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Abstract The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME’s contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME’s implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Organic electrochemical transistors (OECTs) are a class of promising neuromorphic devices due to their exceptional conductivity, ease of fabrication, and cost-effectiveness. These devices exhibit ionic behavior similar to biological synapses, enabling efficient switching. Developing a compact model for OECTs is challenging due to the complex interplay of electrochemical reactions, ion transport, interactions with electrons or holes, and charge carrier dynamics that must be accurately captured and integrated into a simplified framework. In this work, we develop a combined physics-based compact model that integrates the Nernst equation from electrochemistry with thermally activated charges from semiconductor physics. This model enables easy incorporation into circuit simulations and provides a simple core framework for further extensions to account for additional effects. We fabricated, characterized, and analyzed OECTs based on PEDOT:PSS, and the proposed compact model shows good agreement with our experimental data.

The measurement of the electrical resistance of specimens based on the established direct current potential drop (DCPD) method is a widely utilized methodology for the detection of damage mechanisms in the field of crack initiation and propagation and change in microstructural details. These include, e.g., dislocation density, void volume fraction, and micro- and macro-cracks. Given the necessity to consider additional factors influencing the electrical resistance, e.g., specimen geometry and temperature, ex-situ measurement techniques are frequently employed through interruption of fatigue testing. However, ex-situ investigations may result in unintended influences, such as changes in contacting, and analyze only discrete states limiting the characterization possibilities and result interpretation. Accordingly, in-situ electrical resistance measurements were employed in this study to characterize the microstructural changes during fatigue with cyclic creeping. To quantify and compensate the effects of geometry, temperature, and deformation-induced austenite-martensite transformation on the electrical resistance during fatigue loading, a complex experimental setup was developed which includes several measurement systems. The combination of strain measurement and potential drop enables a direct transfer of measured strain to electrical resistance. The method was applied and evaluated on high-temperature diffusion-brazed joints with a metastable austenite as base material and Ni-based filler metal. Finally, the change in microstructure was evaluated through electron channeling contrast imaging (ECCI) analyses at different load cycles.

Abstract The nuclear spin, being much more isolated from the environment than its electronic counterpart, presents opportunities for quantum experiments with prolonged coherence times. Electron spin resonance (ESR) combined with scanning tunnelling microscopy (STM) provides a bottom-up platform to study the fundamental properties of nuclear spins of single atoms on a surface. However, access to the time evolution of nuclear spins remained a challenge. Here, we present an experiment resolving the nanosecond coherent dynamics of a hyperfine-driven flip-flop interaction between the spin of an individual nucleus and that of an orbiting electron. We use the unique local controllability of the magnetic field emanating from the STM probe tip to bring the electron and nuclear spins in tune, as evidenced by a set of avoided level crossings in ESR-STM. Subsequently, we polarize both spins through scattering of tunnelling electrons and measure the resulting free evolution of the coupled spin system using a DC pump-probe scheme. The latter reveals a complex pattern of multiple interfering coherent oscillations, providing unique insight into hyperfine physics on a single atom level.

Abstract Organic electrochemical transistors (OECTs) underpin a range of emerging technologies, from bioelectronics to neuromorphic computing, owing to their unique coupling of electronic and ionic charge carriers. In this context, various OECT systems exhibit significant hysteresis in their transfer curve, which is frequently leveraged to achieve non-volatility. Meanwhile, a general understanding of its physical origin is missing. Here, we introduce a thermodynamic framework that readily explains the emergence of bistable OECT operation via the interplay of enthalpy and entropy. We validate this model through temperature-resolved characterizations, material manipulation, and thermal imaging. Further, we reveal deviations from Boltzmann statistics for the subthreshold swing and reinterpret existing literature. Capitalizing on these findings, we finally demonstrate a single-OECT Schmitt trigger, thus compacting a multi-component circuit into a single device. These insights provide a fundamental advance for OECT physics and its application in non-conventional computing, where symmetry-breaking phenomena are pivotal to unlock new paradigms of information processing.

Because of the low fertility soils native to southeast Florida and the high nutrient demand of citrus trees under citrus greening—an endemic bacterial disease impacting nutrient uptake—growers are returning to the use of cover crops to improve soil fertility. Cover crops, specifically legumes, can improve soil nitrogen (N) availability because of their ability to fix N from the atmosphere. More citrus growers in southeast Florida are growing cover crops; however, there is a lack of recent research of suitable legume species and their impact on soil N cycling. To address this gap in the literature, six different treatments consisting of five legume species monocultures and one fallow plot (control) were organized into a completely randomized design. The experiment was conducted twice under warm and cool season conditions, and each treatment was replicated five times (n = 5), for a total of 30 experimental plots. Legume species were hairy indigo (Indigofera hirsuta), sunn hemp (Crotalaria juncea), cowpea (Vigna unguiculata), alfalfa (Medicago sativa), and aeschynomene (Aeschynomene americana). Biomass production, N concentration, and nodule characteristics as well as their impact on soil N were measured over a 1-year span in both warm and cool seasons. Overall, both cowpea and hairy indigo produced more biomass and, as a result, higher tissue N compared with those of the other legumes at both 60 and 150 days after planting. However, no impact on soil N was observed. Additionally, all legumes were unable to survive in the cool season, resulting in no measurable biomass at 150 days after planting. These results are relevant for citrus growers aiming to enhance soil fertility through cover crops in southeast Florida. While several legume options are available for the warm season (e.g., cowpea, hairy indigo, and sunn hemp), suitable legume species for the cool season have yet to be identified.

Florida citrus production faces multiple challenges, including low nutrient retention, low soil organic matter (SOM) and, more importantly, the devastating impacts of citrus greening, which is a bacterial disease that impacts root growth and nutrient uptake. Growers are exploring management practices to improve SOM and hoping to enhance tree health, nutrient uptake, and yield. Despite these efforts, research of the effects of SOM on citrus root systems and nutrient absorption remains limited, particularly that defining a target SOM range for optimal production. This study investigated the influence of varying SOM levels on citrus tree root system architecture, biomass, and nutrient uptake. This experiment was conducted in a greenhouse where 1-year-old ‘US-942’ rootstocks were assigned to a completely randomized experimental design and exposed to one of six experimental treatments with differing levels of SOM as the growing media [0% (control), 1%, 2%, 3%, 5%, or >10% (100% compost)]. Each pot was considered an experimental unit and replicated six times (n = 6), for a total of 36 seedlings. The results indicated that although root biomass did not change significantly, lower SOM levels resulted in longer roots with greater surface area and volume, likely because of increased soil exploration for nitrogen. Higher SOM treatments, however, showed improved leaf nutrient content, with increased nitrogen, phosphorus, and potassium uptake. In conclusion, the results of this study indicate that 3% SOM may be ideal for citrus because it positively impacted both root system architecture and nutrient uptake, which are both of primary concern because of citrus greening. Further research is necessary to establish critical SOM thresholds and evaluate the effects under field conditions and in combination with different irrigation and fertilizer regimes.

Abstract Background As the return to alcohol use in individuals with alcohol use disorder (AUD) is common during treatment and recovery, it is important that abstinence motivation is maintained after such critical incidences. Our study aims to explore how individuals with AUD participating in an app-based intervention with telephone coaching after inpatient treatment perceived their abstinence motivation after the return to alcohol use, whether their app use behavior was affected and to identify helpful factors to maintain abstinence motivation. Methods Using a mixed-methods approach, ten participants from the intervention group of the randomized controlled trial SmartAssistEntz who returned to alcohol use and recorded this in the app Appstinence, a smartphone application with telephone coaching designed for individuals with AUD, were interviewed about their experiences. The interviews were recorded, transcribed and coded using qualitative content analysis. App use behavior was additionally examined by using log data. Results Of the ten interviewees, seven reported their abstinence motivation increased after the return to alcohol use. Reasons included the reminder of negative consequences of drinking, the desire to regain control of their situation as well as the perceived support provided by the app. App data showed that app use remained stable after the return to alcohol use with an average of 58.70 days of active app use (SD = 25.96, Mdn = 58.50, range = 24–96, IQR = 44.25) after the return to alcohol use which was also indicated by the participants’ reported use behavior. Conclusions The findings of the study tentatively suggest that the app can provide support to individuals after the return to alcohol use to maintain and increase motivation after the incidence. Future research should (1) focus on specifically enhancing identification of high risk situations and reach during such critical incidences, (2) actively integrate the experience of the return to alcohol use into app-based interventions to better support individuals in achieving their personal AUD behavior change goals, and (3) investigate what type of support individuals might need who drop out of the study and intervention and discontinue app use altogether. Trial registration The primary evaluation study is registered in the German Clinical Trials Register (DRKS, registration number DRKS00017700) and received approval of the ethical committee of the Friedrich-Alexander University Erlangen-Nuremberg (193_19 B).

Abstract Quantum technologies play a pivotal role in driving transformative advancements across diverse fields, surpassing classical approaches and empowering us to address complex challenges more effectively; however, the need for ultra-low temperatures limits the use of these technologies to particular fields. This work comes to alleviate this problem. We present a way of phononic bandgap engineering using FEM by which the radiative mechanical energy dissipation of a nanomechanical oscillator can be significantly suppressed through coupling with a complementary oscillating mode of a defect of the surrounding phononic crystal (PnC). Applied to an optomechanically coupled nanobeam resonator in the megahertz regime, we find a mechanical quality factor improvement of up to four orders of magnitude compared to conventional PnC designs. As this method is based on geometrical optimization of the PnC and frequency matching of the resonator and defect mode, it is applicable to a wide range of resonator types and frequency ranges. Taking advantage of the, hereinafter referred to as, “regenerative coupling” in phononic crystals, the presented device is capable of reaching f × Q products exceeding 10E16 Hz with only two rows of PnC shield. Thus, stable quantum states with mechanical decoherence times up to 700 μs at room temperature can be obtained, offering new opportunities for the optimization of mechanical resonator performance and advancing the room temperature quantum field across diverse applications.

Ferroelectrics such as LiNbO_{3} (LN) are wide-band-gap insulators that may show a high local electric conductivity at the domain walls (DWs). The latter are interfaces separating regions of noncollinear polarization, which can be manipulated to build integrated nanoelectronic elements. In the present work, we model different DW types in LN from first principles. Our models reveal the DW morphology and shed light on their electronic properties: A strong band bending is predicted for charged DWs, leading to local metallicity. Defect trapping at the DW may further enhance the electric conductivity.

ABSTRACT Cellular responses to external stress allow microorganisms to adapt to a vast array of environmental conditions, including infection sites. The molecular mechanisms behind these responses are studied to gain insight into microbial pathogenesis, which could lead to new antimicrobial therapies. Here, we explore a role for arrestin protein-mediated ubiquitination in stress response and pathogenesis in the pathogenic fungus Cryptococcus neoformans. In a previous study, we identified four arrestin-like proteins in C. neoformans and found that one of these is required for efficient membrane synthesis, likely by directing interaction between fatty acid synthases and the Rsp5 E3 ubiquitin ligase. Here, we further explore Cn Rsp5 function and determine that this single Ub ligase is absolutely required for pathogenesis and survival in the presence of cellular stress. Additionally, we show that a second arrestin-like protein, Ali2, similarly facilitates interaction between Rsp5 and some of its protein targets. Of the four postulated C. neoformans arrestin-like proteins, Ali2 appears to contribute the most to C. neoformans pathogenesis, likely by directing Rsp5 to pathogenesis-related ubiquitination targets. A proteomics-based differential ubiquitination screen revealed that several known cell surface proteins are ubiquitinated by Rsp5 and a subset also requires Ali2 for their ubiquitination. Rsp5-mediated ubiquitination alters the stability and the localization of these proteins. A loss of Rsp5-mediated ubiquitination results in cell wall defects that increase susceptibility to external stresses. These findings support a model in which arrestin-like proteins guide Rsp5 to ubiquitinate specific target proteins, some of which are required for survival during stress.IMPORTANCEMicrobial proteins involved in human infectious diseases often need to be modified by specific chemical additions to be fully functional. Here, we explore the role of a particular protein modification, ubiquitination, in infections due to the human fungal pathogen Cryptococcus neoformans. We identified a complex of proteins responsible for adding ubiquitin groups to fungal proteins, and this complex is required for virulence. These proteins are fungal specific and might be targets for novel anti-infection therapy.

Summary: Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC’s potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.

Cover crops have a long and significant history in Florida’s citrus industry. During the late 1800s and early 1900s, they were widely used to enhance soil quality, boost fertility, and manage pests; therefore, they served as a critical agricultural tool before the widespread adoption of synthetic fertilizers. However, during the middle of the 20th century, a decline in the use of cover crops occurred as synthetic fertilizers and chemical pest control methods became more prevalent. Despite this decline, a resurgence of interest in cover crops has occurred among Florida’s citrus growers. This renewed interest is driven by the urgent need to increase soil fertility while reducing inputs, particularly in the context of managing citrus groves affected by citrus greening [huanglongbing (HLB)], which is a devastating disease that threatens the viability of the citrus industry. Citrus greening has created a growing interest in the use of management practices that can help mitigate the increasing cost of inputs needed to manage the disease. This literature review delves into the historical use of cover crops in Florida’s citrus industry and highlights their early adoption and subsequent decline. Additionally, it examines current cover crop management practices and focuses on key components such as seed selection, planting techniques, and termination methods. Finally, this review discusses the challenges and limitations associated with integrating cover crops into modern citrus production systems.

Abstract Consistent handling of samples is crucial for achieving reproducible molecular and functional testing results in translational research. Here, we used 229 acute myeloid leukemia (AML) patient samples to assess the impact of sample handling on high-throughput functional drug testing, mass spectrometry-based proteomics, and flow cytometry. Our data revealed novel and previously described changes in cell phenotype and drug response dependent on sample biobanking. Specifically, myeloid cells with a CD117 (c-KIT) positive phenotype decreased after biobanking, potentially distorting cell population representations and affecting drugs targeting these cells. Additionally, highly granular AML cell numbers decreased after freezing. Secondly, protein expression levels, as well as sensitivity to drugs targeting cell proliferation, metabolism, tyrosine kinases (e.g., JAK, KIT, FLT3), and BH3 mimetics were notably affected by biobanking. Moreover, drug response profiles of paired fresh and frozen samples showed that freezing samples can lead to systematic errors in drug sensitivity scores. While a high correlation between fresh and frozen for the entire drug library was observed, freezing cells had a considerable impact at an individual level, which could influence outcomes in translational studies. Our study highlights conditions where standardization is needed to improve reproducibility, and where validation of data generated from biobanked cohorts may be particularly important.

Abstract Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton’s tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma. However, many patients relapse post CAR-T therapy with dismal outcomes. To dissect the underlying mechanisms of sequential resistance to BTKi and CAR-T therapy, we performed single-cell RNA sequencing analysis for 66 samples from 25 patients treated with BTKi and/or CAR-T therapy and conducted in-depth bioinformatics™ analysis. Our analysis revealed that MYC activity progressively increased with sequential resistance. HSP90AB1 (Heat shock protein 90 alpha family class B member 1), a MYC target, was identified as early driver of CAR-T resistance. CDK9 (Cyclin-dependent kinase 9), another MYC target, was significantly upregulated in Dual-R samples. Both HSP90AB1 and CDK9 expression were correlated with MYC activity levels. Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.

Summary: Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the “casual” variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50–0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.

Summary: Orofacial clefts (OFCs) are common congenital birth defects with various etiologies, including genetic variants. Online Mendelian Inheritance in Man (OMIM) annotated several hundred genes involving OFCs. Furthermore, several hundreds of de novo variants (DNVs) have been identified from individuals with OFCs. Some DNVs are related to known OFC genes or pathways, but there are still many DNVs whose relevance to OFC development is unknown. To explore novel gene functions and their cellular expression profiles, we focused on DNVs in genes that were not listed in OMIM. We collected 960 DNVs in 853 genes from published studies and curated these genes, based on the DNVs’ deleteriousness, into 230 and 23 genes related to cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), respectively. For comparison, we curated 178 CL/P and 277 CPO genes from OMIM. In CL/P, the pathways enriched in DNV and OMIM genes were significantly overlapped (p = 0.002). Single-cell RNA sequencing (scRNA-seq) analysis of mouse lip development revealed that both gene sets had abundant expression in the ectoderm (DNV genes: adjusted p = 0.032, OMIM genes: adjusted p

Abstract Perturbations in gene regulation during palatogenesis can lead to cleft palate, which is among the most common congenital birth defects. Here, we perform single-cell multiome sequencing and profile chromatin accessibility and gene expression simultaneously within the same cells (n = 36,154) isolated from mouse secondary palate across embryonic days (E) 12.5, E13.5, E14.0, and E14.5. We construct five trajectories representing continuous differentiation of cranial neural crest-derived multipotent cells into distinct lineages. By linking open chromatin signals to gene expression changes, we characterize the underlying lineage-determining transcription factors. In silico perturbation analysis identifies transcription factors SHOX2 and MEOX2 as important regulators of the development of the anterior and posterior palate, respectively. In conclusion, our study charts epigenetic and transcriptional dynamics in palatogenesis, serving as a valuable resource for further cleft palate research.

1,2,3,4,5-pentathiepines (PTEs) are naturally occurring polysulfides of increasing scientific interest based on their identified pharmacological activities. Artificial PTEs with N-heterocyclic backbones are efficiently synthesized via mediation by a molybdenum–oxo-bistetrasulfido complex. A common feature of all precursor alkynes successfully used to date in this reaction is the presence of a –CH(OEt)2 group since the previously postulated mechanism requires the presence of one OEt– as the leaving group, and the second must become a transient ethoxonium moiety. This raised the question of whether there really is a need for two, maybe only one, or possibly even zero ethoxy substituents. This research problem was systematically addressed by respective variations in the precursor-alkyne derivatives and by employing one related allene species. It was found that the total absence of ethoxy substituents prevents the formation of PTEs entirely, while the presence of a single ethoxy group results in the possibility to distinctly functionalize the position on the resulting N-heterocyclic pyrrole five ring in the target compound. This position was previously exclusively occupied by an –OEt for all products of the molybdenum-mediated reaction. The allene was applied with similar success as precursor as with the related alkyne. The now-employable significant change in precursor composition gives access to a whole new PTE subfamily, allowing further modulation of (physico)-chemical properties such as solubility, and provides additional insight into the mechanism of PTE formation; it comprises a merely partial validation of the previous hypothesis. The new alkyne precursors and pentathiepines were characterized by a variety of instrumental analyses (NMR, mass spec, UV–vis) and in six cases (one alkyne precursor, one unexpected side product, and four PTEs) by single-crystal X-ray diffraction. Syntheses, isolation procedures, analytical data, and the impact of the findings on the previously proposed mechanism are described in detail herein.

Abstract Background Single-cell gene expression profiling provides unique opportunities to understand tumor heterogeneity and the tumor microenvironment. Because of cost and feasibility, profiling bulk tumors remains the primary population-scale analytical strategy. Many algorithms can deconvolve these tumors using single-cell profiles to infer their composition. While experimental choices do not change the true underlying composition of the tumor, they can affect the measurements produced by the assay. Results We generated a dataset of high-grade serous ovarian tumors with paired expression profiles from using multiple strategies to examine the extent to which experimental factors impact the results of downstream tumor deconvolution methods. We find that pooling samples for single-cell sequencing and subsequent demultiplexing has a minimal effect. We identify dissociation-induced differences that affect cell composition, leading to changes that may compromise the assumptions underlying some deconvolution algorithms. We also observe differences across mRNA enrichment methods that introduce additional discrepancies between the two data types. We also find that experimental factors change cell composition estimates and that the impact differs by method. Conclusions Previous benchmarks of deconvolution methods have largely ignored experimental factors. We find that methods vary in their robustness to experimental factors. We provide recommendations for methods developers seeking to produce the next generation of deconvolution approaches and for scientists designing experiments using deconvolution to study tumor heterogeneity.

Abstract Structural anisotropy in crystals is crucial for controlling light propagation, particularly in the infrared spectral regime where optical frequencies overlap with crystalline lattice resonances, enabling light-matter coupled quasiparticles called phonon polaritons (PhPs). Exploring PhPs in anisotropic materials like hBN and MoO3 has led to advancements in light confinement and manipulation. In a recent study, PhPs in the monoclinic crystal β-Ga2O3 (bGO) were shown to exhibit strongly asymmetric propagation with a frequency dispersive optical axis. Here, using scanning near-field optical microscopy (s-SNOM), we directly image the symmetry-broken propagation of hyperbolic shear polaritons in bGO. Further, we demonstrate the control and enhancement of shear-induced propagation asymmetry by varying the incident laser orientation and polariton momentum using different sizes of nano-antennas. Finally, we observe significant rotation of the hyperbola axis by changing the frequency of incident light. Our findings lay the groundwork for the widespread utilization and implementation of polaritons in low-symmetry crystals.

Introduction: This investigation assessed whether the following factors were associated with radiographic local progression in bone metastases from renal cell carcinoma (RCC): (1) high-risk histologic features (2) lesional surgery (3) biologically effective dose (BED) of radiation therapy. Methods and materials: A single-institution database identified all patients who underwent surgery and radiation therapy for bone metastases from RCC to the appendicular skeleton and pelvis from 2006 to 2016. Thirty-six patients underwent radiotherapy for 80 metastases. While all patients had surgical stabilization, 17/36 also had lesional surgery to address the metastatic lesion. Progression of each individual lesion was determined using the application of RECIST criteria to imaging at last follow-up. Results: The rate of progressive disease was 8/25 (32%) in the high-risk group versus 5/55 (9%) in the standard-risk group (p ​= ​0.019). The rate of progression among high-risk metastases undergoing lesional surgery was 0/9 versus 8/16 (50%) having non-lesional surgery (p ​= ​0.0218). The rate of progression among standard-risk metastases undergoing lesional surgery was 1/16 (6%) versus 4/39 (10%) with non-lesional surgery (p ​= ​1.00). High-risk histologic features (OR: 10.592, 95% confidence interval: 1.347–83.271, p ​= ​0.025) and as well as a reduction in risk with every additional Gray of BED (OR: 0.902, 95% confidence interval: 0.827–0.984, p ​= ​0.021) were found to predict progressive disease. Conclusions: Bone metastases from renal cell carcinoma with high-risk histologic features are associated with less favorable response to radiotherapy than those with standard-risk histology. Delivery of a higher BED was associated with lower odds of progression.

Background: It is uncertain whether app-based interventions add value to existing mental health care. Objective: To examine the incremental effects of app-based interventions when used as adjunct to mental health interventions. Methods: We searched PubMed, PsycINFO, Scopus, Web of Science, and Cochrane Library databases on September 15th, 2023, for randomised controlled trials (RCTs) on mental health interventions with an adjunct app-based intervention compared to the same intervention-only arm for adults with mental disorders or respective clinically relevant symptomatology. We conducted meta-analyses on symptoms of different mental disorders at postintervention. PROSPERO, CRD42018098545. Results: We identified 46 RCTs (4869 participants). Thirty-two adjunctive app-based interventions passively or actively monitored symptoms and behaviour, and in 13 interventions, the monitored data were sent to a therapist. We found additive effects on symptoms of depression (g = 0.17; 95 % CI 0.02 to 0.33; k = 7 comparisons), anxiety (g = 0.80; 95 % CI 0.06 to 1.54; k = 3), mania (g = 0.2; 95 % CI 0.02 to 0.38; k = 4), smoking cessation (g = 0.43; 95 % CI 0.29 to 0.58; k = 10), and alcohol use (g = 0.23; 95 % CI 0.08 to 0.39; k = 7). No significant effects were found on symptoms of depression within a bipolar disorder (g = -0.07; 95 % CI -0.37 to 0.23, k = 4) and eating disorders (g = -0.02; 95 % CI -0.44 to 0.4, k = 3). Studies on depression, mania, smoking, and alcohol use had a low heterogeneity between the trials. For other mental disorders, only single studies were identified. Only ten studies had a low risk of bias, and 25 studies reported insufficient statistical power. Discussion: App-based interventions may be used to enhance mental health interventions to further reduce symptoms of depression, anxiety, mania, smoking, and alcohol use. However, the effects were small, except for anxiety, and limited due to study quality. Further high-quality research with larger sample sizes is warranted to better understand how app-based interventions can be most effectively combined with established interventions to improve outcomes.

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here, we combine RNA sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations to isolate the contribution of the locus coeruleus-noradrenaline (LC-NA) system to the acute stress response in mice. We reveal that NA release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.

Abstract Feature selection to identify spatially variable genes or other biologically informative genes is a key step during analyses of spatially-resolved transcriptomics data. Here, we propose nnSVG, a scalable approach to identify spatially variable genes based on nearest-neighbor Gaussian processes. Our method (i) identifies genes that vary in expression continuously across the entire tissue or within a priori defined spatial domains, (ii) uses gene-specific estimates of length scale parameters within the Gaussian process models, and (iii) scales linearly with the number of spatial locations. We demonstrate the performance of our method using experimental data from several technological platforms and simulations. A software implementation is available at https://bioconductor.org/packages/nnSVG .

Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout the central nervous system, playing critical roles in arousal and mood, as well as various components of cognition including attention, learning, and memory. The LC-NE system is also implicated in multiple neurological and neuropsychiatric disorders. Importantly, LC-NE neurons are highly sensitive to degeneration in both Alzheimer’s and Parkinson’s disease. Despite the clinical importance of the brain region and the prominent role of LC-NE neurons in a variety of brain and behavioral functions, a detailed molecular characterization of the LC is lacking. Here, we used a combination of spatially-resolved transcriptomics and single-nucleus RNA-sequencing to characterize the molecular landscape of the LC region and the transcriptomic profile of LC-NE neurons in the human brain. We provide a freely accessible resource of these data in web-accessible and downloadable formats.

Nickel-based filler metals are frequently used in high temperature vacuum diffusion brazing for austenitic stainless-steel joints when components are subjected to high static or dynamic loads, corrosive environments and elevated temperatures. Due to melting point depressing metalloids such as silicon and boron, hard and brittle intermetallic phases are formed during the brazing process depending on the diffusion mechanisms. These brittle phases significantly affect mechanical and corrosive properties of the compounds. To quantify the influences of their amount, morphology and distribution, deep learning image segmentation was applied to segment these phases of the athermal solidification zone and the diffusion zone. Subsequently, characteristic microstructure parameters were calculated from these. The parameters of six different brazed joint variations were compared with their experimental characterization of mechanical and corrosive properties so that several correlations could be identified. Finally, a layer-by-layer removal of a brazed joint was performed using a focused ion beam, and a 3D model was reconstructed from the generated images to gain a mechanism-based understanding beyond the previous 2D investigations.

Abstract Despite some encouraging successes, predicting the therapy response of acute myeloid leukemia (AML) patients remains highly challenging due to tumor heterogeneity. Here we aim to develop and validate MDREAM, a robust ensemble-based prediction model for drug response in AML based on an integration of omics data, including mutations and gene expression, and large-scale drug testing. Briefly, MDREAM is first trained in the BeatAML cohort (n = 278), and then validated in the BeatAML (n = 183) and two external cohorts, including a Swedish AML cohort (n = 45) and a relapsed/refractory acute leukemia cohort (n = 12). The final prediction is based on 122 ensemble models, each corresponding to a drug. A confidence score metric is used to convey the uncertainty of predictions; among predictions with a confidence score >0.75, the validated proportion of good responders is 77%. The Spearman correlations between the predicted and the observed drug response are 0.68 (95% CI: [0.64, 0.68]) in the BeatAML validation set, –0.49 (95% CI: [–0.53, –0.44]) in the Swedish cohort and 0.59 (95% CI: [0.51, 0.67]) in the relapsed/refractory cohort. A web-based implementation of MDREAM is publicly available at https://www.meb.ki.se/shiny/truvu/MDREAM/ .

Topological spin textures are promising for their potential application in racetrack memory devices. Here, the characteristic Hall transport signature of antiskyrmions is investigated in Mn1.4PtSn, providing a platform for higher magnetic and temperature tunability over traditional skyrmion compounds.

Abstract The energy crisis is forcing Germany and other EU countries to reconsider and, if necessary, adjust energy policy decisions. New perspectives envisage a rapid expansion of renewable energies in the next few years. In the short term, Germany is considering reactivating coal-fired power plants from the reserve and revising decisions to decommission coal-fired and nuclear power plants in the coming years. This brief study analyses the price effects for the years 2024 and 2027 to shed light on both the short-term challenges and the medium-term prospects.

IntroductionImproving soil fertility is a top priority in Florida’s citrus growing regions, especially in the age of Huanglongbing (HLB; also known as citrus greening). This disease severely reduces fine root mass, causes higher incidences of nutrient deficiencies, and eventually results in the death of affected trees. Additionally, the soils commonly found in Florida’s citrus growing regions are sandy (greater than 98%) and naturally low in fertility, making the nutrient management of HLB-affected trees even more challenging. As a result, interest in organic amendments to increase soil fertility are being tested. Although hardwood chip mulches are successfully used in other regions of the country, no studies exist observing their use on the soils in Florida’s citrus growing regions; therefore, the objectives of this study were to measure the impacts of hardwood oak mulch on (i) Florida Alfisols characteristics and (ii) HLB-affected citrus trees.MethodsA two-treatment field study using 6-year-old ‘Valencia’ sweet orange trees (Citrus × sinensis) grafted on US-812 (C. reticulata × C. trifoliata) rootstock was conducted in Florida’s Indian River District (IRD). The experimental treatment consisted of 0.08 m of hardwood chip mulch sourced from oak trees applied every September for 3 years (2020, 2021, and 2022) while the control treatment had no mulch applied. Soil chemical and physical properties, leaf nutrient concentration, and leaf Candidatus Liberibacter asiaticus (CLas) titer was collected in the fall (October), winter (January), spring (April), and summer (July).Results and discussionOverall, after 3 years, oak mulch applications increased soil available phosphorus (32%), potassium (66%), magnesium (71%), organic matter (49%), and moisture (25-88%, depending on the season); however, oak mulch inconsistently impacted leaf nutrient concentrations and was not effective at suppressing HLB. The results show that annual applications of hardwood oak mulch can improve the chemical and physical properties of sandy soils within three years, however, these improvements did not reduce the severity of HLB.

Summary: Microbial communities reside at the interface between humans and their environment. Whether the microbiome can be leveraged to gain information on human interaction with museum objects is unclear. To investigate this, we selected objects from the Museum für Naturkunde and the Pergamonmuseum in Berlin, Germany, varying in material and size. Using swabs, we collected 126 samples from natural and cultural heritage objects, which were analyzed through 16S rRNA sequencing. By comparing the microbial composition of touched and untouched objects, we identified a microbial signature associated with human skin microbes. Applying this signature to cultural heritage objects, we identified areas with varying degrees of exposure to human contact on the Ishtar gate and Sam’al gate lions. Furthermore, we differentiated objects touched by two different individuals. Our findings demonstrate that the microbiome of museum objects provides insights into the level of human contact, crucial for conservation, heritage science, and potentially provenance research.

Abstract Modern microelectronic systems and applications demand an every increasing amount of non‐volatile memories that are fast, reliable, and consume little power. Memory concepts based on ferroelectric HfO2 like the ferroelectric field effect transistor (FeFET) and the ferroelectric random access memory (FeRAM) are promising to satisfy these requirements. As a consequence, continuing high attention is given to improve the ferroelectric properties and the reliability characteristics of the ferroelectric HfO2 films – for instance by using different dopant elements, dopant concentrations, and film thicknesses. Superlattices (i.e., a periodic structure of two materials stacked upon each other) are a promising alternative approach. Herein, [HfO2/ZrO2] superlattices of various sublayer thicknesses and a constant total thickness of 10 nm are embedded into metal‐ferroelectric‐metal (MFM) capacitors and then electrically as well as structurally characterized with special focus on remanent polarization, coercive field, endurance, and high temperature reliability. Compared to a 10 nm (Hf,Zr)O2 solid solution reference film, the use of superlattice stacks significantly improves the above mentioned parameters. In addition, most of these parameters depend on the sublayer thickness, which allows, for instance, tailoring the coercive field of the whole device.

The purpose of this work is to explore the potential of deep reinforcement learning (DRL) as a black-box optimizer for turbulence model identification. For this, we consider a Reynolds-averaged Navier–Stokes (RANS) closure model of a round turbulent jet flow at a Reynolds number of 10,000. For this purpose, we augment the widely utilized Spalart–Allmaras turbulence model by introducing a source term that is identified by DRL. The algorithm is trained to maximize the alignment of the augmented RANS model velocity fields and time-averaged large eddy simulation (LES) reference data. It is shown that the alignment between the reference data and the results of the RANS simulation is improved by 48% using the Spalart–Allmaras model augmented with DRL compared to the standard model. The velocity field, jet spreading rate, and axial velocity decay exhibit substantially improved agreement with both the LES reference and literature data. In addition, we applied the trained model to a jet flow with a Reynolds number of 15,000, which improved the mean field alignment by 35%, demonstrating that the framework is applicable to unseen data of the same configuration at a higher Reynolds number. Overall, this work demonstrates that DRL is a promising method for RANS closure model identification. Hurdles and challenges associated with the presented methodology, such as high numerical cost, numerical stability, and sensitivity of hyperparameters are discussed in the study.

Abstract The Russian attack on Ukraine and the German energy industry’s dependence on Russian gas are currently leading to a very tight supply situation, which could worsen in the coming winter. In the medium term, too, the import price for natural gas is likely to be significantly above historical levels as Europe becomes independent of Russian gas. These developments call for a reassessment of German energy policy, including for the energy transition in the power sector.

Though models describing the operating mechanism of organic electrochemical transistors (OECTs) have been developed, these models are unable to accurately reproduce OECT electrical characteristics. Here, the authors report a thermodynamic-based framework that accurately models OECT operation.

Abstract Two homoeologous QTLs for number of spikelets per spike (SPS) were mapped on chromosomes 7AL and 7BL using two wheat MAGIC populations. Sets of lines contrasting for the QTL on 7AL were developed which allowed for the validation and fine mapping of the 7AL QTL and for the identification of a previously described candidate gene, WHEAT ORTHOLOG OF APO1 (WAPO1). Using transgenic overexpression in both a low and a high SPS line, we provide a functional validation for the role of this gene in determining SPS also in hexaploid wheat. We show that the expression levels of this gene positively correlate with SPS in multiple MAGIC founder lines under field conditions as well as in transgenic lines grown in the greenhouse. This work highlights the potential use of WAPO1 in hexaploid wheat for further yield increases. The impact of WAPO1 and SPS on yield depends on other genetic and environmental factors, hence, will require a finely balanced expression level to avoid the development of detrimental pleiotropic phenotypes.

Abstract Organic electrochemical transistors (OECTs) based on Poly(3,4‐ethylenedioxythiophene):poly(styrene sulfonic acid) (PEDOT:PSS) are a benchmark system in organic bioelectronics. In particular, the superior mechanical properties and the ionic‐electronic transduction yield excellent potential for the field of implantable or wearable sensing technology. However, depletion‐mode operation PEDOT:PSS‐based OECTs cause high static power dissipation in electronic circuits, limiting their application in electronic systems. Hence, having control over the threshold voltage is of utmost technological importance. Here, PEDOT:PSS‐based dual‐gate OECTs with solid‐state electrolyte where the threshold voltage is seamlessly adjustable during operation are demonstrated. It is shown that the degree of threshold voltage tuning linearly depends on the gate capacitance, which is a straightforward approach for circuit designers to adjust the threshold voltage only by the device dimensions. The PEDOT:PSS‐based dual‐gate OECTs show excellent device performance and can be pushed to accumulation‐mode operation, resulting in a simplified and relaxed design of complementary inverters.

In order to investigate employees’ needs of the Medical Faculty of the University of Freiburg regarding research data management, the BE-KONFORM study was performed in a two-step approach. First, guideline-based qualitative video interviews with four researchers were performed to identify key constructs of relevance. Second, a standardized online survey was conducted from 1st to 15th of November 2020 based on e-mail invitation by the dean and a faculty newsletter. The questionnaire was provided bilingual (English and German) using a backward-forward translation method, no reminders and incentives were used to increase the response rate. The online survey was programmed in REDCap and was accessible via online link. The target population were members of the Medical Faculty (listed in the newsletter mailing list) regardless of the type of working contract signed. The final dataset contains 236 complete cases (90% German and 10% English). The study includes a randomised module asking for data publication (group A) or not (group B). 113 cases were randomized into group A and 99% of them consented to the publication of the collected research data in anonymized form (n=112). The dataset comprised questions about work-related characteristics (professional status, working experience, scientific field of work), data management-related items (definition of research data management, type of data used, type of storage used for saving data, use of electronic laboratory notebooks), experience and attitudes towards data publication in data repositories, as well as needs and preferences regarding research data management support. The produced data offers the possibility to connect with other data collected in this field in other contexts (faculties or universities).

In Switzerland, the Opalinus Clay unit was chosen as host rock for a repository for nuclear waste and has recently been investigated in a deep drilling campaign at possible repository construction sites. X-ray images of drill cores were compiled into virtual rock columns and were statistically analyzed with respect to layered compositional variations. This provides insight into scale-dependent homogenization and improves sampling strategy. To predict the repository behavior, using continuum-based models of Opalinus Clay, requires the knowledge of effective properties related to a minimum volume at which Opalinus Clay behaves homogeneously. It turned out that with respect to rock composition, such a volume does not exist in the sense that a single sample of manageable size provides a reliable mean composition. This is because the variation of the cm to dm thick layers, which differ in composition, does not sufficiently homogenize even at the 10-m scale. Thus, effective properties must be obtained by averaging several handleable samples. Regarding the composition of Opalinus Clay at a particular location, about 30 samples, distributed over the whole thickness, with a length of about 30 cm should be measured so that the relative error of the mean value is not higher than 5%–10%. For the statistical analyses computed tomography (CT) values of X-ray data were calibrated with respect to rock composition based on laboratory measurements. The CT values are largely controlled by the respective volume fraction of calcite, quartz, and porous clay matrix. These three components form >80 vol% of the sedimentary rocks studied (also above and below Opalinus Clay). The relationship between CT value and component contents depends on the rock type. The use of data from different rock types to calibrate CT values with respect to composition can lead to erroneous results.

Abstract Background Spatially-resolved transcriptomics has now enabled the quantification of high-throughput and transcriptome-wide gene expression in intact tissue while also retaining the spatial coordinates. Incorporating the precise spatial mapping of gene activity advances our understanding of intact tissue-specific biological processes. In order to interpret these novel spatial data types, interactive visualization tools are necessary. Results We describe spatialLIBD, an R/Bioconductor package to interactively explore spatially-resolved transcriptomics data generated with the 10x Genomics Visium platform. The package contains functions to interactively access, visualize, and inspect the observed spatial gene expression data and data-driven clusters identified with supervised or unsupervised analyses, either on the user’s computer or through a web application. Conclusions spatialLIBD is available at https://bioconductor.org/packages/spatialLIBD . It is fully compatible with SpatialExperiment and the Bioconductor ecosystem. Its functionality facilitates analyzing and interactively exploring spatially-resolved data from the Visium platform.

We study the quench dynamics of noninteracting fermionic quantum many-body systems that are subjected to Markovian drive and dissipation and are described by a quadratic Liouvillian which has parity-time (PT) symmetry. In recent work, we have shown that such systems relax locally to a maximum entropy ensemble that we have dubbed the PT-symmetric generalized Gibbs ensemble (PTGGE), in analogy to the generalized Gibbs ensemble that describes the steady state of isolated integrable quantum many-body systems after a quench. Here, using driven-dissipative versions of the Su-Schrieffer-Heeger (SSH) model and the Kitaev chain as paradigmatic model systems, we corroborate and substantially expand upon our previous results. In particular, we confirm the validity of a dissipative quasiparticle picture at finite dissipation by demonstrating light cone spreading of correlations and the linear growth and saturation to the PTGGE prediction of the quasiparticle-pair contribution to the subsystem entropy in the PT-symmetric phase. Further, we introduce the concept of directional pumping phases, which is related to the non-Hermitian topology of the Liouvillian and based upon qualitatively different dynamics of the dual string order parameter and the subsystem fermion parity in the SSH model and the Kitaev chain, respectively: depending on the postquench parameters, there can be pumping of string order and fermion parity through both ends of a subsystem corresponding to a finite segment of the one-dimensional lattice, through only one end, or there can be no pumping at all. We show that transitions between dynamical pumping phases give rise to a new and independent type of dynamical critical behavior of the rates of directional pumping, which are determined by the soft modes of the PTGGE.

Electron-induced fragmentation of the HFeCo3(CO)12 precursor allows direct-write fabrication of 3D nanostructures with metallic contents of up to >95 at %. While microstructure and composition determine the physical and functional properties of focused electron beam-induced deposits, they also provide fundamental insights into the decomposition process of precursors, as elaborated in this study based on EDX and TEM. The results provide solid information suggesting that different dominant fragmentation channels are active in single-spot growth processes for pillar formation. The use of the single source precursor provides a unique insight into high- and low-energy fragmentation channels being active in the same deposit formation process.

Rhizosphere interactions are an understudied component of citrus production. This is even more important in Florida flatwood soils, which pose significant challenges in achieving sustainable and effective fruit production due to low natural fertility and organic matter. Citrus growers apply soil amendments, including oak mulch, to ameliorate their soil conditions. Thus, the aim of this research was to evaluate the effects of oak mulch on citrus nutrient uptake, soil characteristics, and rhizosphere composition. The plant material consisted of ‘Valencia’ sweet orange (Citrus × sinensis) trees grafted on ‘US-812’ (C. reticulata × C. trifoliata) rootstock. The experiment consisted of two treatments, which included trees treated with oak mulch (300 kg of mulch per plot) and a control. The soil and leaf nutrient contents, soil pH, cation exchange capacity, moisture, temperature, and rhizosphere bacterial compositions were examined over the course of one year (spring and fall 2021). During the spring samplings, the citrus trees treated with oak mulch resulted in significantly greater soil Zn and Mn contents, greater soil moisture, and greater rhizosphere bacterial diversity compared to the control, while during the fall samplings, only a greater soil moisture content was observed in the treated trees. The soil Zn and Mn content detected during the spring samplings correlated with the significant increases in the diversity of the rhizosphere bacterial community composition. Similarly, the reduced rates of leaching and evaporation (at the soil surface) of oak mulch applied to Florida sandy soils likely played a large role in the significant increase in moisture and nutrient retention.

Acute stress can help individuals to respond to challenging events, although chronic stress leads to maladaptive changes. Here, the authors present a multi omic analysis profiling acute stress-induced changes in the mouse hippocampus, providing a resource for the scientific community.

Fraence Hardtstock,1 Julia Krieger,1 Thomas Wilke,1 Marco Lukas,2 Bernhard Ultsch,2 Robert Welte,2 Renate Quinzler,3 Ulf Maywald,4 Hartmut Timmermann5 1IPAM e.V, Wismar, Germany; 2GlaxoSmithKline GmbH & Co. KG, München, Germany; 3AOK Baden-Württemberg, Stuttgart, Germany; 4AOK PLUS, Dresden, Germany; 5Schwerpunktpraxis Colonnaden, Hamburg, GermanyCorrespondence: Fraence Hardtstock, Email Fraence.hardtstock@ipam-wismar.deBackground: Asthma is one of the most common chronic diseases in Germany. While many patients achieve asthma control under standard therapies, some patients still experience exacerbations and persistent airway obstructions. Thus, further pharmacological treatment is needed, and biologics could fill this gap, as they have shown clinical benefit in patients with severe asthma. Therefore, this real-world study aimed to compare healthcare resource utilization (HCRU) and associated costs before and after biologic therapy initiation.Methods: A retrospective claims data analysis has been conducted on adult asthma patients who initiated a long-term biologic therapy between January 2015 and June 2018. Patients were therapy-naïve to biologics for at least 12 months. HCRU and cost incurred by patients during 12 months before and after therapy initiation were compared.Results: Overall, 571 asthma patients initiated a biologic therapy during the observational period (316 omalizumab, 232 mepolizumab, 16 benralizumab, and 7 reslizumab). Patients had a mean age of 54.86 (62.70% female), and the majority (93.70%) received at least one follow-up prescription of their index-biologic agent within one year. During baseline, patients received on average 2.75 OCS prescriptions compared to 2.17 during follow-up. Most patients received less or the same amount of OCS after therapy initiation. Moreover, hospitalizations and asthma-related sick leave days decreased significantly. The average total costs per patient were € 6618.90 during baseline and € 22,832.33 during follow-up. Biologics mainly drove the increase; however, hospitalization costs were reduced significantly (€ 2443.37 vs € 1941.93; p< 0.001).Conclusion: Our study demonstrates an improved asthma control due to the initiation of a biologic therapy in terms of decreased hospitalization frequency, OCS consumption, and sick leave days. However, biologics are associated with high costs for healthcare providers during the first year after initiation. Therefore, short- and long-term clinical benefits and financial burden must be considered in the overall context of healthcare.Keywords: biologics, treatment pattern, claims data, real-world evidence, Germany

Abstract Ferroelectricity in crystalline hafnium oxide thin films is strongly investigated for the application in non-volatile memories, sensors and other applications. Especially for back-end-of-line (BEoL) integration the decrease of crystallization temperature is of major importance. However, an alternative method for inducing ferroelectricity in amorphous or semi-crystalline hafnium zirconium oxide films is presented here, using the newly discovered effect of electric field-induced crystallization in hafnium oxide films. When applying this method, an outstanding remanent polarization value of 2P $$_{\mathrm{R}}$$ R = 47 $$\upmu$$ μ C/cm $$^{2}$$ 2 is achieved for a 5 nm thin film. Besides the influence of Zr content on the film crystallinity, the reliability of films crystallized with this effect is explored, highlighting the controlled crystallization, excellent endurance and long-term retention.

Spatially resolved transcriptomics (SRT) is a growing field that links gene expression to anatomical context. SRT approaches that use next-generation sequencing (NGS) combine RNA sequencing with histological or fluorescent imaging to generate spatial maps of gene expression in intact tissue sections. These technologies directly couple gene expression measurements with high-resolution histological or immunofluorescent images that contain rich morphological information about the tissue under study. While broad access to NGS-based spatial transcriptomic technology is now commercially available through the Visium platform from the vendor 10× Genomics, computational tools for extracting image-derived metrics for integration with gene expression data remain limited. We developed VistoSeg as a MATLAB pipeline to process, analyze and interactively visualize the high-resolution images generated in the Visium platform. VistoSeg outputs can be easily integrated with accompanying transcriptomic data to facilitate downstream analyses in common programing languages including R and Python. VistoSeg provides user-friendly tools for integrating image-derived metrics from histological and immunofluorescent images with spatially resolved gene expression data. Integration of this data enhances the ability to understand the transcriptional landscape within tissue architecture. VistoSeg is freely available at http://research.libd.org/VistoSeg/.

Background: It is difficult to assess the risk for aortic dissection beyond the aortic root in patients with Marfan syndrome (MFS). To aid risk assessment in these patients, we investigated aortic flow and wall shear stress (WSS) by 4D flow magnetic resonance imaging (MRI) in patients with MFS and compared the results with healthy volunteers. We hypothesized that MFS patients with a high-risk profile for aortic dissection would show abnormal hemodynamics in aortic regions associated with aortic dissection. Methods: MFS patients (n = 55) and healthy subjects (n = 25), matched for age and sex, prospectively underwent 4D flow MRI. 4D flow maps were constructed to detect elevated (defined as higher than the three-dimensional 95 % confidence interval) and deviant directed (defined as vector angle differences higher than 120°) WSS in MFS patients as compared to the controls. Univariate and multivariate associations with risk factors for aortic dissection in MFS patients were assessed. Results: The maximum incidence for elevated WSS was 20 % (CI 9 %-31 %) and found in the ascending aorta. The maximum for deviant directed WSS was 39 % (CI 26 %-52 %) and found in the inner descending aorta. Significantly more male patients had deviant directed WSS in the inner proximal descending aorta (63 % vs 24 %, p = 0.014). Multivariate analysis showed that deviant directed WSS was associated with male sex (p = 0.019), and a haplo-insufficient FBN1 mutation type (p = 0.040). In 60 % of MFS patients with a previous aortic root replacement surgery, abnormal hemodynamics were found in the ascending aorta. No significant differences between hemodynamics were found in the descending aorta between operated and non-operated patients. Conclusion: Deviant directed WSS in the proximal descending aorta is associated with known risk factors for aortic dissection in MFS patients, namely male sex and a haploinsufficient FBN1 mutation type.