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Searching for relevant publications is becoming more difficult with the increasing number of scientific articles. Text mining as a specific form of computer-based data analysis may be helpful in this context. Highlighting relations between authors and finding relevant publications concerning a specific subject using text analysis programs are illustrated graphically by 2 performed examples., (© Georg Thieme Verlag KG Stuttgart · New York.)

Abstract Most non-muscle invasive bladder cancers have been treated by transurethral resection and following intravesical injection of immunotherapeutic agents. However, the delivery efficiency of therapeutic agents into bladder wall is low due to frequent urination, which leads to the failure of treatment with side effects. Here, we report a urease-powered nanomotor containing the agonist of stimulator of interferon genes (STING) for the efficient activation of immune cells in the bladder wall. After characterization, we perform in vitro motion analysis and assess in vivo swarming behaviors of nanomotors. The intravesical instillation results in the effective penetration and retention of nanomotors in the bladder. In addition, we confirm the anti-tumor effect of nanomotor containing the STING agonist (94.2% of inhibition), with recruitment of CD8+ T cells (11.2-fold compared with PBS) and enhanced anti-tumor immune responses in bladder cancer model in female mice. Furthermore, we demonstrate the better anti-tumor effect of nanomotor containing the STING agonist than those of the gold standard Bacille Calmette-Guerin therapy and the anti-PD-1 inhibitor pembrolizumab in bladder cancer model. Taken together, the urease-powered nanomotor would provide a paradigm as a next-generation platform for bladder cancer immunotherapy.

The Soutpansberg Mountain (SM) range in the northern part of the Limpopo Province within the Vhembe Biosphere Reserve, is a refuge for high diversity of organisms due to its geological history and location. As part of the South African National Survey of Arachnida (SANSA), the spider diversity of the Soutpansberg Mountain was determined over 27 years: 58 families, 293 genera, and 585 species were recorded. The Salticidae with 85 species, followed by Thomisidae (81 species), Araneidae, and Gnaphosidae, with 45 species each, are the most species-rich, while 11 families are represented by single species. Global distributions, endemicity, and conservation assessment are provided for each species using IUCN criteria. Most species (516, 88.1%) are widely distributed with no known threats and are of Least Concern, whereas eight species (1.4%) are of special concern. Of these, five species are Rare and one each is Critically Rare, Vulnerable, and Near Threatened. Twenty-five new species have been described from the SM since 1997, but 17 species (2.9%) are still Data Deficient, and 44 species were not evaluated due to unresolved taxonomy. The SM represents a spider biodiversity hotspot in the Limpopo Province, representing 25.4% of the total spider fauna of South Africa and 64.3% of the known spider fauna of the Limpopo Province.

Abstract Quantifying fair national shares of the remaining global carbon budget has proven challenging. Here, we propose an indicator—additional carbon accountability—that quantifies countries’ responsibility for mitigation and CO2 removal in addition to achieving their own targets. Considering carbon debts since 1990 and future claims based on countries’ emission pathways, the indicator uses an equal cumulative per capita emissions approach to allocate accountability for closing the mitigation gap among countries with a positive total excessive carbon claim. The carbon budget is exceeded by 576 Gigatonnes of fossil CO2 when limiting warming below 1.5 °C (50% probability). Additional carbon accountability is highest for the United States and China, and highest per capita for the United Arab Emirates and Russia. Assumptions on carbon debts strongly impact the results for most countries. The ability to pay for this accountability is challenging for Iran, Kazakhstan and several BRICS+ members, in contrast to the G7 members.

Abstract Transfer RNA halves (tRHs) have various biological functions. However, the biogenesis of specific 5′-tRHs under certain conditions remains unknown. Here, we report that inositol-requiring enzyme 1α (IRE1α) cleaves the anticodon stem-loop region of tRNAGly(GCC) to produce 5′-tRHs (5′-tRH-GlyGCC) with highly selective target discrimination upon endoplasmic reticulum (ER) stress. Levels of 5′-tRH-GlyGCC positively affect cancer cell proliferation and modulate mRNA isoform biogenesis both in vitro and in vivo; these effects require co-expression of two nuclear ribonucleoproteins, HNRNPM and HNRNPH2, which we identify as binding proteins of 5′-tRH-GlyGCC. In addition, under ER stress in vivo, we observe simultaneous induction of IRE1α and 5′-tRH-GlyGCC expression in mouse organs and a distantly related organism, Cryptococcus neoformans. Thus, collectively, our findings indicate an evolutionarily conserved function for IRE1α-generated 5′-tRH-GlyGCC in cellular adaptation upon ER stress.

Abstract The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) plays an essential role in glycolysis and in the antioxidant pathway associated with glutathione. Therefore, we investigated the effects of PFKFB3 on oxidative and ischemic damage. We synthesized a fusion protein of transactivator of transcription (Tat)-PFKFB3 to facilitate its passage into the intracellular space and examine its effects against oxidative stress induced by hydrogen peroxide (H2O2) treatment and ischemic damage caused by occlusion of the common carotid arteries for 5 min in gerbils. The Tat-PFKFB3 protein was efficiently delivered into HT22 cells in a concentration- and time-dependent manner, with higher levels observed 18 h after treatment. Furthermore, treatment with 6 µM Tat-PFKFB3 demonstrated intracellular delivery into HT22 cells, as analyzed through immunocytochemical staining. Moreover, it significantly ameliorated the reduction of cell viability induced by 200 µM H2O2 treatment. Tat-PFKFB3 treatment also alleviated H2O2-induced DNA fragmentation and reactive oxygen species formation in HT22 cells. In gerbils, the intraperitoneal administration of 2 mg/kg Tat-PFKFB3 efficiently delivered the substance to all hippocampal areas, including the hippocampal CA1 region. This administration significantly mitigated ischemia-induced hyperlocomotion, long-term memory deficits, and ischemic neuronal death in the hippocampal CA1 region after ischemia. Additionally, treatment with 2 mg/kg Tat-PFKFB3 significantly ameliorated the translocation of Cdk5 from the cytosol to the nucleus in the hippocampal CA1 region 24 h after ischemia, but not in other regions. The treatment also significantly reduced reactive oxygen species formation in the CA1 region. These findings suggest that Tat-PFKFB3 reduces neuronal damage in the hippocampal CA1 region after ischemia through the reduction of Cdk5 signaling and reactive oxygen species formation. Therefore, Tat-PFKFB3 may have potential applications in reducing ischemic damage.

Abstract Explainability of convolutional neural networks (CNNs) is integral for their adoption into radiological practice. Commonly used attribution methods localize image areas important for CNN prediction but do not characterize relevant imaging features underlying these areas, acting as a barrier to the adoption of CNNs for clinical use. We therefore propose Semantic Exploration and Explainability using a Style-based Generative Adversarial Autoencoder Network (SEE-GAAN), an explainability framework that uses latent space manipulation to generate a sequence of synthetic images that semantically visualizes how clinical and CNN features manifest within medical images. Visual analysis of changes in these sequences then facilitates the interpretation of features, thereby improving explainability. SEE-GAAN was first developed on a cohort of 26,664 chest radiographs across 15,409 patients from our institution. SEE-GAAN sequences were then generated across several clinical features and CNN predictions of NT-pro B-type natriuretic peptide (BNPP) as a proxy for acute heart failure. Radiological interpretations indicated SEE-GAAN sequences captured relevant changes in anatomical and pathological morphology associated with clinical and CNN predictions and clarified ambiguous areas highlighted by commonly used attribution methods. Our study demonstrates SEE-GAAN can facilitate our understanding of clinical features for imaging biomarker exploration and improve CNN transparency over commonly used explainability methods.

Abstract Healthcare organisations worldwide are affected by the shortage of health professionals due to work-related stress and health professional leaders play an important role by implementing effective strategies. Therefore, this study aims to investigate whether the STRAIN intervention program (using evidence-based training for health professional leaders) can reduce work-related stress among health professionals. This study is based on a cluster randomised controlled trial, consists of three measurements and includes 165 participating hospitals, nursing homes and home care organisations. A total of 206 health professional leaders took part in the intervention programme and 19,340 health professionals participated in the study. Results showed no significant differences (p > 0.05) between the intervention and control group regarding the effort-reward imbalance ratio, quantitative demands, opportunities for development, bond with the organisation, quality of leadership, social community, role clarity, rewards, difficulties with demarcation and work–private life conflict. Pre-/post-test analysis revealed a tendency for significant positive results (p

Abstract To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC–MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4–28 months and adults aged 19–65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.

Abstract As governments race to implement new climate adaptation solutions that prepare for more frequent flooding, they must seek policies that are effective for all communities and uphold climate justice. This requires evaluating policies not only on their overall effectiveness but also on whether they benefit all communities. Using the USA as an example, we illustrate the importance of considering such disparities for flood adaptation through a FEMA dataset of ~ 2.5 million flood insurance claims. We use CausalFlow, a causal inference method based on deep generative models, to estimate the treatment effect of flood adaptation interventions based on a community’s income, racial demographics, population, flood risk, educational attainment, and precipitation. We find that the program saves communities $5,000–15,000 per household. However, these savings are not evenly spread across communities. For example, for low-income communities savings sharply decline as flood-risk increases in contrast to their high-income counterparts. Even among low-income communities, savings are >$6,000 per household higher in predominantly white communities. Future flood adaptation efforts should go beyond reducing losses overall and aim to equitably support communities in the race for climate adaptation.

Abstract Pompe disease (PD) is a rare autosomal recessive glycogen storage disorder that causes proximal muscle weakness and loss of respiratory function. While enzyme replacement therapy (ERT) is the only effective treatment, biomarkers for disease monitoring are scarce. Following ex vivo biomarker validation in phantom studies, we apply multispectral optoacoustic tomography (MSOT), a laser- and ultrasound-based non-invasive imaging approach, in a clinical trial (NCT05083806) to image the biceps muscles of 10 late-onset PD (LOPD) patients and 10 matched healthy controls. MSOT is compared with muscle magnetic resonance imaging (MRI), ultrasound, spirometry, muscle testing and quality of life scores. Next, results are validated in an independent LOPD patient cohort from a second clinical site. Our study demonstrates that MSOT enables imaging of subcellular disease pathology with increases in glycogen/water, collagen and lipid signals, providing higher sensitivity in detecting muscle degeneration than current methods. This translational approach suggests implementation in the complex care of these rare disease patients.

Abstract Stretchable optoelectronic devices are typically realized through a 2D integration of rigid components and elastic interconnectors to maintain device performance under stretching deformation. However, such configurations inevitably sacrifice the area ratio of active components to enhance the maximum interconnector strain. We herein propose a 3D buckled height-alternant architecture for stretchable OLEDs that enables the high active-area ratio and the enhanced maximum strain simultaneously. Along with the optimal dual serpentine structure leading to a low critical buckling strain, a pop-up assisting adhesion blocking layer is proposed based on an array of micro concave structures for spatially selective adhesion control, enabling a reliable transition to a 3D buckled state with OLED-compatible processes. Consequently, we demonstrate stretchable OLEDs with both the high initial active-area ratio of 85% and the system strain of up to 40%, which would require a lateral interconnector strain of up to 512% if it were attained with conventional 2D rigid-island approaches. These OLEDs are shown to exhibit reliable performance under 2,000 biaxial cycles of 40% system strain. 7 × 7 passive-matrix OLED displays with the similar level of the initial active-area ratio and maximum system strain are also demonstrated.

Abstract REBa $$_2$$ 2 Cu $$_3$$ 3 O $$_{7-\text {x}}$$ 7 - x (REBCO, RE = rare earth)-coated conductor is a competitive option in terms of current-carrying capacity and high-stress durability in developing high-field magnets for nuclear magnetic resonance (NMR) research. Meanwhile, a technical challenge in utilizing a stand-alone REBCO NMR magnet is an unexpected difference in the field uniformity between the designed and measured values after being constructed and charged, i.e., harmonic errors. Bortot et al., and Li et al., reported analytic evidence of the related issue. However, sufficient research has not yet been conducted, so evidence should be supplemented further. Here we report harmonic errors due to screening current and inconsistent conductor thickness, confirmed by a 400 MHz 1H NMR magnet development project. The magnet was first charged up to its operating current, and then multiple overcharge-discharge cycles were applied, which was an empirically optimized operation protocol. A field mapping device obtained magnetic fields at designated locations in the room-temperature bore. The result showed over 100 ppm field uniformity difference between designed and measured values. A simulation model was developed considering screening current and inconsistent conductor thickness for reproducing the field distribution. Comparison of voltages and fields between simulation and measurement validated the model. Further analysis of the overcharge-discharge effect on harmonic errors demonstrated that even and odd-order harmonics are mainly attributed to screening current and geometric inconsistency while confirming the limitation of the screening current mitigation effect. Hence, we concluded that the desirable requirement of the sub-ppm level field uniformity generation might be barely possible with the current REBCO NMR magnet design approach.

Abstract Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington’s disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.

Abstract The aim of this study was to evaluate the long-term efficacy of a single ultrasound-guided high-intensity focused ultrasound (US-HIFU) treatment in patients with breast fibroadenoma (FA) in terms of volume and pain reduction as well as palpation findings. From december 2013 until november 2014 27 women with a symptomatic FA were treated in one HIFU-session. Follow-up visits were performed after 7 days, 6 months and 1, 2, 3 and 5 years with clinical examination and ultrasound. One year after the procedure, a core needle biopsy of the residual lesion was offered. There was a significant volume reduction 6 months after HIFU from 1083.10 to 347.13 mm3 (p

Abstract We investigated the long-term patterns and effects of transfusion on the clinical outcome of patients undergoing percutaneous coronary intervention (PCI) using a nationwide registry. Five-year clinical outcome of all Koreans undergoing PCI using stent in year 2011 (n = 48,786) was investigated. Primary outcome was the incidence density of transfusion. The association of transfusion with major adverse clinical event (MACE) consisting all-cause death, revascularization, critically ill cardiovascular status, or stroke was assessed after adjusting the propensity of each patient for transfusion. The 5-year incidence density of transfusion was 4.74 (95% confidence interval [CI] 4.70–4.79) per 100 person-year. Patients who received transfusion were older and had higher frequency of clinical risk factors (p

Abstract Protecting qubits from accidental measurements is essential for controlled quantum operations, especially during state-destroying measurements or resets on adjacent qubits, in protocols like quantum error correction. Current methods to preserve atomic qubits against such disturbances waste coherence time, extra qubits, and introduce additional errors. We demonstrate the feasibility of in-situ state-reset and state-measurement of trapped ions, achieving >99.9% fidelity in preserving an ‘asset’ ion-qubit while a neighboring ‘process’ qubit is reset, and >99.6% preservation fidelity while applying a detection beam for 11 μs on the same neighbor at a distance of 6 μm. This is achieved through precise wavefront control of addressing optical beams and using a single ion as both a quantum sensor for optical aberrations and an intensity probe with >50 dB dynamic range. Our demonstrations advance quantum processors, enhancing speed and capabilities for tasks like quantum simulations of dissipation and measurement-driven phases, and implementing error correction.

Abstract Gene expression is regulated by changes in chromatin architecture intrinsic to cellular differentiation and as an active response to environmental stimuli. Chromatin dynamics are a major driver of phenotypic diversity, regulation of development, and manifestation of disease. Remarkably, we know little about the evolutionary dynamics of chromatin reorganisation through time, data essential to characterise the impact of environmental stress during the ongoing biodiversity extinction crisis (20th–21st century). Linking the disparate fields of chromatin biology and museum science through their common use of the preservative formaldehyde (a constituent of formalin), we have generated historical chromatin profiles in museum specimens up to 117 years old. Historical chromatin profiles are reproducible, tissue-specific, sex-specific, and environmental condition-dependent in vertebrate specimens. Additionally, we show that over-fixation modulates differential chromatin accessibility to enable semi-quantitative estimates of relative gene expression in vertebrates and a yeast model. Our approach transforms formalin-fixed biological collections into an accurate, comprehensive, and global record of environmental impact on gene expression and phenotype.

Abstract Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p

Abstract Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Abstract We here introduce the Aquamarine (AQM) dataset, an extensive quantum-mechanical (QM) dataset that contains the structural and electronic information of 59,783 low-and high-energy conformers of 1,653 molecules with a total number of atoms ranging from 2 to 92 (mean: 50.9), and containing up to 54 (mean: 28.2) non-hydrogen atoms. To gain insights into the solvent effects as well as collective dispersion interactions for drug-like molecules, we have performed QM calculations supplemented with a treatment of many-body dispersion (MBD) interactions of structures and properties in the gas phase and implicit water. Thus, AQM contains over 40 global and local physicochemical properties (including ground-state and response properties) per conformer computed at the tightly converged PBE0+MBD level of theory for gas-phase molecules, whereas PBE0+MBD with the modified Poisson-Boltzmann (MPB) model of water was used for solvated molecules. By addressing both molecule-solvent and dispersion interactions, AQM dataset can serve as a challenging benchmark for state-of-the-art machine learning methods for property modeling and de novo generation of large (solvated) molecules with pharmaceutical and biological relevance.

Abstract Telomerase reverse transcriptase (TERT) promoter mutations are associated with tumor aggressiveness. This study aimed to demonstrate the ultrasonographic (US) features of TERT promoter-mutated follicular thyroid cancer (FTC) and evaluate their predictive performance. A total of 63 patients with surgically confirmed FTC between August 1995 and April 2021 were included. All data were available for analysis of preoperative US findings and TERT promoter mutation results. Genomic DNA was extracted from the archived surgical specimens to identify TERT promoter mutations. Logistic regression analysis was performed to compare US findings between TERT promoter-mutated and wild-type FTCs. Of the 63 patients with FTC, 10 (15.9%) had TERT promoter mutations. TERT promoter-mutated FTCs demonstrated significantly different US suspicion categories compared to wild-type FTCs (Ps = 0.0054 for K-TIRADS and 0.0208 for ACR-TIRADS), with a trend toward an increasing prevalence of the high suspicion category (40.0% for both K-TIRADS and ACR-TIRADS; Ps for trend = 0.0030 for K-TIRADS and 0.0032 for ACR-TIRADS). Microlobulated margins and punctate echogenic foci were independent risk factors associated with TERT promoter mutation in FTC (odds ratio = 9.693, 95% confidence interval = 1.666–56.401, p = 0.0115 for margins; odds ratio = 8.033, 95% confidence interval = 1.424–45.309, p = 0.0182 for punctate echogenic foci). There were no significant differences in the composition and echogenicity of the TERT promoter-mutated and wild-type FTCs. TERT promoter-mutated FTCs were categorized more frequently as high suspicion by the K-TIRADS and ACR-TIRADS. Based on US findings, the independent risk factors for TERT promoter mutations in FTC are microlobulated margins and punctate echogenic foci.

Abstract Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Abstract Stretchable organic light-emitting diodes (OLEDs) have emerged as promising optoelectronic devices with exceptional degree of freedom in form factors. However, stretching OLEDs often results in a reduction in the geometrical fill factor (FF), that is the ratio of an active area to the total area, thereby limiting their potential for a broad range of applications. To overcome these challenges, we propose a three-dimensional (3D) architecture adopting a hidden active area that serves a dual role as both an emitting area and an interconnector. For this purpose, an ultrathin OLED is first attached to a 3D rigid island array structure through quadaxial stretching for precise, deformation-free alignment. A portion of the ultrathin OLED is concealed by letting it ‘fold in’ between the adjacent islands in the initial, non-stretched condition and gradually surfaces to the top upon stretching. This design enables the proposed stretchable OLEDs to exhibit a relatively high FF not only in the initial state but also after substantial deformation corresponding to a 30% biaxial system strain. Moreover, passive-matrix OLED displays that utilize this architecture are shown to be configurable for compensation of post-stretch resolution loss, demonstrating the efficacy of the proposed approach in realizing the full potential of stretchable OLEDs.

Abstract Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Abstract Understanding the functional connectivity between brain regions and its emergent dynamics is a central challenge. Here we present a theory-experiment hybrid approach involving iteration between a minimal computational model and in vivo electrophysiological measurements. Our model not only predicted spontaneous persistent activity (SPA) during Up-Down-State oscillations, but also inactivity (SPI), which has never been reported. These were confirmed in vivo in the membrane potential of neurons, especially from layer 3 of the medial and lateral entorhinal cortices. The data was then used to constrain two free parameters, yielding a unique, experimentally determined model for each neuron. Analytic and computational analysis of the model generated a dozen quantitative predictions about network dynamics, which were all confirmed in vivo to high accuracy. Our technique predicted functional connectivity; e. g. the recurrent excitation is stronger in the medial than lateral entorhinal cortex. This too was confirmed with connectomics data. This technique uncovers how differential cortico-entorhinal dialogue generates SPA and SPI, which could form an energetically efficient working-memory substrate and influence the consolidation of memories during sleep. More broadly, our procedure can reveal the functional connectivity of large networks and a theory of their emergent dynamics.

Abstract The path of tokamak fusion and International thermonuclear experimental reactor (ITER) is maintaining high-performance plasma to produce sufficient fusion power. This effort is hindered by the transient energy burst arising from the instabilities at the boundary of plasmas. Conventional 3D magnetic perturbations used to suppress these instabilities often degrade fusion performance and increase the risk of other instabilities. This study presents an innovative 3D field optimization approach that leverages machine learning and real-time adaptability to overcome these challenges. Implemented in the DIII-D and KSTAR tokamaks, this method has consistently achieved reactor-relevant core confinement and the highest fusion performance without triggering damaging bursts. This is enabled by advances in the physics understanding of self-organized transport in the plasma edge and machine learning techniques to optimize the 3D field spectrum. The success of automated, real-time adaptive control of such complex systems paves the way for maximizing fusion efficiency in ITER and beyond while minimizing damage to device components.

Abstract In contrast to inherited transthyretin amyloidosis (A-ATTRv), neuropathy is not a classic leading symptom of wild type transthyretin amyloidosis (A-ATTRwt). However, neurological symptoms are increasingly relevant in A-ATTRwt as well. To better understand the role of neurological symptoms in A-ATTRwt, A-ATTRwt patients were prospectively characterized at Amyloidosis Center Charité Berlin (ACCB) between 2018 and 2023 using detailed neurological examination, quality of life questionnaires, and analysis of age- and BMI-adapted serum neurofilament light chain (NFL) levels. 16 out of 73 (21.9%) patients presented with a severe neuropathy which we defined by a Neuropathy Impairment Score (NIS) of 20 or more. In this group, quality of life was reduced, peripheral neuropathy was more severe, and spinal stenosis and joint replacements were frequent. Age- and BMI matched serum NFL levels were markedly elevated in patients with a NIS ≥ 20. We therefore conclude that highly abnormal values in neuropathy scores such as the NIS occur in A-ATTRwt, and have an important impact on quality of life. Both peripheral neuropathy and spinal canal stenosis are likely contributors. Serum NFL may serve as a biomarker for neurological affection in patients with A-ATTRwt. It will be important to consider neurological aspects of A-ATTRwt for diagnosis, clinical follow-up, and future treatment development.

Abstract Pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis, but critical information regarding their mass, distribution and composition is lacking within a whole organ context. Here, we apply a 3D imaging pipeline to generate a complete account of the insulin-producing islets throughout the human pancreas at a microscopic resolution and within a maintained spatial 3D context. These data show that human islets are far more heterogenous than previously accounted for with regards to their size distribution and cellular make up. By deep tissue 3D imaging, this in-depth study demonstrates that 50% of the human insulin-expressing islets are virtually devoid of glucagon-producing α-cells, an observation with significant implications for both experimental and clinical research.

Abstract Indirect Drive Inertial Confinement Fusion Experiments on the National Ignition Facility (NIF) have achieved a burning plasma state with neutron yields exceeding 170 kJ, roughly 3 times the prior record and a necessary stage for igniting plasmas. The results are achieved despite multiple sources of degradations that lead to high variability in performance. Results shown here, for the first time, include an empirical correction factor for mode-2 asymmetry in the burning plasma regime in addition to previously determined corrections for radiative mix and mode-1. Analysis shows that including these three corrections alone accounts for the measured fusion performance variability in the two highest performing experimental campaigns on the NIF to within error. Here we quantify the performance sensitivity to mode-2 symmetry in the burning plasma regime and apply the results, in the form of an empirical correction to a 1D performance model. Furthermore, we find the sensitivity to mode-2 determined through a series of integrated 2D radiation hydrodynamic simulations to be consistent with the experimentally determined sensitivity only when including alpha-heating.

Abstract Rechargeable multivalent‐ion batteries are attractive alternatives to Li‐ion batteries to mitigate their issues with metal resources and metal anodes. However, many challenges remain before they can be practically used due to the low solid‐state mobility of multivalent ions. In this study, a promising material identified by high‐throughput computational screening is investigated, ε‐VOPO4, as a Mg cathode. The experimental and computational evaluation of ε‐VOPO4 suggests that it may provide an energy density of >200 Wh kg−1 based on the average voltage of a complete cycle, significantly more than that of well‐known Chevrel compounds. Furthermore, this study finds that Mg‐ion diffusion can be enhanced by co‐intercalation of Li or Na, pointing at interesting correlation dynamics of slow and fast ions.

Summary: Deleted in liver cancer 3 (DLC3) is a Rho GTPase-activating protein (RhoGAP) that plays a crucial role in maintaining adherens junction integrity and coordinating polarized vesicle transport by modulating Rho activity at the plasma membrane and endomembranes. By employing bioinformatical sequence analysis, in vitro experiments, and in cellulo assays we here identified a polybasic region (PBR) in DLC3 that facilitates the association of the protein with cellular membranes. Within the PBR, we mapped two serines whose phosphorylation can alter the electrostatic character of the region. Consequently, phosphomimetic mutations of these sites impaired the membrane association of DLC3. Furthermore, we found a new PBR-dependent localization of DLC3 at the midbody region, where the protein locally controlled Rho activity. Here, the phosphorylation-dependent regulation of DLC3 appeared to be required for proper cytokinesis. Our work thus provides a novel mechanism for spatiotemporal termination of Rho signaling by the RhoGAP protein DLC3.

Abstract While onion cultivars, irrigation and soil and crop management have been given much attention in Brazil to boost onion yields, nutrient management at field scale is still challenging due to large dosage uncertainty. Our objective was to develop an accurate feature-based fertilization model for onion crops. We assembled climatic, edaphic, and managerial features as well as tissue tests into a database of 1182 observations from multi-environment fertilizer trials conducted during 13 years in southern Brazil. The complexity of onion cropping systems was captured by machine learning (ML) methods. The RReliefF ranking algorithm showed that the split-N dosage and soil tests for micronutrients and S were the most relevant features to predict bulb yield. The decision-tree random forest and extreme gradient boosting models were accurate to predict bulb yield from the relevant predictors (R2 > 90%). As shown by the gain ratio, foliar nutrient standards for nutritionally balanced and high-yielding specimens producing > 50 Mg bulb ha−1 set apart by the ML classification models differed among cultivars. Cultivar × environment interactions support documenting local nutrient diagnosis. The split-N dosage was the most relevant controllable feature to run future universality tests set to assess models’ ability to generalize to growers’ fields.

Abstract The clinical impact of different polymer technologies in newer-generation drug-eluting stents (DESs) for patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) remains poorly understood. We investigated the efficacy and safety of durable polymer DESs (DP-DESs) compared with biodegradable polymer DESs (BP-DESs). A total of 620 patients who underwent percutaneous coronary intervention with newer-generation DESs for AMI complicated by CS was divided into two groups based on polymer technology: the DP-DES group (n = 374) and the BP-DES group (n = 246). The primary outcome was target vessel failure (TVF) during a 12-month follow-up, defined as a composite of cardiac death, myocardial infarction, or target vessel revascularization. Both the DP-DES and BP-DES groups exhibited low stent thrombosis rates (1.3% vs. 1.6%, p = 0.660). The risk of TVF did not significantly differ between the two groups (34.2% vs. 28.5%, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.69–1.29, p = 0.721). This finding remained consistent after adjustment with inverse probability of treatment weighting (28.1% vs. 25.1%, HR 0.98, 95% CI 0.77–1.27, p = 0.899). In AMI patients complicated by CS, the risk of a composite of cardiac death, myocardial infarction, or target vessel revascularization was not significantly different between those treated with DP-DESs and those treated with BP-DESs. Trial registration: RESCUE registry, https://clinicaltrials.gov/ct2/show/NCT02985008 , NCT02985008.

Abstract Behavior can be remarkably consistent, even over extended time periods, yet whether this is reflected in stable or ‘drifting’ neuronal responses to task features remains controversial. Here, we find a persistently active ensemble of neurons in the medial prefrontal cortex (mPFC) of mice that reliably maintains trajectory-specific tuning over several weeks while performing an olfaction-guided spatial memory task. This task-specific reference frame is stabilized during learning, upon which repeatedly active neurons show little representational drift and maintain their trajectory-specific tuning across long pauses in task exposure and across repeated changes in cue-target location pairings. These data thus suggest a ‘core ensemble’ of prefrontal neurons forming a reference frame of task-relevant space for the performance of consistent behavior over extended periods of time.

Abstract Morning chronotypes are associated with healthier metabolic profiles and lifestyles compared to evening chronotypes. However, limited research examined the relationship between chronotype, dietary intake, and metabolic health using accurate measures such as food records. This cross-sectional study aimed to investigate the association between chronotype, dietary intake, and metabolic health markers in a cohort of Ukrainian individuals. Chronotypes were determined using the Morningness-Eveningness Questionnaire (MEQ) in 110 healthy to obese individuals (30–75 years) without type 2 diabetes. Dietary intake was derived from weighed seven days food diaries, anthropometrics and blood markers of glucose and lipid metabolism were measured. Morning chronotypes were significantly older and exhibited distinct dietary patterns, including lower intake of fat and animal protein and higher intake of carbohydrates when compared to evening chronotypes (p

Abstract This study aimed to develop and evaluate a sarcopenia prediction model by fusing numerical features from shear-wave elastography (SWE) and gray-scale ultrasonography (GSU) examinations, using the rectus femoris muscle (RF) and categorical/numerical features related to clinical information. Both cohorts (development, 70 healthy subjects; evaluation, 81 patients) underwent ultrasonography (SWE and GSU) and computed tomography. Sarcopenia was determined using skeletal muscle index calculated from the computed tomography. Clinical and ultrasonography measurements were used to predict sarcopenia based on a linear regression model with the least absolute shrinkage and selection operator (LASSO) regularization. Furthermore, clinical and ultrasonography features were combined at the feature and score levels to improve sarcopenia prediction performance. The accuracies of LASSO were 70.57 ± 5.00–81.54 ± 4.83 (clinical) and 69.00 ± 4.52–69.73 ± 5.47 (ultrasonography). Feature-level fusion of clinical and ultrasonography (accuracy, 70.29 ± 6.63 and 83.55 ± 4.32) showed similar performance with clinical features. Score-level fusion by AdaBoost showed the best performance (accuracy, 73.43 ± 6.57–83.17 ± 5.51) in the development and evaluation cohorts, respectively. This study might suggest the potential of machine learning fusion techniques to enhance the accuracy of sarcopenia prediction models and improve clinical decision-making in patients with sarcopenia.

Abstract Echocardiographic differentiation of cardiac amyloidosis (CA) and Fabry disease (FD) is often challenging using standard echocardiographic parameters. We retrospectively analyzed the diagnostic accuracy of right heart and left atrial strain parameters to discriminate CA from FD using receiver operating characteristic curve analyses and logistic regression models. A total of 47 FD and 88 CA patients with left ventricular wall thickening were analyzed. The comparison of both cardiomyopathies revealed significantly reduced global and free wall longitudinal right ventricular strain (RVS; global RVS: CA − 13 ± 4%, n = 67, vs. FD − 18 ± 4%, n = 39, p

Abstract In mammals, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) execute sequential thermogenesis to maintain body temperature during cold stimuli. BAT rapidly generates heat through brown adipocyte activation, and further iWAT gradually stimulates beige fat cell differentiation upon prolonged cold challenges. However, fat depot-specific regulatory mechanisms for thermogenic activation of two fat depots are poorly understood. Here, we demonstrate that E3 ubiquitin ligase RNF20 orchestrates adipose thermogenesis with BAT- and iWAT-specific substrates. Upon cold stimuli, BAT RNF20 is rapidly downregulated, resulting in GABPα protein elevation by controlling protein stability, which stimulates thermogenic gene expression. Accordingly, BAT-specific Rnf20 suppression potentiates BAT thermogenic activity via GABPα upregulation. Moreover, upon prolonged cold stimuli, iWAT RNF20 is gradually upregulated to promote de novo beige adipogenesis. Mechanistically, iWAT RNF20 mediates NCoR1 protein degradation, rather than GABPα, to activate PPARγ. Together, current findings propose fat depot-specific regulatory mechanisms for temporal activation of adipose thermogenesis.

Abstract Miniaturized spectrometers are of immense interest for various on-chip and implantable photonic and optoelectronic applications. State-of-the-art conventional spectrometer designs rely heavily on bulky dispersive components (such as gratings, photodetector arrays, and interferometric optics) to capture different input spectral components that increase their integration complexity. Here, we report a high-performance broadband spectrometer based on a simple and compact van der Waals heterostructure diode, leveraging a careful selection of active van der Waals materials- molybdenum disulfide and black phosphorus, their electrically tunable photoresponse, and advanced computational algorithms for spectral reconstruction. We achieve remarkably high peak wavelength accuracy of ~2 nanometers, and broad operation bandwidth spanning from ~500 to 1600 nanometers in a device with a ~ 30×20 μm2 footprint. This diode-based spectrometer scheme with broadband operation offers an attractive pathway for various applications, such as sensing, surveillance and spectral imaging.

Abstract The lateral hypothalamus (LH) is involved in feeding behavior and defense responses by interacting with different brain structures, including the Ventral Tegmental Area (VTA). Emerging evidence indicates that LH-glutamatergic neurons infrequently synapse on VTA-dopamine neurons but preferentially establish multiple synapses on VTA-glutamatergic neurons. Here, we demonstrated that LH-glutamatergic inputs to VTA promoted active avoidance, long-term aversion, and escape attempts. By testing feeding in the presence of a predator, we observed that ongoing feeding was decreased, and that this predator-induced decrease in feeding was abolished by photoinhibition of the LH-glutamatergic inputs to VTA. By VTA specific neuronal ablation, we established that predator-induced decreases in feeding were mediated by VTA-glutamatergic neurons but not by dopamine or GABA neurons. Thus, we provided evidence for an unanticipated neuronal circuitry between LH-glutamatergic inputs to VTA-glutamatergic neurons that plays a role in prioritizing escape, and in the switch from feeding to escape in mice.

Ambitious biodiversity goals to protect 30% or more of the Earth’s surface by 2030 (30x30) require strategic near-term targets. To define areas that must be protected to prevent the most likely and imminent extinctions, we propose Conservation Imperatives—16,825 unprotected sites spanning ~164 Mha of the terrestrial realm that harbor rare and threatened species. We estimate that protecting the Conservation Imperatives would cost approximately US$169 billion (90% probability: US$146—US$228 billion). Globally, 38% of the 16,825 sites are either adjacent to or within 2.5 km of an existing protected area, potentially reducing land acquisition and management costs. These sites should be prioritized for conservation action over the next 5 years as part of a broader strategy to expand the global protected area network. The expansion of global protected areas between 2018 and 2023 incorporated only 7% of sites harboring range-limited and threatened species, highlighting a renewed urgency to conserve these habitats. Permanently protecting only 0.74% of land found in the tropics, where Conservation Imperatives are concentrated, could prevent the majority of predicted near-term extinctions once adequately resourced. We estimate this cost to be from US$29 billion to US$46 billion per year over the next 5 years. Multiple approaches will be required to meet long-term protection goals: providing rights and titles to Indigenous Peoples and Local Communities (IPLCs) conserving traditional lands, government designation of new protected areas on federal and state lands, and land purchase or long-term leasing of privately held lands.

Abstract Cryotherapy leverages controlled freezing temperature interventions to engender a cascade of tumor‐suppressing effects. However, its bottleneck lies in the standalone ineffectiveness. A promising strategy is using nanoparticle therapeutics to augment the efficacy of cryotherapy. Here, a cold‐responsive nanoplatform composed of upconversion nanoparticles coated with silica – chlorin e6 – hyaluronic acid (UCNPs@SiO2‐Ce6‐HA) is designed. This nanoplatform is employed to integrate cryotherapy with photodynamic therapy (PDT) in order to improve skin cancer treatment efficacy in a synergistic manner. The cryotherapy appeared to enhance the upconversion brightness by suppressing the thermal quenching. The low‐temperature treatment afforded a 2.45‐fold enhancement in the luminescence of UCNPs and a 3.15‐fold increase in the photodynamic efficacy of UCNPs@SiO2‐Ce6‐HA nanoplatforms. Ex vivo tests with porcine skins and the subsequent validation in mouse tumor tissues revealed the effective HA‐mediated transdermal delivery of designed nanoplatforms to deep tumor tissues. After transdermal delivery, in vivo photodynamic therapy using the UCNPs@SiO2‐Ce6‐HA nanoplatforms resulted in the optimized efficacy of 79% in combination with cryotherapy. These findings underscore the Cryo‐PDT as a truly promising integrated treatment paradigm and warrant further exploring the synergistic interplay between cryotherapy and PDT with bright upconversion to unlock their full potential in cancer therapy.

Abstract Adipose tissue invariant natural killer T (iNKT) cells are a crucial cell type for adipose tissue homeostasis in obese animals. However, heterogeneity of adipose iNKT cells and their function in adipocyte turnover are not thoroughly understood. Here, we investigate transcriptional heterogeneity in adipose iNKT cells and their hierarchy using single-cell RNA sequencing in lean and obese mice. We report that distinct subpopulations of adipose iNKT cells modulate adipose tissue homeostasis through adipocyte death and birth. We identify KLRG1+ iNKT cells as a unique iNKT cell subpopulation in adipose tissue. Adoptive transfer experiments showed that KLRG1+ iNKT cells are selectively generated within adipose tissue microenvironment and differentiate into a CX3CR1+ cytotoxic subpopulation in obese mice. In addition, CX3CR1+ iNKT cells specifically kill enlarged and inflamed adipocytes and recruit macrophages through CCL5. Furthermore, adipose iNKT17 cells have the potential to secrete AREG, and AREG is involved in stimulating adipose stem cell proliferation. Collectively, our data suggest that each adipose iNKT cell subpopulation plays key roles in the control of adipocyte turnover via interaction with adipocytes, adipose stem cells, and macrophages in adipose tissue.

Abstract With the slowdown of improvement in conventional von Neumann systems, increasing attention is paid to novel paradigms such as Ising machines. They have very different approach to solving combinatorial optimization problems. Ising machines have shown great potential in solving binary optimization problems like MaxCut. In this paper, we present an analysis of these systems in boolean satisfiability (SAT) problems. We demonstrate that, in the case of 3-SAT, a basic architecture fails to produce meaningful acceleration, largely due to the relentless progress made in conventional SAT solvers. Nevertheless, careful analysis attributes part of the failure to the lack of two important components: cubic interactions and efficient randomization heuristics. To overcome these limitations, we add proper architectural support for cubic interaction on a state-of-the-art Ising machine. More importantly, we propose a novel semantic-aware annealing schedule that makes the search-space navigation much more efficient than existing annealing heuristics. Using numerical simulations, we show that such an “Augmented” Ising Machine for SAT is projected to outperform state-of-the-art software-based, GPU-based and conventional hardware SAT solvers by orders of magnitude.

Abstract Zika virus infection causes multiple clinical issues, including Guillain–Barré syndrome and neonatal malformation. Vaccination is considered as the only strategy for the prevention of ZIKV-induced clinical issues. This study developed a plant-based recombinant vaccine that transiently expressed the ZIKV envelope protein (ZikaEnv:aghFc) in Nicotiana benthamiana and evaluated the protective immunity afforded by it in immunocompetent mice. ZikaEnv:aghFc induced both humoral and cellular immunity at a low dose (1–5 μg). This immune-inducing potential was enhanced further when adjuvanted CIA09A. In addition, antigen-specific antibodies and neutralizing antibodies were vertically transferred from immunized females to their progeny and afforded both protective immunity to ZIKV and cross-protection to Dengue virus infection. These results suggest that our plant-based ZIKV vaccine provides a safe and efficient protective strategy with a competitive edge.

Abstract Isozymes are enzymes that catalyze identical biological reactions, yet exhibit slight variations in structures and catalytic efficiency, which enables the precise adjustment of metabolism to fulfill the specific requirements of a particular tissue or stage of development. Methionine aminopeptidase (MetAP) isozymes function a critical role in cleaving N-terminal methionine from nascent proteins to generate functional proteins. In humans, two distinct MetAP types I and II have been identified, with type I further categorized into cytosolic (MetAP1) and mitochondrial (MetAP1D) variants. However, despite extensive structural studies on both bacterial and human cytosolic MetAPs, the structural information remains unavailable for human mitochondrial MetAP. This study was aimed to elucidate the high-resolution structures of human mitochondrial MetAP1D in its apo-, cobalt-, and methionine-bound states. Through a comprehensive analysis of the determined structures and a docking simulation model with mitochondrial substrate peptides, we present mechanistic insights into the cleavage process of the initiator methionine from mitochondrial proteins. Notably, despite the shared features at the active site between the cytosolic and mitochondrial MetAP type I isozymes, we identified distinct structural disparities within the active-site pocket primarily contributed by two specific loops that could play a role in accommodating specific substrates. These structural insights offer a basis for the further exploration of MetAP isozymes as critical players in cellular processes and potential therapeutic applications.

Abstract We aimed to assess DPNCheck’s reliability for repeated sural nerve conduction (NC) parameters. This post hoc analysis used data from the randomized controlled ACUDPN trial assessing NC of the N. Suralis every eight weeks over a 6-month period in 62 patients receiving acupuncture against diabetic peripheral neuropathy (DPN) symptoms. The reliability of DPNCheck for nerve conduction velocity and amplitude was assessed using intraclass correlation coefficients (ICC) and was calculated using data from single time points and repeated measures design. The results of the NC measurements were correlated with the Total Neuropathy Score clinical (TNSc). Overall, for both nerve velocity and amplitude, the reliability at each measurement time point can be described as moderate to good and the reliability using repeated measures design can be described as moderate. Nerve velocity and amplitude showed weak correlation with TNSc. DPNCheck’s reliability results question its suitability for monitoring DPN’s progression. Given the limitation of our analysis, a long-term, pre-specified, fully crossed study should be carried out among patients with DPN to fully determine the suitability of the device for DPN progression monitoring. This was the first analysis assessing the reliability of the DPNCheck for DPN progression monitoring using data from multiple collection time points.

Abstract This work reports the epitaxial growth of 8.5 µm-thick GaN layers on 200 mm engineered substrates with a polycrystalline AlN core (QST by QROMIS) for CMOS compatible processing of vertical GaN power devices. The epitaxial stack contains a 5 $$\upmu$$ μ m thick drift layers with a Si doping density of 2 × 1016 cm−3 and total threading dislocation density of 4 × 108 cm−2. The thick drift layer requires fine-tuning of the epitaxial growth conditions to keep wafer bow under control and to avoid the formation of surface defects. Diode test structures processed with this epitaxial stack achieved hard breakdown voltages > 750 V, which is shown to be limited by impurity or metal diffusion from the contact metal stack into threading dislocations. Conductive Atomic Force Microscopy (cAFM) reveals some leakage contribution from mixed type dislocations, which have their core structure identified as the double 5/6 atom configuration by scanning transmission electron microscopy images. Modelling of the leakage conduction mechanism with one-dimensional hopping conduction shows good agreement with the experimental data, and the resulting fitting parameters are compared to similar findings on silicon substrates. The outcome of this work is important to understand the possibilities and limitations of vertical GaN devices fabricated on large diameter wafers.