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This paper introduces a modular simulation testbed developed for decision support in logistics and urban planning within the tourism sector, specifically applied to Şanlıurfa, Turkey, as part of the GeostaloVR project. The testbed integrates tourism value chains, urban development processes, and mobility flows to facilitate scenario testing and evaluation. By incorporating real-world data, the simulation framework enables the analysis of key performance indicators for sustainable urban tourism development. This approach aims to advance the application of modeling techniques to address complex challenges in urban tourism in order to provide valuable insights for stakeholders involved in urban and logistics planning.

Abstract Background Symptoms in acute cerebral sinus venous thrombosis (CSVT) are highly variable, ranging from headaches to fatal stroke, and the basis for this high inter-individual variability is poorly understood. The present study aimed to assess whether acute CSVT significantly alters regional cerebral blood flow (CBF), if findings differ from CBF patterns know from large-artery occlusion in stroke, and whether the pattern of CBF alterations depends on clot location. Therefore, we retrospectively analyzed 12 patients with acute CSVT 10.6 ± 4.6 days after symptom onset and ten healthy volunteers who underwent [15O]water PET (two scans each, 300 ± 14 MBq [15O]water). Static image datasets (15–75 s after injection; normalized to cerebellum) reflecting relative CBF (rCBF) were analyzed using voxel- and region-of-interest-based analysis (AAL3-atlas). We mirrored datasets of patients with left-sided CSVT to harmonize the affected hemisphere. Results Seven and five patients showed right- and left-sided CSVT, respectively. The superior sagittal sinus (SSS) was involved in 8/12 patients. CSVT patients had extensive rCBF deficits in the voxel-based analysis with accentuation in the right (ipsilateral) frontal cortex and caudate nucleus compared to controls, which were most pronounced in cortical areas in those with involvement of the SSS (8/12), and in subcortical areas in those without involvement of the SSS (4/12; p

Abstract High levels of thyroid hormones are linked to increased risk and advanced stages of breast cancer. Our previous work demonstrated that the biologically active triiodothyronine (T3) facilitates mitochondrial ATP production by upregulating Ca2+ handling proteins, thereby boosting mitochondrial Ca2+ uptake and Krebs cycle activity. In this study, different cell types were utilized to investigate whether T3 activates a Ca2+-induced signaling pathway to boost cancer cell proliferation. Using live-cell imaging, biochemical assays, and molecular profiling, differences in intracellular signaling among MCF7 and MDA-MB-468 breast cancer cells, non-cancerous breast cells hTERT-HME1, and PC3 prostate carcinoma cells, previously found to be insensitive to thyroid hormones in terms of proliferation, were investigated. Our findings revealed that T3 upregulates 1,4,5-trisphosphate receptor 3 via thyroid hormone receptor α. This boosts mitochondrial Ca2+ uptake, reduction equivalent yield, and mitochondrial ATP production, supporting the viability and proliferation of breast cancer cells without affecting non-cancerous hTERT-HME1 or PC3 prostate carcinoma cells. Understanding the interplay between T3 signaling, organellar interaction, and breast cancer metabolism could lead to targeted therapies that exploit cancer cell vulnerabilities. Our findings highlight T3 as a crucial regulator of cancer metabolism, reinforcing its potential as a therapeutic target in breast cancer. Graphical Abstract

Abstract Against conventional wisdom, corrugated grain boundaries in polycrystalline graphene, grown on Pt(111) surfaces, are shown to exhibit negative friction coefficients and non-monotonic velocity dependence. Using combined experimental, simulation, and modeling efforts, the underlying energy dissipation mechanism is found to be dominated by dynamic buckling of grain boundary dislocation protrusions. The revealed mechanism is expected to appear in a wide range of polycrystalline two-dimensional material interfaces, thus supporting the design of large-scale dry superlubric contacts.

Abstract Low injectivity is often experienced in geothermal doublets installed in sandstone reservoirs. This even led to a shutdown of the Mezőberény (Hungary) geothermal site. An on-site campaign was carried out in January 2021 to prepare a stimulation aiming to enhance the transmissivity of the sedimentary reservoir and the near-wellbore zone of this site. Previous studies have concluded that insufficient injectivity may be linked to a high skin effect in the near well-bore zone and pore clogging in combination with the low net sandstone content of the fluvio-deltaic reservoir. A chemical soft stimulation based on the injection of hydrochloric acid (HCl) was successfully used to unclog and recover the well injectivity. Despite such empirical evidence, the geochemical mechanisms leading to both, detrimental formation of clogging and the HCl-driven transmissivity restoration, have not yet been elucidated. This work presents the results of a novel analysis aiming at (a) predicting the dominant type of clogging forming in the near-well bore zone; (b) quantifying the drop in hydraulic conductivity as clogging occurs; and (c) supporting the optimization of the HCl dosage during the chemical soft stimulation. The study is supported by new experimental datasets never presented before from the Mezőberény site and a geochemical model set-up simulating the main mechanisms involved in the clogging and unclogging processes. It is concluded that the biofilm formation was the dominant, while the precipitation of calcite and amorphous ferrihydrite—later reduced to magnetite by microbes—was the secondary clogging mechanism: In the long-term (yearly scale) simulating the hydraulic conductivity showed a decline with forming scales; therefore, biofilm was presumably responsible for the experienced rapid (1 month) clogging. When modelling the chemical stimulation, the estimated amount of precipitated minerals was dissolved already with 2.5 mol of HCl per liter of water (~ 10 m/m%). Therefore, the 20 m/m% of HCl chosen during the field campaign might had a beneficial effect dissolving the potentially higher amount of scaling and/or the carbonate minerals of the matrix near the wellbore. Overall, it is concluded that the chemical and the microbial analyses together with the geochemical model were critical to tailor the remediation attempts and to propose further development or reconstruction of the surface system before going into operation to prevent recurrent impairments. Our findings highlight the importance of interactions of various clogging mechanisms with each other as well as with the reservoir processes and provide approaches to tackle the issue of injectivity drop by characterizing and quantifying their effects.

Abstract Among the common strategies to design next-generation COVID-19 vaccines is broadening the antigenic repertoire thereby aiming to increase efficacy against emerging variants of concern (VoC). This study describes a new Orf virus-based vector (ORFV) platform to design a multiantigenic vaccine targeting SARS-CoV-2 spike and nucleocapsid antigens. Vaccine candidates were engineered, either expressing spike protein (ORFV-S) alone or co-expressing nucleocapsid protein (ORFV-S/N). Mono- and multiantigenic vaccines elicited comparable levels of spike-specific antibodies and virus neutralization in mice. Results from a SARS-CoV-2 challenge model in hamsters suggest cross-protective properties of the multiantigenic vaccine against VoC, indicating improved viral clearance with ORFV-S/N, as compared to equal doses of ORFV-S. In a nonhuman primate challenge model, vaccination with the ORFV-S/N vaccine resulted in long-term protection against SARS-CoV-2 infection. These results demonstrate the potential of the ORFV platform for prophylactic vaccination and represent a preclinical development program supporting first-in-man studies with the multiantigenic ORFV vaccine.

Abstract Photonic integrated circuits (PICs) represent a promising technology for the much-needed medical devices of today. Their primary advantage lies in their ability to integrate multiple functions onto a single chip, thereby reducing the complexity, size, maintenance requirements, and costs. When applied to optical coherence tomography (OCT), the leading tool for state-of-the-art ophthalmic diagnosis, PICs have the potential to increase accessibility, especially in scenarios, where size, weight, or costs are limiting factors. In this paper, we present a PIC-based CMOS-compatible spectrometer for spectral domain OCT with an unprecedented level of integration. To achieve this, we co-integrated a 512-channel arrayed waveguide grating with electronics. We successfully addressed the challenge of establishing a connection from the optical waveguides to the photodiodes monolithically co-integrated on the chip with minimal losses achieving a coupling efficiency of 70%. With this fully integrated PIC-based spectrometer interfaced to a spectral domain OCT system, we reached a sensitivity of 92dB at an imaging speed of 55kHz, with a 6dB signal roll-off occurring at 2mm. We successfully applied this innovative technology to obtain 3D in vivo tomograms of zebrafish larvae and human skin. This ground-breaking fully integrated spectrometer represents a significant step towards a miniaturised, cost-effective, and maintenance-free OCT system.

The minnows of the Phoxinus genus were long thought to be a single species, as even experts found it difficult to distinguish them by external features. In the last 20 years, however, their status has changed dramatically as molecular studies have revealed a high level of genetic diversity within this group of fish. Currently, more than 23 genetic lineages are known in Europe, of which 14 are recognised as valid species. In Austria, instead of one common minnow, studies have revealed at least four species, three of which are presumed native and one introduced. The Citizen Science project “Biodiversity of minnows in Austria”, funded by the Federal Ministry of Education, Science and Research as part of the “Sparkling Science 2.0” Programme, aims to collect and analyse the missing data to determine the number of minnow species swimming in Austrian waters. With the help of pupils from six different schools across Austria, fisheries associations and numerous independent fishermen, the minnows are being sampled extensively and their genetic lineages determined. Basic data on their habitat is also being collected using standardised forms. At the same time, the project team is analysing up to 200-year-old specimens from the fish collection of the National History Museum in Vienna to assess the rate of change in the minnow’s biodiversity. Our initial results confirm the native distribution of three minnow species in Austria and show several mixing zones between them, which may not be natural. This is therefore a study of change: on the one hand, changes in genetic diversity over time are evaluated. On the other hand, it highlights the changes that new methods are bringing to our scientific and general knowledge about biodiversity. One of the most dramatic consequences of human impact on our planet is the continuing loss of global biodiversity. What better way to experience these changes than by actively participating in a study designed to assess them?

3D ultrasound imaging is a promising modality for therapy guidance, e.g. in radiation therapy. It is able to provide volumetric soft tissue images in real-time. However, due to low image quality, high noise ratio and high data dimensionality, real-time capable US image processing methods like target tracking are challenging. In this study, a feature-based tracking approach is investigated. The FAST feature detector is used to detect local image features in 3D ultrasound images. Two different feature descriptors are tested and evaluated in terms of target tracking: The BRIEF descriptor as well as a slicedwasserstein autoencoder. On the basis of a feature matching algorithm, tracking experiments are executed and evaluated using eight labeled 3D US sequences. The mean tracking error measured is 2.08±1.50mm and 2.29±1.59mm using the autoencoder and the BRIEF descriptor, respectively. The results indicate that using an autoencoder for feature description improves the tracking performance compared to a binary descriptor. The proposed tracking method could be executed in fast runtimes of 137 ms and 256 ms per image on average making it real-time capable.

Ultrasound gel is used as a coupling medium in ultrasound procedures, thereby ensuring the entry of sound waves into the body of the patient and providing ultrasound images of high quality. In this paper, we present an approach to automatically supply ultrasound gel during robot guided ultrasound examinations. For this purpose, we combine a simple mechanical design consisting of a gel tube and a push mechanism with a specialized control strategy exploiting the robotic nullspace of 7 DoF redundant manipulator. Functionality is demonstrated by robotic ultrasound scans on phantoms, with gel being automatically applied when needed.

In radiation therapy, breathing and other influences cause a constant movement of the tissue to be irradiated. Thus, a continuous position control is required which could be handled by the usage of 3D ultrasound imaging. For this purpose, two approaches for target tracking in 3D ultrasound (US) sequences of the liver are analyzed in this study. Therefore, an image-by-image localization of the target is performed using a deep localization network. A singletarget and a multiple-target approach are investigated where deep localization networks are trained for locating one specific and multiple specific targets, respectively. Training the networks and evaluating the tracking algorithm is performed on the basis of a labeled 3D US liver data set in 2-fold crossvalidation experiments. The single-target and multiple-target approaches performed comparable with a mean tracking error of 2.28±1.20mm and 2.23±1.28 mm, respectively. The proposed tracking algorithm is real-time capable with a mean runtime per 3D ultrasound image of 68ms.

Abstract Aluminum and magnesium are the lightest structural metals, and therefore, various alloys based on them are widely used in both, automotive and aerospace industries. However, aluminum and magnesium are very easily affected by atmospheric and aqueous corrosion, and, therefore, the alloying elements should enhance their corrosion stability. In this work, the thermodynamic analysis of phase and chemical equilibria involving aluminum and magnesium alloys doped with silicon in oxygen–containing air environments, as well as the analysis of chemical and electrochemical equilibria involving these alloys in aqueous environments is conducted. The phase and chemical equiliibria in the Al–Mg, Al–Si, Mg–Si, and Al–Mg–Si systems at 298 K are considered, and the thermodynamic activities of the components of common Al–Mg–Si system alloys are calculated. The invariant chemical equilibria in the systems Al–Mg–O, Al–Si–O, Mg–Si–O at 298 K are considered, the isothermal section of the state diagrams of these systems are plotted, and the oxidation scheme of the Al–Mg–Si system alloys in excess oxygen is proposed. The chemical and electrochemical equilibria in the Al–Mg–Si–H2O system at 298 K are considered and presented in form of the activity – pH and the potential – pH diagrams, and the oxidation of the Al–Mg–Si system alloys in aqueous environments is discussed.

Abstract Insulin-like growth factor (IGF) signaling is required for proper growth and skeletal development in vertebrates. Consequently, its dysregulation may lead to abnormalities of growth or skeletal structures. IGF is involved in the regulation of cell proliferation and differentiation of chondrocytes. However, the availability of bioactive IGF may be controlled by antagonizing IGF binding proteins (IGFBPs) in the circulation and tissues. As the metalloproteinase PAPP-A specifically cleaves members of the IGFBP family, we hypothesized that PAPP-A activity liberates bioactive IGF in cartilage. In PAPP-A knockout mice, the femur length was reduced and the mice showed a disorganized columnar organization of growth plate chondrocytes. Similarly, zebrafish lacking pappaa showed reduced length of Meckel’s cartilage and disorganized chondrocytes, reminiscent of the mouse knockout phenotype. Expression of chondrocyte differentiation markers (sox9a, ihha, and col10a1) was markedly affected in Meckel’s cartilage of pappaa knockout zebrafish, indicating that differentiation of chondrocytes was compromised. Additionally, the zebrafish pappaa knockout phenotype was mimicked by pharmacological inhibition of IGF signaling, and it could be rescued by treatment with exogenous recombinant IGF-I. In conclusion, our data suggests that IGF activity in the growing cartilage, and hence IGF signaling in chondrocytes, requires the presence of PAPP-A. The absence of PAPP-A causes aberrant chondrocyte organization and compromised growth in both mice and zebrafish.

Abstract Deployment of ultracold atom interferometers (AI) into space will capitalize on quantum advantages and the extended freefall of persistent microgravity to provide high-precision measurement capabilities for gravitational, Earth, and planetary sciences, and to enable searches for subtle forces signifying physics beyond General Relativity and the Standard Model. NASA’s Cold Atom Lab (CAL) operates onboard the International Space Station as a multi-user facility for fundamental studies of ultracold atoms and to mature space-based quantum technologies. We report on pathfinding experiments utilizing ultracold 87Rb atoms in the CAL AI. A three-pulse Mach–Zehnder interferometer was studied to understand the influence of ISS vibrations. Additionally, Ramsey shear-wave interferometry was used to manifest interference patterns in a single run that were observable for over 150 ms free-expansion time. Finally, the CAL AI was used to remotely measure the Bragg laser photon recoil as a demonstration of the first quantum sensor using matter-wave interferometry in space.

Abstract Phosphorus pentamers (cyclo-P5) are unstable in nature but can be synthesized at the Ag(111) surface. Unlike monolayer black phosphorous, little is known about their electronic properties when in contact with metal electrodes, although this is crucial for future applications. Here, we characterize the atomic structure of cyclo-P5 assembled on Ag(111) using atomic force microscopy with functionalized tips and density functional theory. Combining force and tunneling spectroscopy, we find that a strong charge transfer induces an inward dipole moment at the cyclo-P5/Ag interface as well as the formation of an interface state. We probe the image potential states by field-effect resonant tunneling and quantify the increase of the local change of work function of 0.46 eV at the cyclo-P5 assembly. Our experimental approach suggest that the cyclo-P5/Ag interface has the characteristic ingredients of a p-type semiconductor-metal Schottky junction with potential applications in field-effect transistors, diodes, or solar cells.

We present the Gaussian Mixture Periodicity Detection Algorithm (GMPDA), a novel method for detecting periodicity in the binary time series of event onsets. The GMPDA addresses the periodicity detection problem by inferring parameters of a generative model. We introduce two models, the Clock Model and the Random Walk Model, which describe distinct periodic phenomena and provide a comprehensive generative framework. The GMPDA demonstrates robust performance in test cases involving single and multiple periodicities, as well as varying noise levels. Additionally, we evaluate the GMPDA on real-world data from recorded leg movements during sleep, where it successfully identifies expected periodicities despite high noise levels. The primary contributions of this paper include the development of two new models for generating periodic event behavior and the GMPDA, which exhibits high accuracy in detecting multiple periodicities even in noisy environments.

Abstract Background Colombian indigenous Wiwas are exposed to a variety of partly complex medical conditions with a predominance of infectious diseases. The study provided here aims at verifying of falsifying previous suspicions on therapeutic shortcomings and neglect of disease categories. Material and methods Local diagnoses within various subpopulations of indigenous Wiwas obtained by a study physician and local health brigades and health points between 2017 and 2018 were coded following the ICD 10 classification from 2019. Proportions of diagnoses per ICD-10 sub-chapter were evaluated to find diseases and to rank the occurrence of diagnoses in the population of indigenous people. Thereafter, the available medication provided by the indigenous health care provider Dusakawi for the treatment of the indigenous patients was analyzed in regard of its sufficiency to cover the recorded diseases. Results The majority of the diseases found in the communities cannot at all (32%) or only partially (56%) be treated according to available guidelines. Only few (12%), predominantly infectious diseases, were covered completely by the provided medication. Notably, there are some ICD chapters with diseases that do only rarely appear at all in the gained datasets, e.g., complications during birth, mental disorders or cancer. Conclusions An expansion and revision of the medical supply for the indigenous population of the Sierra Nevada de Santa Marta is needed. An emergency kit for medical brigades and health points should be provided and in place. Awareness for neglected diseases needs to be created.

Abstract Houseflies provide a good experimental model to study the initial evolutionary stages of a primary sex-determining locus because they possess different recently evolved proto-Y chromosomes that contain male-determining loci (M) with the same male-determining gene, Mdmd. We investigate M-loci genomically and cytogenetically revealing distinct molecular architectures among M-loci. M on chromosome V (M V ) has two intact Mdmd copies in a palindrome. M on chromosome III (M III ) has tandem duplications containing 88 Mdmd copies (only one intact) and various repeats, including repeats that are XY-prevalent. M on chromosome II (M II ) and the Y (M Y ) share M III -like architecture, but with fewer repeats. M Y additionally shares M V -specific sequence arrangements. Based on these data and karyograms using two probes, one derives from M III and one Mdmd-specific, we infer evolutionary histories of polymorphic M-loci, which have arisen from unique translocations of Mdmd, embedded in larger DNA fragments, and diverged independently into regions of varying complexity.

Jana L Flener,1 Brian Po-Han Chen,2 Frank R Ernst,3 Aaron Libolt,1 Najmuddin J Gunja,2 William P Barrett1 1Proliance Orthopedic Associates, Renton, WA, USA; 2Health Economics and Market Access, Ethicon Inc., Raritan, NJ, USA; 3Real World Evidence and Late Phase, CTI Clinical Trial and Consulting Services, Covington, KY, USACorrespondence: Najmuddin J Gunja, Health Economics and Market Access, 1000 US Highway 202, Raritan, NJ, 08869-1425, USA, Tel +1(908)685-2151, Email ngunja@its.jnj.comBackground: In total joint replacement procedures, surgeons have increasingly adopted advanced multi-layer, watertight closure. The objective of the study was to compare the clinical and economic outcomes for advanced multi-layer, watertight closure patients to those with conventional closure with sutures and skin staples.Methods: Patients aged ≥ 18 years were included in the study if they underwent total joint arthroplasty of the hip or knee as an elective, primary, inpatient procedure between January 2014 and March 2019. Cohorts having advanced multi-layer, watertight closure or conventional closure were compared using multivariable regression analysis of surgical site infections, length of stay, operating room time, procedure time, discharge status, readmissions, reoperations, and hospital emergency department visits.Results: A total of 1828 patients received at least one total hip or knee replacement, of which 434 (23.7%) had advanced multi-layer, watertight closure and 1394 (76.3%) had conventional closure. Unadjusted time to readmission, when occurring, was considerably longer following advanced multi-layer, watertight closure (89.9 vs 51.1 days, p < 0.0001), and a lower proportion of the advanced multi-layer, watertight closure cohort required reoperation within 90 days (0.0% vs 2.6%, p < 0.0001). Adjusted mean hospital length of stay was approximately half of a day shorter for advanced multi-layer, watertight closure patients (1.10 vs 1.65 days; p < 0.001), and they were also more likely to be discharged to home (Odds Ratio: 4.61; p = 0.002).Conclusion: Among patients undergoing total hip and knee arthroplasty in a highly optimized real-world clinical practice, advanced multi-layer, watertight closure was associated with significantly shorter inpatient length of stay and increased likelihood of being discharged to home compared with conventional closure. These findings suggest that advanced multi-layer, watertight closure is a valuable component of an optimal workflow for total hip or knee replacement, and may be especially valuable for high-risk patients.Keywords: wound closure, total joint arthroplasty, stratafix, dermabond prineo

This paper discusses disadvantaging situations that deaf students encounter in higher education in Sweden. We report two recent cases of deaf students’ academic welfare being put at risk. We foreground in these cases the ‘odd situations’ that arise when provisions that fail to access the particular nature of deaf experience also fail to secure deaf students’ participation rights, to be and become the deaf person they wish to be, lead the life they wish to live, and so on. Often, the ‘oddness’ of the situations that arise is in part indicated by no-one involved lacking in good intentions or not doing their very best: there is no lack of good will, but a lack of shared understanding. What deaf students know differently is rarely present in deliberation and not part of forward planning. We infer that situations of this sort reflect epistemic injustice. We propose that this form of formative epistemic injustice – educators not taking on board what deaf students know – can perhaps be overcome by higher education institutions proactively involving deaf students in matters that concern both them and future deaf students.

Abstract The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals’ genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

Abstract Background Frailty is an indicator of a decline in quality of life and functional capacity in cardiac rehabilitation (CR) patients. Currently, there is no standardized assessment tool for frailty used in CR. The aim of this study was to determine if the Clinical Frailty Scale (CFS) is feasible for assessing frailty in CR. Methods Prospective, cross-sectional study within the framework of the ongoing multicenter prehabilitation study "PRECOVERY". Patients ≥75 years undergoing CR after cardiac procedure (n=122) were recruited in four German inpatient CR facilities. Assessments included: CFS, Katz-Index, hand grip strength (HGS), Short Physical Performance Battery (SPPB) and six-minute-walk test (6MWT). Outcomes were frailty (CFS≥4) and the correlation of frailty with assessments of functional capacity, activities of daily living and clinical parameters. Statistical analysis included descriptive statistics and correlations, using the spearman correlation coefficient and chi-square test to test for significance. Results Data from 101 patients (79.9±4.0 years; 63% male) were analyzed. The mean CFS score was 3.2±1.4; 41.6% were defined as frail (CFS≥4). The mean time required to assess the CFS was 0.20 minutes. The findings show that CFS correlates significantly (p

Theresa Klett,1,&ast; Martin Schwer,1,&ast; Larissa N Ernst,1,&ast; Marc U Engelhardt,1 Simon J Jaag,2 Benedikt Masberg,2 Cornelius Knappe,2 Michael Lämmerhofer,2 Matthias Gehringer,3,4 Frank M Boeckler1,5 1Laboratory for Molecular Design & Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 2Pharmaceutical (Bio-) Analysis, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 3Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 4Medicinal Chemistry, Institute for Biomedical Engineering, Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany; 5Interfaculty Institute for Biomedical Informatics (IBMI), Eberhard Karls Universität Tübingen, Tübingen, 72076, Germany&ast;These authors contributed equally to this workCorrespondence: Frank M Boeckler, Laboratory for Molecular Design & Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8 (Haus B), Tübingen, D – 72076, Germany, Tel +49 7071 29 74567, Email frank.boeckler@uni-tuebingen.dePurpose: Over the last few years, covalent fragment-based drug discovery has gained significant importance. Thus, striving for more warhead diversity, we conceived a library consisting of 20 covalently reacting compounds. Our covalent fragment library (CovLib) contains four different warhead classes, including five α-cyanoacacrylamides/acrylates (CA), three epoxides (EO), four vinyl sulfones (VS), and eight electron-deficient heteroarenes with a leaving group (SNAr/SN).Methods: After predicting the theoretical solubility of the fragments by LogP and LogS during the selection process, we determined their experimental solubility using a turbidimetric solubility assay. The reactivities of the different compounds were measured in a high-throughput 5,5’-dithiobis-(2-nitrobenzoic acid) DTNB assay, followed by a (glutathione) GSH stability assay. We employed the CovLib in a (differential scanning fluorimetry) DSF-based screening against different targets: c-Jun N-terminal kinase 3 (JNK3), ubiquitin-specific protease 7 (USP7), and the tumor suppressor p53. Finally, the covalent binding was confirmed by intact protein mass spectrometry (MS).Results: In general, the purchased fragments turned out to be sufficiently soluble. Additionally, they covered a broad spectrum of reactivity. All investigated α-cyanoacrylamides/acrylates and all structurally confirmed epoxides turned out to be less reactive compounds, possibly due to steric hindrance and reversibility (for α-cyanoacrylamides/acrylates). The SNAr and vinyl sulfone fragments are either highly reactive or stable. DSF measurements with the different targets JNK3, USP7, and p53 identified reactive fragment hits causing a shift in the melting temperatures of the proteins. MS confirmed the covalent binding mode of all these fragments to USP7 and p53, while additionally identifying the SNAr-type electrophile SN002 as a mildly reactive covalent hit for p53.Conclusion: The screening and target evaluation of the CovLib revealed first interesting hits. The highly cysteine-reactive fragments VS004, SN001, SN006, and SN007 covalently modify several target proteins and showed distinct shifts in the melting temperatures up to +5.1 °C and − 9.1 °C. Keywords: covalent fragment-based drug discovery, differential scanning fluorimetry, 5,5’-dithiobis-(2-nitrobenzoic acid), intact protein mass spectrometry, glutathione

Abstract Introduction Parents of children with a neurodevelopmental disorder (NDD) experience more stress than parents of typically developing children. In a cocreation process with experts and parents, a low-threshold application that uses exercises based on the principles of positive psychology and mindfulness was developed. This application, called “Adappt,” aims at enhancing the ability to adapt of the parents and caregivers of children with NDDs and at supporting their mental health. This protocol describes the evaluation study of the effectiveness of Adappt, its core working mechanisms and user experiences. Method A pragmatic international multicenter randomized controlled trial will compare the effectiveness of Adappt with a (delayed) waitlist control condition. At least 212 parents or primary caregivers of children younger than 18 years diagnosed with or suspected of a NDD will be randomly assigned to the intervention or waitlist control condition. Participants are excluded if they have severe anxiety or depression levels or are in treatment for mental health issues. Measures will be collected online at baseline, post-intervention (1 month after baseline), and 4 and 7 months after baseline. The primary outcome is the improvement in generic sense of ability to adapt as measured with the Generic Sense of Ability to Adapt Scale (GSAAS; (Front Psychol 14:985408, 2023)) at 4-month follow-up. Secondary outcomes are mental well-being, (parental) distress, and client satisfaction with “Adappt.” Discussion Results of this study will contribute to knowledge on the effectiveness of a low-threshold application for parents of children with a NDD in multiple countries. If the application is found to be effective in improving mental health, recommendations will be made for implementation in health care. Trial registration This study is registered on clinicaltrials.gov (NCT06248762) on February 8, 2024, and the Open Science Framework ( https://osf.io/5znqv ).

Abstract Conformal prediction has seen many applications in pharmaceutical science, being able to calibrate outputs of machine learning models and producing valid prediction intervals. We here present the open source software CPSign that is a complete implementation of conformal prediction for cheminformatics modeling. CPSign implements inductive and transductive conformal prediction for classification and regression, and probabilistic prediction with the Venn-ABERS methodology. The main chemical representation is signatures but other types of descriptors are also supported. The main modeling methodology is support vector machines (SVMs), but additional modeling methods are supported via an extension mechanism, e.g. DeepLearning4J models. We also describe features for visualizing results from conformal models including calibration and efficiency plots, as well as features to publish predictive models as REST services. We compare CPSign against other common cheminformatics modeling approaches including random forest, and a directed message-passing neural network. The results show that CPSign produces robust predictive performance with comparative predictive efficiency, with superior runtime and lower hardware requirements compared to neural network based models. CPSign has been used in several studies and is in production-use in multiple organizations. The ability to work directly with chemical input files, perform descriptor calculation and modeling with SVM in the conformal prediction framework, with a single software package having a low footprint and fast execution time makes CPSign a convenient and yet flexible package for training, deploying, and predicting on chemical data. CPSign can be downloaded from GitHub at https://github.com/arosbio/cpsign . Scientific contribution CPSign provides a single software that allows users to perform data preprocessing, modeling and make predictions directly on chemical structures, using conformal and probabilistic prediction. Building and evaluating new models can be achieved at a high abstraction level, without sacrificing flexibility and predictive performance—showcased with a method evaluation against contemporary modeling approaches, where CPSign performs on par with a state-of-the-art deep learning based model.

Abstract Background Body conformation, including withers height, is a major selection criterion in horse breeding and is associated with other important traits, such as health and performance. However, little is known about the genomic background of equine conformation. Therefore, the aim of this study was to use imputed sequence-level genotypes from up to 4891 German Warmblood horses to identify genomic regions associated with withers height and linear conformation traits. Furthermore, the traits were genetically characterised and putative causal variants for withers height were detected. Results A genome-wide association study (GWAS) for withers height confirmed the presence of a previously known quantitative trait locus (QTL) on Equus caballus (ECA) chromosome 3 close to the LCORL/NCAPG locus, which explained 16% of the phenotypic variance for withers height. An additional significant association signal was detected on ECA1. Further investigations of the region on ECA3 identified a few promising candidate causal variants for withers height, including a nonsense mutation in the coding sequence of the LCORL gene. The estimated heritability for withers height was 0.53 and ranged from 0 to 0.34 for the conformation traits. GWAS identified significantly associated variants for more than half of the investigated conformation traits, among which 13 showed a peak on ECA3 in the same region as withers height. Genetic parameter estimation revealed high genetic correlations between these traits and withers height for the QTL on ECA3. Conclusions The use of imputed sequence-level genotypes from a large study cohort led to the discovery of novel QTL associated with conformation traits in German Warmblood horses. The results indicate the high relevance of the QTL on ECA3 for various conformation traits, including withers height, and contribute to deciphering causal mutations for body size in horses.

Abstract Key message A Soil Monitoring Law to improve soil health across all land uses has been proposed by the European Commission. As forests soils have different chemical and physical properties as well as biogeochemical dynamics compared to agricultural land, they also face different challenges in maintaining and restoring soil health. Examples are soil acidification, eutrophication by atmospheric deposition, responses to climate change, and loss of biodiversity. Therefore, we propose forest soil specific health descriptors and thresholds based on experience and knowledge from existing long-term monitoring programs.