yielded exciting molecular insights into various biological processes including light sensing and photochemical energy conversion. However, to achieve sufficient levels of activation within an optically dense crystal, high laser power densities are often used, which has led to an ongoing debate to which extent photodamage may compromise interpretation of the results. Here we compare time-resolved serial crystallographic data of the bacteriorhodopsin K-intermediate collected at laser power densities ranging from 0.04 to 2493 GW/cm2 and follow energy dissipation of the absorbed photons logarithmically from picoseconds to milliseconds. Although the effects of high laser power densities on the overall structure are small, in the upper excitation range we observe significant changes in retinal conformation and increased heating of the functionally critical counterion cluster. We compare light-activation within crystals to that in solution and discuss the impact of the observed changes on bacteriorhodopsin biology.

Abstract Melting properties are critical for designing novel materials, especially for discovering high-performance, high-melting refractory materials. Experimental measurements of these properties are extremely challenging due to their high melting temperatures. Complementary theoretical predictions are, therefore, indispensable. One of the most accurate approaches for this purpose is the ab initio free-energy approach based on density functional theory (DFT). However, it generally involves expensive thermodynamic integration using ab initio molecular dynamic simulations. The high computational cost makes high-throughput calculations infeasible. Here, we propose a highly efficient DFT-based method aided by a specially designed machine learning potential. As the machine learning potential can closely reproduce the ab initio phase-space distribution, even for multi-component alloys, the costly thermodynamic integration can be fully substituted with more efficient free energy perturbation calculations. The method achieves overall savings of computational resources by 80% compared to current alternatives. We apply the method to the high-entropy alloy TaVCrW and calculate its melting properties, including the melting temperature, entropy and enthalpy of fusion, and volume change at the melting point. Additionally, the heat capacities of solid and liquid TaVCrW are calculated. The results agree reasonably with the CALPHAD extrapolated values.

Abstract Epithelial cadherin (E-cad) mediated cell-cell junctions play a crucial role in the establishment and maintenance of tissues and organs. In this study, we employed metal-induced energy transfer imaging and spectroscopy to investigate variations in intermembrane distance during adhesion between two model membranes adorned with E-cad. By correlating the measured intermembrane distances with the distinct E-cad junction states, we probed the dynamic behavior and diversity of E-cad junctions across different binding pathways. Our observations led to the identification of a transient intermediate state referred to as the X-dimeric state and enabled a detailed analysis of its kinetics. We discovered that the formation of the X-dimer leads to significant membrane displacement, subsequently impacting the formation of other X-dimers. These direct experimental insights into the subtle dynamics of E-cad-modified membranes and the resultant changes in intermembrane distance provide perspectives on the assembly of E-cad junctions between cells. This knowledge enhances our comprehension of tissue and organ development and may serve as a foundation for the development of innovative therapeutic strategies for diseases linked to cell-cell adhesion abnormalities.

Abstract Background Recently, radiotheranostics comprising the true matched radionuclide pair 203/212Pb could serve as real dosimetric planning utility using 203Pb-radiolabelled pharmaceuticals before therapy with 212Pb-radiolabelled counterparts. 212Pb might act as the missing radionuclide therapy between standard β– therapies (e.g. with 177Lu or 90Y), in some cases leading to β– resistance and highly cytotoxic α therapies (e.g. with 225Ac) leading in some cases to renal insufficiency or even renal failure, due to the daughter nuclide 213Bi, which accumulates in > 90% within the kidneys during 225Ac therapy. 212Pb converts to 212Bi by β–-decay and the following pathway of decay bears in sum only one α decay, which certainly happens within the targeted tumour tissue. Following daughter nuclides (e.g. 208Tl), which could distribute in organs at risk have only β− or γ decay, which is not as cytotoxic as α decay. Results By ingenious customization of the standard cassettes of the ML EAZY it was possible to adapt the manual radiosynthesis of [212Pb]Pb-PSC-PEG2-TOC ([212Pb]Pb-VMT-α-NET) to a GMP-compliant synthesis module. The whole process of production, namely conditioning of C18 cartridge for purification, elution of the 224Ra/212Pb-generator, radiolabelling, C18 purification and sterile filtration performed automatically within one hour to access [212Pb]Pb-VMT-α-NET for patient application. [212Pb]Pb-VMT-α-NET was radiolabelled with high radiochemical purity > 95% and high radiochemical yield > 95% with molar activity ~ 15.8 MBq/nmol. Conclusions The Lead-it-EAZY process performed stable and robust over ten radiosyntheses and yielded sterile [212Pb]Pb-VMT-α-NET in high purity for patient application. By changing the precursor this process could easily be adapted to other 212Pb-radiopharmaceuticals.

Abstract We present detailed annual land cover maps for the Baltic Sea region, spanning more than two decades (2000–2022). The maps provide information on eighteen land cover (LC) classes, including eight general LC types, eight major crop types and grassland, and two peat bog-related classes. Our maps represent the first homogenized annual dataset for the region and address gaps in current land use and land cover products, such as a lack of detail on crop sequences and peat bog exploitation. To create the maps, we used annual multi-temporal remote sensing data combined with a data encoding structure and deep learning classification. We obtained the training data from publicly available open datasets. The maps were validated using independent field survey data from the Land Use/Cover Area Frame Survey (LUCAS) and expert annotations from high-resolution imagery. The quantitative and qualitative results of the maps provide a reliable data source for monitoring agricultural transformations, peat bog exploitation, and restoration activities in the Baltic Sea region and its surrounding countries.

Abstract Purpose This retrospective single-center study aimed to investigate incidence and risk factors influencing tibial periprosthetic fractures (TPF) in Oxford unicompartmental knee arthroplasty (UKA), with a specific focus on tibial component positioning and sizing. Methods A total of 2063 patients with medial UKA using the Oxford® mobile partial knee implant were analyzed between July 2014 and September 2022. Various preoperative and postoperative radiographic parameters determining pre- and postoperative alignment and implant positioning, incidence and characteristics of periprosthetic fractures, and patient demographics were assessed. Statistical analyses, including Mann–Whitney U test and logistic regression, were conducted to identify significant associations and predictors of tibial fractures. Results Of the 1853 cases that were finally included in the study, 19 (1%) patients experienced TPF. The fracture group presented with a significantly shorter relative mediolateral and posteroanterior distance between the keel and cortex [mediolateral: 23.3% (23.2–24.8%) versus 27.1% (25.7–28.3%), p

Abstract First principles approaches have revolutionized our ability in using computers to predict, explore, and design materials. A major advantage commonly associated with these approaches is that they are fully parameter-free. However, numerically solving the underlying equations requires to choose a set of convergence parameters. With the advent of high-throughput calculations, it becomes exceedingly important to achieve a truly parameter-free approach. Utilizing uncertainty quantification (UQ) and linear decomposition we derive a numerically highly efficient representation of the statistical and systematic error in the multidimensional space of the convergence parameters for plane wave density functional theory (DFT) calculations. Based on this formalism we implement a fully automated approach that requires as input the target precision rather than convergence parameters. The performance and robustness of the approach are shown by applying it to a large set of elements crystallizing in a cubic fcc lattice.

Abstract Psoriasis is a prevalent, inflammatory skin disease without cure. Further research is required to unravel dysregulated processes and develop new therapeutic interventions. The lack of suitable in vivo and in vitro preclinical models is an impediment in the psoriasis research. Recently, the development of 3D skin models has progressed including replicas with disease-like features. To investigate the use of in vitro models as preclinical test tools, the study focused on treatment responses of 3D skin replicas. Cytokine-priming of skin organoids induced psoriatic features like inflammation, antimicrobial peptides (AMP), hyperproliferation and impaired differentiation. Topical application of dexamethasone (DEX) or celastrol (CEL), a natural anti-inflammatory compound reduced the secretion of pro-inflammatory cytokines. DEX and CEL decreased the gene expression of inflammatory mediators. DEX barely affected the psoriatic AMP transcription but CEL downregulated psoriasis-driven AMP genes. Subcutaneous application of adalimumab (ADM) or bimekizumab (BMM) showed anti-psoriatic effects via protein induction of the differentiation marker keratin-10. Dual blockage of TNF-α and IL-17A repressed the inflammatory psoriasis phenotype. BMM inhibited the psoriatic expression of AMP genes and induced KRT10 and cell-cell contact genes. The present in vitro model provides a 3D environment with in vivo-like cutaneous responses and represents a promising tool for preclinical investigations.

Abstract Background The COVID-19 pandemic and the associated measures have had a significant impact on millions of individuals and families worldwide. Although cross-sectional studies have demonstrated the considerable burden placed on families during the pandemic, trends over different phases of the pandemic including later stages and using population-based samples is scarce. Objective In this study, we aimed to assess trends in family functioning across four population-based surveys between December 2020 and March 2023 using a repeated cross-sectional design. The surveys were conducted using a similar sampling strategy and measures. We included individuals residing in a household with at least one minor below the age of 16. Results The most notable changes across surveys over time were related to quality of life. While 54.3% of respondents reported a decline in quality of life during the winter of 20/21 compared to pre-pandemic levels, this was observed in only 22.6% of participants during the spring of 23. The proportion of respondents who indicated a deterioration in their relations with their children also decreased during the pandemic. While 9.9% of respondents reported a deterioration in their relationship with their children during the winter of 20/21 in comparison to the initial phase of the pandemic, this was reported by only 5.2% in the spring 23. The relationship with one’s partner and health status exhibited minimal fluctuations. Mental health problems were associated with a decline in quality of life, health status and relationships with children and partners compared to pre-pandemic levels at all time points. Moreover, lower income levels were associated with poorer relationship quality with the partner in the most recent wave. Conclusions Our findings demonstrate significant improvements in family functioning since the onset of the pandemic, indicating that individuals and families in our sample were generally adapting well. However, a subgroup of the population still reports suboptimal family functioning compared to before the pandemic. Psychosocial care and social policy support for families are needed.

Abstract Introduction Dysregulated androgen receptor (AR) activity is central to various diseases, particularly prostate cancer (PCa), in which it drives tumour initiation and progression. Consequently, antagonising AR activity via anti-androgens is an indispensable treatment option for metastatic PCa. However, despite initial tumour remission, drug resistance occurs. Therefore, the AR signalling pathway has been intensively investigated. However, the role of AR protein stability in AR signalling and therapy resistance has not yet been deciphered. Therefore, this study aimed to investigate the role of AR protein changes in transactivity and assess its mechanism as a possible target in PCa. Methods LNCaP, C4-2, and 22Rv1 cells were treated with R1881, enzalutamide, cycloheximide, and Rocaglamide. Mass spectrometry analyses were performed on LNCaP cells to identify the pathways enriched by the treatments. Western blotting was performed to investigate AR protein levels and localisation changes. Changes in AR transactivity were determined by qPCR. Results Mass spectrometry analyses were performed on LNCaP cells to decipher the molecular mechanisms underlying androgen- and antiandrogen-induced alterations in the AR protein. Pathway analysis revealed the enrichment of proteins involved in different pathways that regulate translation. Translational and proteasome inhibitor experiments revealed that these AR protein changes were attributable to modifications in translational activity. Interestingly, the effects on AR protein levels in castration-resistant PCa (CRPC) cells C4-2 or enzalutamide-resistant cells 22Rv1 were less prominent and non-existent. This outcome was similarly observed in the alteration of AR transactivation, which was suppressed in hormone-sensitive prostate cancer (HSPC) LNCaP cells by translational inhibition, akin to the effect of enzalutamide. In contrast, treatment-resistant cell lines showed only a slight change in AR transcription. Conclusion This study suggests that in HSPC, AR activation triggers a signalling cascade that increases AR protein levels by enhancing its translation rate, thereby amplifying AR activity. However, this mechanism appears to be dysregulated in castration-resistant PCa cells.

Abstract Participant management in a lung cancer screening (LCS) depends on the assigned Lung Imaging Reporting and Data System (Lung-RADS) category, which is based on reliable detection and measurement of pulmonary nodules. The aim of this study was to compare the agreement of two AI-based software tools for detection, quantification and categorization of pulmonary nodules in an LCS program in Northern Germany (HANSE-trial). 946 low-dose baseline CT-examinations were analyzed by two AI software tools regarding lung nodule detection, quantification and categorization and compared to the final radiologist read. The relationship between detected nodule volumes by both software tools was assessed by Pearson correlation (r) and tested for significance using Wilcoxon signed-rank test. The consistency of Lung-RADS classifications between Software tool 1 (S1, Aview v2.5, Coreline Soft, Seoul, Korea) and Software tool 2 (S2, Prototype ‘’ChestCTExplore’’, software version ToDo, Siemens Healthineers, Forchheim, Germany) was evaluated by Cohen’s kappa (κ) and percentual agreement (PA).The derived volumes of true positive nodules were strongly correlated (r > 0.95), the volume derived by S2 was significantly higher than by S1 (P

Abstract Mountain forests are biodiversity hotspots with competing hypotheses proposed to explain elevational trends in habitat specialization and species richness. The altitudinal-niche-breadth hypothesis suggests decreasing specialization with elevation, which could lead to decreasing species richness and weaker differences in species richness and beta diversity among habitat types with increasing elevation. Testing these predictions for bacteria, fungi, plants, arthropods, and vertebrates, we found decreasing habitat specialization (represented by forest developmental stages) with elevation in mountain forests of the Northern Alps – supporting the altitudinal-niche-breadth hypothesis. Species richness decreased with elevation only for arthropods, whereas changes in beta diversity varied among taxa. Along the forest developmental gradient, species richness mainly followed a U-shaped pattern which remained stable along elevation. This highlights the importance of early and late developmental stages for biodiversity and indicates that climate change may alter community composition not only through distributional shifts along elevation but also across forest developmental stages.

Abstract Background With over 65,000 new cases per year in Germany, prostate cancer (PC) is the most common cancer in men in Germany. Localized PC is often treated by radical prostatectomy and has a very good prognosis. Postoperative quality of life (QoL) is significantly influenced by the side effects of surgery. One possible approach to improve QoL is postoperative symptom monitoring using ePROMs (electronic patient-reported outcome measures) to accurately identify any need for support. Methods The PRO-P (“Influence of ePROMS in surgical therapy of PC on the postoperative course”) study is a randomized controlled trial employing 1:1 randomization at 6 weeks postoperatively, involving 260 patients with incontinence (≥ 1 pad/day) at six participating centers. Recruitment is planned for 1 year with subsequent 1-year follow-up. PRO-monitoring using domains of EPIC-26, psychological burden, and QoL are assessed 6, 12, 18, 24, 36, and 52 weeks postoperatively. Exceeding predefined PRO-score cutoffs triggers an alert at the center, prompting patient contact, medical consultation, and potential interventions. The primary endpoint is urinary continence. Secondary endpoints refer to EPIC-26 domains, psychological distress, and QoL. Aspects of feasibility, effect, and implementation of the intervention will be investigated within the framework of a qualitative process evaluation. Discussion PRO-P investigates the effect on postoperative symptom monitoring of a structured follow-up using ePROMs in the first year after prostatectomy. It is one of the first studies in cancer surgery investigating PRO-monitoring and its putative applicability to routine care. Patient experiences with intensified monitoring of postoperative symptoms and reflective counseling will be examined in order to improve primarily urinary continence, and secondly other burdens of physical and psychological symptoms, quality-of-life, and patient competence. The potential applicability of the intervention in clinical practice is facilitated by IT adaption to the certification standards of the German Cancer Society and the integration of the ePROMs survey via a joint patient portal. Positive outcomes could readily translate this complex intervention into routine clinical care. PRO-P might improve urinary incontinence and QoL in patients with radical prostatectomy through the structured use of ePROMs. Trial registration ClinicalTrials.gov NCT05644821. Registered on 09 December 2022.

Abstract Juvenile crossbred pigs are widely used for acute and chronic animal testing due to their anatomical and physiological resemblance to humans. They are particularly prevalent in preclinical cardiovascular research, including studies investigating extracorporeal resuscitation and mechanical circulatory support devices. However, the availability of comprehensive laboratory reference values is limited. In a single-center study at the University Medical Center Freiburg, Germany, the hematologic and biochemical laboratory values of anesthetized healthy juvenile German crossbred farm pigs were determined. Blood samples were collected at the beginning of surgical procedures, either arterially or venously. Females and males were compared, and correlation with body weight was assessed. In total, 268 animals (weight 57.8 ± 12.4 kg) were included, thereof 180 castrated males (55.2 ± 7.7 kg) and 79 females (63.6 ± 18.3 kg). There were significant differences between males and females in 11 of 45 parameters and a moderate correlation between body weight and creatinine (R = 0.41, p

Abstract Acquired or de novo resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) is a major challenge to ovarian cancer treatment. Therefore, strategies to overcome PARPi resistance are critical to improve prognosis. The purpose of this study is to evaluate whether inhibition of ADAM17 sensitizes ovarian cancer to treatment with olaparib, a PARPi, thereby bypassing resistance mechanisms and improving treatment response. Thus, we analyzed the effect of olaparib in combination with the ADAM17 inhibitor GW280264X in ovarian cancer using a 2D monolayer and a 3D spheroid model followed by a multicontent readout (viability, caspase activation and cytotoxicity). To emphasize the translational aspect of our work, we performed corresponding experiments on primary cells derived from ovarian cancer patients initially screened for their mutation status of the breast cancer gene (BRCA 1/2). In 2D, we observed a significant reduction in cell viability and a subsequent increase in apoptosis of the combined treatment (olaparib + GW280264X) compared with olaparib mono-treatment. The combined treatment allows a substantial dose reduction of olaparib rendering a strong synergistic effect. Using a 3D spheroid model from primary cells, we confirmed the 2D monoculture results and demonstrated not only increased caspase activity under the combined treatment but also a substantial gain in cytotoxicity compared to the mono-treatment. Our study proposes ADAM17 inhibition sensitizing ovarian cancer to olaparib treatment and improving treatment response.

Abstract The genomes of many plants, animals, and fungi frequently comprise dispensable B chromosomes that rely upon various chromosomal drive mechanisms to counteract the tendency of non-essential genetic elements to be purged over time. The B chromosome of rye – a model system for nearly a century – undergoes targeted nondisjunction during first pollen mitosis, favouring segregation into the generative nucleus, thus increasing their numbers over generations. However, the genetic mechanisms underlying this process are poorly understood. Here, using a newly-assembled, ~430 Mb-long rye B chromosome pseudomolecule, we identify five candidate genes whose role as trans-acting moderators of the chromosomal drive is supported by karyotyping, chromosome drive analysis and comparative RNA-seq. Among them, we identify DCR28, coding a microtubule-associated protein related to cell division, and detect this gene also in the B chromosome of Aegilops speltoides. The DCR28 gene family is neo-functionalised and serially-duplicated with 15 B chromosome-located copies that are uniquely highly expressed in the first pollen mitosis of rye.

With an eye on the role of structure size and topology, this study explores the mechanical behavior of nanoporous (NP) Nb made by liquid-metal dealloying. Results from X-ray nanotomography and macro-compression tests confirm that coarsening degrades the yield strength and that Young's modulus deviates from scaling laws developed for NP Au made by dealloying in aqueous media. We find that the scaled genus of NP Nb is lower than what has been reported for NP Au, and this low connectivity provides an obvious explanation for the low modulus. Furthermore, the structural dispersion implies that additional structural descriptors should be acknowledged.

Abstract Fossil fuel subsidy removal may hinder access to clean fuels like LPG. Our analysis of urban Senegal shows that LPG use fell sharply after subsidies ended in 2009, despite later price drops. Households switched to charcoal, and the new availability of energy-efficient charcoal stoves made a return to LPG less appealing. This highlights how energy transitions among the poor are price sensitive, with implications for subsidy and carbon-tax policies.

Abstract Background Intra- and postoperative hemorrhage is a relevant problem in major abdominal surgery, leading to acute anemia and necessitating transfusion of packed red blood cells. It is estimated that in 30% of abdominal surgeries, intra- or postoperative transfusion is required. Transfusion potentially has detrimental health effects and poses a considerable socioeconomic burden. Tranexamic acid, a lysine analog inhibiting plasminogen activation and providing clot stability, has been used to reduce hemorrhage. While there is ample evidence in other surgical disciplines, it is almost completely lacking in abdominal surgery. Methods This multicenter double-blind parallel group randomized superiority trial will compare tranexamic acid (loading dose 1000 mg over 10 min prior to skin incision, maintenance dose 125 mg/h continuously until skin closure or until 1000 mg have been administered) to placebo in patients ≥ 18 years undergoing elective esophagectomy, gastrectomy, colectomy, rectal resection, pancreatic resection, or hepatectomy. The primary efficacy endpoint is the intra- or postoperative transfusion of at least one unit of packed red blood cells. Key secondary endpoints are the number of transfused units per patient, estimated intraoperative blood loss, postoperative complications/mortality, length of hospital stay, operation/anesthesia time, D-dimer levels, and quality of life. Sample size calculation is based on the assumption that in the control group, 30% of patients require transfusion while the intervention achieves a risk reduction of 33%, reducing the probability to 20%. With a type one error of 5% and a power of 90%, using a two-sided χ 2 test, this results in 412 patients per group. Accounting for non-compliance, 425 patients are to be randomized per group. The total trial duration will be 30 months with a recruitment period of 18 months. Discussion If the proposed trial yielded positive results, the routine use of tranexamic acid in major abdominal surgery would be supported. This would avoid acute anemia with detrimental effects such as tissue hypoxia and organ injury, as well as the negative immediate and delayed effects of transfusions. Trial registration EU CT Nr: 2023–509970-43–01, NCT06414031 . Registered on 10 May 2024.

Abstract Objective Patients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival. Methods Patients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and ≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis. Results Of 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations. Conclusion We found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials.

Abstract Background Nonsuicidal self-injury (NSSI) is highly prevalent in adolescents and young adults worldwide. It is linked to a broad variety of mental disorders and an increased suicide risk. Despite its high prevalence, research on the underlying mechanisms and on potential risk and resilience factors for maintaining or quitting NSSI remains scarce. This manuscript presents an overview of the “Self-injury: Treatment-Assessment-Recovery” (STAR) collaboration, which aimed to address these gaps. Methods We investigated the natural course of NSSI as well as its social, psychological, and neurobiological predictors (observational study; OS). OS data collection occurred at four timepoints (baseline [T0], 4 [post, T1], 12 [follow-up (FU), T2], and 18 [FU, T3] months after baseline) for the NSSI group, which was compared to a healthy control (HC) group at T0 only. Online self-report was used at all timepoints, while semi-structured interviews (face-to-face (f2f)) were conducted at T0 and T3. At T0 only, we conducted ecological momentary assessment and neurobiological investigations. Here, we present the general methodology and sample characteristics of the completed OS including the f2f subprojects, while other subprojects are not within the scope of this paper. Sample description The OS sample consists of 343 participants at T0 (180 NSSI, 163 HC). Mean age in the NSSI group (T0) was 18.1 years (SD = 2.09, range: 15–25), gender-related data is available for 166: 156 = female, 7 = male, 3 = transgender, 10 = not disclosed). In the HC group, mean age (T0) was 19.1 years (SD = 2.35, range: 15–25) (142 = female, 21 = male). At T1, 128 (71.11%) of the NSSI participants completed the questionnaires, at T2 125 (69.44%) and at T3 104 (57.78%). In the fMRI subproject, 126 adolescents participated (NSSI = 66, HC = 60, 100% female; mean age (T0): NSSI = 18.10 years, SD = 2.21; HC = 19.08, SD = 2.36). Conclusion Understanding predictors is of utmost importance for adequate diagnosis and intervention for NSSI. Our OS applied a multimodal investigation of social, psychological, and neurobiological parameters and is the largest sample of adolescents with NSSI to date including follow-up assessments. As health care providers require specific knowledge to develop new treatments, we believe that our in-depth assessments can potentially enhance care for youths engaging in NSSI.

Abstract Background Adolescents face many challenges when coping with out-of-home placement, and life story work can be helpful in this context. Typically conducted in individual settings, life story work’s high resource requirements pose a challenge for implementation in the standard care of youth welfare institutions. To address this issue, the ANKOMMEN intervention was developed as a manualized group program for adolescents in residential care focusing on processing and coping with experiences associated with their out-of-home placement. Method The intervention was evaluated in a single-arm pilot study with questionnaires administered at three time points (pre-intervention, post-intervention, and 3-month follow-up). The primary outcome was self-efficacy, while secondary outcomes included self-esteem, depressive symptoms, posttraumatic stress symptoms, and behavioral problems. A total of 31 intervention groups with 115 adolescents (M = 14.91 years; SD = 1.45; 52.2% male) were conducted between October 2020 and September 2022 in Germany. Data were analysed using mixed effect models. Results Pre-post comparisons revealed increased self-efficacy (d = −0.80) and self-esteem (d = −0.68) among participants with below-average scores prior to the intervention. Additionally, there was a decrease in self-reported depressive symptoms (d = 0.76), self-reported posttraumatic stress symptoms (d = 0.58), self-reported internalizing behavior problems (d = 0.74), caregiver-reported internalizing behavior problems (d = 0.76), and self-reported externalizing behavior problems (d = 0.52) for participants with clinically relevant scores prior to the intervention. These improvements were stable in the 3-month follow-up assessment. Furthermore, the intervention proved its feasibility in standard care within the context of the evaluation study. Conclusions The results of the pilot study provide preliminary evidence for the feasibility and potential effectiveness of ANKOMMEN but further research is needed to obtain valid evidence for the efficacy of the intervention.

Abstract Our species and other hominins have used earth mineral pigments since at least ~500,000 years ago, if not earlier. Its preservation and ubiquity within archaeological records across sub-Saharan Africa are well documented, but regional-scale networks of mineral selection, mining, transport, and use is an underdeveloped field. Here, we present a framework for interpreting regional variations within an overarching ochre-behavioral community of practice. Deep-time records of ochre provisioning span the final Middle Stone Age and Late Stone Age in modern day Eswatini, revealing longstanding cultural continuities in the intergenerational transmission of shared knowledge on landscapes, geology, and the desired physicochemical properties of mineral pigments. These communities of practice did not develop in isolation, and were part of a wider system of relations that were influenced and mediated by social interactions, such as technological learning, seasonal traveling, material culture exchange, and symbolic expression. We use compositional analyses to determine localized ochre procurement strategies and long-distance transport across a network of fifteen archaeological sites and mineral resources. Newly refined chronologies from Lion Cavern at Ngwenya using optically stimulated luminescence dating also reaffirm its antiquity as the oldest known evidence for intensive ochre mining worldwide (~48,000 years ago).

Abstract Background Periodontitis, a prevalent chronic inflammatory disease, offers insights into the broader landscape of chronic inflammatory conditions. The progression and treatment outcomes of periodontitis are closely related to the oral microbiota’s composition. Adjunctive systemic Amoxicillin 500 mg and Metronidazole 400 mg, often prescribed thrice daily for 7 days to enhance periodontal therapy’s efficacy, have lasting effects on the oral microbiome. However, the precise mechanism through which the oral microbiome influences clinical outcomes in periodontitis patients remains debated. This investigation explores the pivotal role of the oral microbiome's composition in mediating the outcomes of adjunctive systemic antibiotic treatment. Methods Subgingival plaque samples from 10 periodontally healthy and 163 periodontitis patients from a randomized clinical trial on periodontal therapy were analyzed. Patients received either adjunctive amoxicillin/metronidazole or a placebo after mechanical periodontal treatment. Microbial samples were collected at various intervals up to 26 months post-therapy. Using topic models, we identified microbial communities associated with normobiotic and dysbiotic states, validated with 86 external and 40 internal samples. Logistic regression models evaluated the association between these microbial communities and clinical periodontitis parameters. A Directed Acyclic Graph (DAG) determined the mediating role of oral microbiota in the causal path of antibiotic treatment effects on clinical outcomes. Results We identified clear distinctions between dysbiotic and normobiotic microbial communities, differentiating healthy from periodontitis subjects. Dysbiotic states consistently associated with below median %Pocket Probing Depth ≥ 5 mm (OR = 1.26, 95% CI [1.14–1.42]) and %Bleeding on Probing (OR = 1.09, 95% CI [1.00–1.18]). Factors like microbial response to treatment, smoking, and age were predictors of clinical attachment loss progression, whereas sex and antibiotic treatment were not. Further, we showed that the oral microbial treatment response plays a crucial role in the causal effect of antibiotic treatment on clinical treatment outcomes. Conclusions The shift towards a normobiotic subgingival microbiome, primarily induced by adjunctive antibiotics, underscores the potential for microbiome-targeted interventions to enhance therapeutic efficacy in chronic inflammatory conditions. This study reaffirms the importance of understanding the oral microbiome's role in periodontal health and paves the way for future research exploring personalized treatment strategies based on individual microbiome profiles. Video Abstract

Abstract Background Glycosphingolipids (GSLs) are membrane lipids composed of a ceramide backbone linked to a glycan moiety. Ganglioside biosynthesis is a part of the GSL metabolism, which involves sequential reactions catalyzed by specific enzymes that in part have a poor substrate specificity. GSLs are deregulated in cancer, thus playing a role as potential biomarkers for personalized therapy or subtype classification. However, the analysis of GSL profiles is complex and requires dedicated technologies, that are currently not included in the commonly utilized high-throughput assays adopted in contexts such as molecular tumor boards. Methods In this study, we developed a method to discriminate the enzyme activity among the four series of the ganglioside metabolism pathway by incorporating transcriptome data and topological information of the metabolic network. We introduced three adjustment options for reaction activity scores (RAS) and demonstrated their application in both exploratory and comparative analyses by applying the method on neuroblastic tumors (NTs), encompassing neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Furthermore, we interpreted the results in the context of earlier published GSL measurements in the same tumors. Results By adjusting RAS values using a weighting scheme based on network topology and transition probabilities (TPs), the individual series of ganglioside metabolism can be differentiated, enabling a refined analysis of the GSL profile in NT entities. Notably, the adjustment method we propose reveals the differential engagement of the ganglioside series between NB and GNB. Moreover, MYCN gene expression, a well-known prognostic marker in NTs, appears to correlate with the expression of therapeutically relevant gangliosides, such as GD2. Using unsupervised learning, we identified subclusters within NB based on altered GSL metabolism. Conclusion Our study demonstrates the utility of adjusting RAS values in discriminating ganglioside metabolism subtypes, highlighting the potential for identifying novel cancer subgroups based on sphingolipid profiles. These findings contribute to a better understanding of ganglioside dysregulation in NT and may have implications for stratification and targeted therapeutic strategies in these tumors and other tumor entities with a deregulated GSL metabolism.

Abstract Natural Killer (NK) cells are pivotal in immune responses to viral infections, malignancies, autoimmune diseases, and transplantation. Assessment of NK cell adhesion, migration, and cytotoxicity is fundamental for in vitro studies. We propose a novel live-cell tracking method that addresses these three major aspects of NK cell function using human NK cells and primary porcine aortic endothelial cells (PAECs) in two-dimensional (2D) static assays and an in-house cylindrical 3D microfluidic system. The results showed a significant increase of NK cytotoxicity against pTNF-activated PAECs, with apoptotic cell death observed in the majority of dead cells, while no difference was observed in the conventional Delfia assay. Computed analysis of NK cell trajectories revealed distinct migratory behaviors, including trajectory length, diameter, average speed, and arrest coefficient. In 3D microfluidic experiments, NK cell attachment to pTNF-activated PAECs substantially increased, accompanied by more dead PAECs compared to control conditions. NK cell trajectories showed versatile migration in various directions and interactions with PAECs. This study uniquely demonstrates NK attachment and killing in a 3D system that mimics blood vessel conditions. Our microscope method offers sensitive single-cell level results, addressing diverse aspects of NK functions. It is adaptable for studying other immune and target cells, providing insights into various biological questions.

Abstract Structural chirality and magnetism, when intertwined, can have profound implications on materials properties. Using X-ray imaging and spectroscopic measurements that leverage the natural and magnetic circular dichroic effects present in magnetized chiral crystal structures, we probe the interplay between chirality and magnetism across the field-induced spin-flop transition of Dy ferroborate, $$\hbox {DyFe}_3$$ DyFe 3 ( $$\hbox {BO}_3$$ BO 3 ) $$_4$$ 4 . Deconvolution of natural and magnetic circular dichroic signals at the Fe K and Dy L $$_{2,3}$$ 2 , 3 absorption edges of the non-centrosymmetric structure was enabled by use of tunable temperature and magnetic field, providing access to element-specific magnetic information across the spin-flop transition. The magnetic response of Fe and Dy sublattices was found to be independent of domain chirality. The chiral domains were robust against both the (chirality preserving) R32 to P3 $$_1$$ 1 21/P3 $$_2$$ 2 21 structural phase transition at 280 K, and application of magnetic field up to 4 Tesla. A third flavor of X-ray dichroism, magneto-chiral dichroism, was not detected within the accuracy of our measurements. The absence of significant Fe magnetization along the screw, c-axis for the magnetic field strength used in this study, together with non-linear coupling of magnetic field to electric polarization across the spin-flop transition, may hinder observation of magneto-chiral dichroic effects in this system.

Abstract Promiscuous enzymes often serve as the starting point for the evolution of novel functions. Yet, the extent to which the promiscuity of an individual enzyme can be harnessed several times independently for different purposes during evolution is poorly reported. Here, we present a case study illustrating how NAD(P)+-dependent succinate semialdehyde dehydrogenase of Escherichia coli (Sad) is independently recruited through various evolutionary mechanisms for distinct metabolic demands, in particular vitamin biosynthesis and central carbon metabolism. Using adaptive laboratory evolution (ALE), we show that Sad can substitute for the roles of erythrose 4-phosphate dehydrogenase in pyridoxal 5’-phosphate (PLP) biosynthesis and glyceraldehyde 3-phosphate dehydrogenase in glycolysis. To recruit Sad for PLP biosynthesis and glycolysis, ALE employs various mechanisms, including active site mutation, copy number amplification, and (de)regulation of gene expression. Our study traces down these different evolutionary trajectories, reports on the surprising active site plasticity of Sad, identifies regulatory links in amino acid metabolism, and highlights the potential of an ordinary enzyme as innovation reservoir for evolution.

Abstract When defending against hostile enemies, individual group members can benefit from others staying in the group and fighting. However, individuals themselves may be better off by leaving the group and avoiding the personal risks associated with fighting. While fleeing is indeed commonly observed, when and why defenders fight or flee remains poorly understood and is addressed here with three incentivized and preregistered experiments (total n = 602). In stylized attacker-defender contest games in which defenders could stay and fight or leave, we show that the less costly leaving is, the more likely individuals are to abandon their group. In addition, more risk-averse individuals are more likely to leave. Conversely, individuals more likely stay and fight when they have pro-social preferences and when fellow group members cannot leave. However, those who stay not always contribute fully to group defense, to some degree free-riding on the efforts of other group members. Nonetheless, staying increased intergroup conflict and its associated costs.

Abstract Background Maxillary retrognathia and/or mandibular prognathia are resulting in class III malocclusion. Regarding orthodontic class III malocclusion treatment, the literature reports several treatment approaches. This comparative clinical study investigated two maxillary protraction protocols including bone anchors and Delaire type facemask. Methods Cephalometric radiographs of n = 31 patients were used for data acquisition. The patients were divided into two groups according to their treatment protocol: bone anchored protraction (n = 12, 8 female, 4 male; mean age 11.00 ± 1.76 years; average application: 13.50 ± 5.87 months) and facemask protraction (n = 19, 11 female, 8 male; mean age 6.74 ± 1.15 years; average application: 9.95 ± 4.17 months). The evaluation included established procedures for measurements of the maxilla, mandibula, incisor inclination and soft tissue. Statistics included Shapiro-Wilk- and T-Tests for the radiographs. The level of significance was set at p