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Background: Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory., Methods: We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma., Results: The testing of a library of established drugs on patient-derived xenografts identified histone deacetylase inhibitors, most notably panobinostat, to be highly efficacious on hepatoblastoma cells, as compared to non-cancerous cells. Molecularly, the anti-tumor effect of panobinostat is mediated by posttranslational obstruction of the MYC oncoprotein as a result of dual specificity phosphatase 1 upregulation, thereby leading to growth inhibition and programmed cell death. Of clinical importance, upregulation of the MYC target gene nucleophosmin 1 is indicative of response to panobinostat and associated with metastatic disease in patients with hepatoblastoma. The combination of panobinostat with the current SIOPEL 4 induction protocol, consisting of cisplatin and doxorubicin, revealed high synergies already at low nanomolar levels. The simulation of a clinical trial, with this combination therapy, in patient-derived xenograft models, and ultimately heterotypic lung metastasis mimics clearly underscored the potency of this approach., Conclusion: Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma., Competing Interests: Declarations Ethics approval and consent to participate In vivo testing in mice was carried out according to the Italian Decree (08/2023-UT). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Various approaches have been reported to achieve correctly aligned total knee arthroplasty in cases of knee arthritis with pronounced extra-articular bone malalignment. Revision instrumentation and implants have enabled bone correction coincident with knee arthroplasty in notable tibial and/or femoral deviation, however increasing operative complexity and inherent risks. In the presented patient with hereditary multiple exostoses disease and progressing knee arthritis for extra-articular malalignment, elected treatment strategy was to primarily correct joint plane deformity through femoral and tibial osteotomies, ahead of and preparing for later knee arthroplasty. Staged osteotomies prior to total knee arthroplasty are effective for managing severe extra-articular malalignment, improving surgical outcome and prosthetic longevity., (© 2024 The Authors.)

Background: Minimally invasive surgery is becoming the method of choice for the resection of esophageal cancer worldwide., Methods: Retrospective analysis of prospectively collected clinical data in a tertiary care center with a detailed description of the course of the program., Results: A total of 136 transthoracic esophageal resections were performed between 2010 and 2023. The study group included 116 operations, 69 of which were fully minimally invasive and 47 hybrid. 80.0% of the study group underwent surgery using a multimodality approach. The median operation time was 431 min (± 103). The R0 resection rate was 100%. Forty-two patients (36.2%) had no postoperative complications. The postoperative Clavien-Dindo > IIIb morbidity was 27%. The postoperative 90-d mortality rate was 1.7%. The average number of lymph nodes removed in the last quarter of cancer patients was 31. The anastomotic insufficiency rate for reoperation was 4% (Ivor-Lewis 4.2%, McKeown 5%)., Conclusions: With extensive expertise in high-end minimally invasive abdominal and thoracic surgery, implementation of a minimally invasive esophageal resection program with a clinical and oncologic outcome within generally accepted limits is feasible., (© 2024. The Author(s).)

Previous studies have shown that exposure to simulated natural environments can elevate state body appreciation, but stimulus sets have been limited to the use of images and 2-dimensional (2D) film. To extend this work, we examined the relative impact of images, 2D film, and a 360° immersive film on immediate, state body appreciation. A total of 136 German-speaking adults from Austria (71.3 % women; age range 18-69 years) were randomly assigned to one of three conditions, in which they viewed an image set, a 2D film, or a 360° film depicting the same natural environment. Before and after viewing the stimuli, they completed measures of state body appreciation, affect, and desire for aesthetics. Our results showed that state body appreciation improved in all three conditions, with effect sizes ranging from Cohen's d = 0.26 (2D film) to 0.52 (360° film). Presentation modality did not significantly shape improvements in state body appreciation; that is, the elevation in state body appreciation was equivalent across all three groups. Participants also experienced improvements in feelings of pleasantness, but again this was independent of the experimental group. These results suggest exposure to simulated nature may improve state body appreciation irrespective of the presentation modality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The inhibitor-kappaB kinase epsilon (IKKε) represents a non-canonical IκB kinase that modulates NF-κB activity and interferon I responses. Inhibition of this pathway has been linked with atherosclerosis and metabolic dysfunction-associated steatotic liver disease (MASLD), yet the results are contradictory. In this study, we employed a combined model of hepatic PCSK9 D377Y overexpression and a high-fat diet for 16 weeks to induce atherosclerosis and liver steatosis. The development of atherosclerotic plaques, serum lipid concentrations, and lipid metabolism in the liver and adipose tissue were compared between wild-type and IKKε knock-out mice. The formation and progression of plaques were markedly reduced in IKKε knockout mice, accompanied by reduced serum cholesterol levels, fat deposition, and macrophage infiltration within the plaque. Additionally, the development of a fatty liver was diminished in these mice, which may be attributed to decreased levels of multiple lipid species, particularly monounsaturated fatty acids, triglycerides, and ceramides in the serum. The modulation of several proteins within the liver and adipose tissue suggests that de novo lipogenesis and the inflammatory response are suppressed as a consequence of IKKε inhibition. In conclusion, our data suggest that the knockout of IKKε is involved in mechanisms of both atherosclerosis and MASLD. Inhibition of this pathway may therefore represent a novel approach to the treatment of cardiovascular and metabolic diseases.

The study tested a brief intervention to stimulate and help supervisors reduce work-related interruptions among their employees, both at work and during leisure time. The core of the short-term intervention was a workplace analysis of work-related interruptions, which was fed back to supervisors in combination with a work redesign stimulation explaining why and how to reduce interruptions. Two intervention sessions, as one-on-one physical meetings, that lasted 1.5 h each and were 2 wk apart. The sample consisted of 20 managers and 89 employees. The non-experimental repeated measurement design comprised three questionnaire measurements of the 89 employees (two pre-measurements and one post-measurement). Repeated measure hierarchical linear models showed that the intervention significantly predicted reduced interruptions during work and work-related interruptions of leisure time. Although the intervention effect sizes were small, the current work design intervention with supervisors as mediating actors can reasonably contribute to occupational health prevention.

Palm fat has uniquely optimal melting characteristics that are difficult to replace in products such as baked goods and chocolate-based items. This study investigates the efficacy of using Pickering emulsions derived from Swiss plant oils and their micromilled press cakes. Emulsification was carried out at both the lab and pilot scales using sunflower- and rapeseed-based recipes, with and without additional surfactants, for both oil-in-water and water-in-oil emulsions. The resulting emulsions were measured for viscosity and short- and long-term stability and linked to the properties of the raw materials. The results indicated that the contact angle, size, and macronutrient composition of the particles significantly impact emulsion quality, though differences in oil pressing methods might predominate these effects. The combination of particles and surfactants demonstrated a clear advantage with respect to interface stabilisation, with a suggested link between the wax content of the oil and particles and the resulting emulsion quality and stability.

Background and Objective: Artificial intelligence (AI)-powered conversational agents are increasingly finding application in health care, as these can provide patient education at any time. However, their effectiveness in medical settings remains largely unexplored. This study aimed to assess the impact of the chatbot "PROState cancer Conversational Agent" (PROSCA), which was trained to provide validated support from diagnostic tests to treatment options for men facing prostate cancer (PC) diagnosis., Methods: The chatbot PROSCA, developed by urologists at Heidelberg University Hospital and SAP SE, was evaluated through a randomized controlled trial (RCT). Patients were assigned to either the chatbot group, receiving additional access to PROSCA alongside standard information by urologists, or the control group (1:1), receiving standard information. A total of 112 men were included, of whom 103 gave feedback at study completion., Key Findings and Limitations: Over time, patients' information needs decreased significantly more in the chatbot group than in the control group ( p  = 0.035). In the chatbot group, 43/54 men (79.6%) used PROSCA, and all of them found it easy to use. Of the men, 71.4% agreed that the chatbot improved their informedness about PC and 90.7% would like to use PROSCA again. Limitations are study sample size, single-center design, and specific clinical application., Conclusions and Clinical Implications: With the introduction of the PROSCA chatbot, we created and evaluated an innovative, evidence-based AI health information tool as an additional source of information for PC. Our RCT results showed significant benefits of the chatbot in reducing patients' information needs and enhancing their understanding of PC. This easy-to-use AI tool provides accurate, timely, and accessible support, demonstrating its value in the PC diagnosis process. Future steps include further customization of the chatbot's responses and integration with the existing health care systems to maximize its impact on patient outcomes., Patient Summary: This study evaluated an artificial intelligence-powered chatbot-PROSCA, a digital tool designed to support men facing prostate cancer diagnosis by providing validated information from diagnosis to treatment. Results showed that patients who used the chatbot as an additional tool felt better informed than those who received standard information from urologists. The majority of users appreciated the ease of use of the chatbot and expressed a desire to use it again; this suggests that PROSCA could be a valuable resource to improve patient understanding in prostate cancer diagnosis., (© 2024 The Author(s).)

Background: The excessive cardiovascular mortality of patients with chronic kidney disease (CKD) could be linked to mineral stress, the biological consequence of calcium-phosphate nanoparticle exposure. This study investigated whether zinc is associated with mineral stress markers in CKD., Methods: Z inc and T50 (serum calcification propensity) as well as hydrodynamic radius of secondary calciprotein particles (CPP2) were measured in blood donors and CKD patients with/out dialysis., Results: Serum zinc concentrations and T50 were reduced, while CPP2 radius was increased in CKD patients. Serum zinc levels positively correlated with T50 and inversely correlated with CPP2 radius. In a hierarchical linear regression model, T50 was associated with age, calcium, phosphate, magnesium and albumin. Addition of zinc significantly improved prediction of the model, confirming an additional contribution of zinc to T50. Similar observations were made for the association of zinc and CPP2 radius, but spiking experiments indicated that zinc may stronger modify T50 than CPP2 radius. Also, urinary zinc excretion was increased in patients with kidney disease and correlated to T50 and CPP2 radius. S erum zinc further correlated with markers of arterial stiffness in blood donors and CKD patients, but these associations did not remain significant in a multivariate linear regression model., Conclusions: Reduced serum zinc levels in CKD appear directly linked to lower T50 and associated with larger CPP2 radius. Further studies on the associations of zinc and mineral stress as well as putative therapeutic benefits of zinc supplementation are required., Competing Interests: A.P. is stockholder of Calciscon AG (Biel, Switzerland), which commercializes the mineral stress analysis used in this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3' untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: The higher detection efficacy of PSMA PET for oligometastatic recurrence of prostate cancer has promoted new loco-regional treatment options. PSMA-targeted radioguided surgery (PSMA-RGS) was introduced to facilitate salvage surgery of small tumor deposits. The objectives of this retrospective analysis are to describe an independent single-center consecutive cohort of patients undergoing PSMA-RGS and to evaluate its clinical and oncological outcomes., Method: Between 2018 and 2022, 53 patients were treated with PSMA-RGS and 50 patients were available for final analyses. All patients were initially treated with radical prostatectomy (RP) and presented with biochemical recurrence (BCR) with at least one positive lesion on PSMA-PET imaging. After preparation of 99mTc-PSMA-I&S and intravenous injection, surgery was performed by using a gamma-probe intraoperatively., Results: Median age was 70 years (IQR 65-73) and the median PSA at salvage surgery was 1.2 ng/mL (IQR 0.6-3.0). In all patients pathologically positive lesions could be removed during PSMA-RGS. 29 (58%) patients had one pathologically positive lesion, 14 (28%) had two and 7 (14%) had three or more, respectively. The overall complication rate was 26% with 4 (8%), 1 (2%), and 8 (16%) having Clavien-Dindo (CD) type I, II, and IIIb complications, respectively. During the follow-up period 31 (62%) patients experienced BCR and 29 (58%) received further therapy., Conclusions: PSMA-RGS is a promising treatment option to enhance salvage surgery in early biochemical recurrence. However, only 42% of the patients treated with PSMA RGS remain without a biochemical recurrence. Further research is mandatory to identify patients, who profit from PSMA-RGS., (© 2024. The Author(s).)

The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies. In addition to its well-established antitumor activity, accumulating evidence attributes anti-inflammatory effects to HHT, which have mainly been studied in leukocytes to date. However, a potential influence of HHT on inflammatory activation processes in endothelial cells, which are a key feature of inflammation and a prerequisite for the leukocyte-endothelial cell interaction and leukocyte extravasation, remains poorly understood. In this study, the anti-inflammatory potential of HHT and its derivative harringtonine (HT) on the TNF-induced leukocyte-endothelial cell interaction was assessed, and the underlying mechanistic basis of these effects was elucidated. HHT affected inflammation in vivo in a murine peritonitis model by reducing leukocyte infiltration and proinflammatory cytokine expression as well as ameliorating abdominal pain behavior. In vitro, HT and HHT impaired the leukocyte-endothelial cell interaction by decreasing the expression of the endothelial cell adhesion molecules intracellular adhesion molecule -1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was mediated by a bipartite mechanism. While HHT did not affect the prominent TNF-induced pro-inflammatory NF-ĸB signaling cascade, the compound downregulated the VCAM1 mRNA expression in an IRF-1-dependent manner and diminished active ICAM1 mRNA translation as determined by polysome profiling. This study highlights HHT as an anti-inflammatory compound that efficiently hampers the leukocyte-endothelial cell interaction by targeting endothelial activation processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current anti-angiogenic treatments still have major drawbacks like limited efficacy in diseases that also rely on inflammation. Therefore, new anti-angiogenic approaches are sorely needed, and simultaneous inhibition of angiogenesis and inflammation is desirable. Here, we show that 2-desaza-annomontine (C81), a derivative of the plant alkaloid annomontine previously shown to inhibit endothelial inflammation, impedes angiogenesis by inhibiting CDC2-like kinases (CLKs) and WNT/β-catenin signaling. C81 reduced choroidal neovascularization in a laser-induced murine in vivo model, inhibited sprouting from vascular endothelial growth factor A (VEGF-A)-activated murine aortic rings ex vivo, and reduced angiogenesis-related activities of endothelial cells in multiple functional assays. This was largely phenocopied by CLK inhibitors and knockdowns, but not by inhibitors of the other known targets of C81. Mechanistically, CLK inhibition reduced VEGF receptor 2 (VEGFR2) mRNA and protein expression as well as downstream signaling. This was partly caused by a reduction of WNT/β-catenin pathway activity, as activating the pathway induced, while β-catenin knockdown impeded VEGFR2 expression. Surprisingly, alternative splicing of VEGFR2 was not detected. In summary, C81 and other CLK inhibitors could be promising compounds in the treatment of diseases that depend on angiogenesis and inflammation due to their impairment of both processes., (© 2024. The Author(s).)

In this work, a measurement setup to study the Seebeck and Nernst effect at high temperatures and high magnetic fields is introduced and discussed. The measurement system allows for simultaneous measurements of both thermoelectric effects up to 700 K and magnetic fields up to 12 T. Based on theoretical concepts, measurement equations are derived that counteract constant spurious offset voltages and, therefore, inhibit systematic errors in the measurement setup. The functionality is demonstrated on polycrystalline samples of elemental bismuth as well as various full-Heusler materials, exhibiting an anomalous Nernst effect. In all samples, the measured Seebeck and Nernst coefficients align excellently with the reported values. This allows future research to substantially extend the measured temperature and field intervals, commonly limited to temperatures below room temperature. For the first time, the thermoelectric and thermomagnetic properties of these materials are reported up to temperatures of 560 K., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90 %. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 h post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Influenza A virus (IAV) infection can cause the often-lethal acute respiratory distress syndrome (ARDS) of the lung. Concomitantly, acute kidney injury (AKI) is frequently noticed during IAV infection, correlating with an increased mortality. The aim of this study was to elucidate the interaction of IAV with human kidney cells and, thereby, to assess the mechanisms underlying IAV-mediated AKI., Methods: To investigate IAV effects on nephron cells we performed infectivity assays with human IAV, as well as with human isolates of either low or highly pathogenic avian IAV. Also, transcriptome and proteome analysis of IAV-infected primary human distal tubular kidney cells (DTC) was performed. Furthermore, the DTC transcriptome was compared to existing transcriptomic data from IAV-infected lung and trachea cells., Results: We demonstrate productive replication of all tested IAV strains on primary and immortalized nephron cells. Comparison of our transcriptome and proteome analysis of H1N1-type IAV-infected human primary distal tubular cells (DTC) with existing data from H1N1-type IAV-infected lung and primary trachea cells revealed enrichment of specific factors responsible for regulated cell death in primary DTC, which could be targeted by specific inhibitors., Discussion: IAV not only infects, but also productively replicates on different human nephron cells. Importantly, multi-omics analysis revealed regulated cell death as potential contributing factor for the clinically observed kidney pathology in influenza., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Koch, Shehata, Müller-Ruttloff, Gouda, Wetzstein, Patyna, Scholz, Schmid, Dietrich, Münch, Ziebuhr, Geiger, Martinez-Sobrido, Baer, Mostafa and Pleschka.)

Objectives: This study quantified the long-term occlusal wear in the natural posterior teeth and the associations per tooth type within the dentition., Methods: The sample included 70 orthodontically treated subjects (52 females and 18 males; median age, 14.3 years), followed for a 12.7-year period. They were consecutively selected with no tooth wear-related criteria. Post-treatment (T1) and follow-up dental casts (T2) were scanned and superimposed through three-dimensional methods. Occlusal wear volume of posterior teeth and tooth wear patterns were investigated through non-parametric statistics and analysis of covariance., Results: There were no significant differences between contralateral teeth. The average occlusal wear per posterior tooth was 2.3 mm 3 , with 65.2% of teeth showing values greater than 1 mm 3 . Males, mandibular teeth, and first molars exhibited slightly greater wear levels than females (median, 2.57 and 2.21 mm 3 , respectively; p = 0.005), maxillary teeth, and first or second premolars, respectively. In all first premolars and in the mandibular second premolars, the buccal cusps were primarily affected with no other distinct patterns. There were weak to moderate correlations between tooth types, apart from certain strong correlations detected in males., Conclusions: Posterior tooth wear was highly prevalent after a 13-year period starting at the onset of permanent dentition. The detected patterns are in accordance with the concept of canine guidance occlusion that is transforming into group synergy through function., Clinical Relevance: The widespread tooth wear occurrence and the high intra- and inter-individual variability underline the need for individual patient monitoring to identify high-risk patients at early stages., (© 2024. The Author(s).)

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER's potency and versatility.

High-linear energy transfer (LET) radiation, such as heavy ions is associated with a higher relative biological effectiveness (RBE) than low-LET radiation, such as photons. Irradiation with low- and high-LET particles differ in the interaction with the cellular matter and therefore in the spatial dose distribution. When a single high-LET particle interacts with matter, it results in doses of up to thousands of gray (Gy) locally concentrated around the ion trajectory, whereas the mean dose averaged over the target, such as a cell nucleus is only in the range of a Gy. DNA damage therefore accumulates in this small volume. In contrast, up to hundreds of low-LET particle hits are required to achieve the same mean dose, resulting in a quasi-homogeneous damage distribution throughout the cell nucleus. In this study, we investigated the dependence of RBE from different spatial dose depositions using different focused beam spot sizes of proton radiation with respect to the induction of chromosome aberrations and clonogenic cell survival. Human-hamster hybrid (AL) as well as Chinese hamster ovary cells (CHO-K1) were irradiated with focused low LET protons of 20 MeV (LET = 2.6 keV/µm) beam energy with a mean dose of 1.7 Gy in a quadratic matrix pattern with point spacing of 5.4 × 5.4 µm2 and 117 protons per matrix point at the ion microbeam SNAKE using different beam spot sizes between 0.8 µm and 2.8 µm (full width at half maximum). The dose-response curves of X-ray reference radiation were used to determine the RBE after a 1.7 Gy dose of radiation. The RBE for the induction of dicentric chromosomes and cell inactivation was increased after irradiation with the smallest beam spot diameter (0.8 µm for chromosome aberration experiments and 1.0 µm for cell survival experiments) compared to homogeneous proton radiation but was still below the RBE of a corresponding high LET single ion hit. By increasing the spot size to 1.6-1.8 µm, the RBE decreased but was still higher than for homogeneously distributed protons. By further increasing the spot size to 2.7-2.8 µm, the RBE was no longer different from the homogeneous radiation. Our experiments demonstrate that varying spot size of low-LET radiation gradually modifies the RBE. This underlines that a substantial fraction of enhanced RBE originates from inhomogeneous energy concentrations on the µm scale (mean intertrack distances of low-LET particles below 0.1 µm) and quantifies the link between such energy concentration and RBE. The missing fraction of RBE enhancement when comparing with high-LET ions is attributed to the high inner track energy deposition on the nanometer scale. The results are compared with model results of PARTRAC and LEM for chromosomal aberration and cell survival, respectively, which suggest mechanistic interpretations of the observed radiation effects., (© 2024 by Radiation Research Society.)

Despite the importance of rapid adaptive responses in the course of inflammation and the notion that post-transcriptional regulation plays an important role herein, relevant translational alterations, especially during the resolution phase, remain largely elusive. In the present study, we analyzed translational changes in inflammatory bone marrow-derived macrophages upon resolution-promoting efferocytosis. Total RNA-sequencing confirmed that apoptotic cell phagocytosis induced a pro-resolution signature in LPS/IFNγ-stimulated macrophages (Mϕ). While inflammation-dependent transcriptional changes were relatively small between efferocytic and non-efferocytic Mϕ; considerable differences were observed at the level of de novo synthesized proteins. Interestingly, translationally regulated targets in response to inflammatory stimuli were mostly downregulated, with only minimal impact of efferocytosis. Amongst these targets, pro-resolving matrix metallopeptidase 12 (Mmp12) was identified as a translationally repressed candidate during early inflammation that recovered during the resolution phase. Functionally, reduced MMP12 production enhanced matrix-dependent migration of Mϕ. Conclusively, translational control of MMP12 emerged as an efficient strategy to alter the migratory properties of Mϕ throughout the inflammatory response, enabling Mϕ migration within the early inflammatory phase while restricting migration during the resolution phase.

Introduction: Emerging technologies such as three-dimensional (3D) cell culture and the generation of biological matrices offer exciting new possibilities in disease modelling and tumour therapy. The paucity of laboratory models for hepatoblastoma (HB), the most prevalent malignant liver tumour in children, has hampered the identification of new treatment options for HB patients. We aimed to establish a reliable 3D testing platform using liver-derived scaffolds and HB cell lines that reflect the heterogeneous biology of the disease so as to allow reproducible preclinical research and drug testing. Methods: In a sequence of physical, chemical and enzymatic decellularisation techniques mouse livers were stripped off all cellular components to obtain a 3D scaffold. HB cell lines were then seeded onto these scaffolds and cultivated for several weeks. Results: Our newly generated biological scaffolds consist of liver-specific extracellular matrix components including collagen IV and fibronectin. A cultivation of HB cell lines on these scaffolds led to the formation of 3D tumour structures by infiltration into the matrix. Analyses of drug response to standard-of-care medication for HB showed reliable reproducibility of our stocked models. Discussion: Our HB models are easy-to-handle, producible at large scale, and can be cryopreserved for ready-to-use on-demand application. Our newly generated 3D HB platform may therefore represent a faithful preclinical model for testing treatment response in precision cancer medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Weigl, Demir, Schmid, Hotes, Muensterer and Kappler.)

Macrophages are a highly versatile and heterogenic group of immune cells, known for their involvement in inflammatory reactions. However, our knowledge about distinct subpopulations of macrophages and their specific contribution to the resolution of inflammation remains incomplete. We have previously shown, in an in vivo peritonitis model, that inhibition of the synthesis of the pro-inflammatory lipid mediator prostaglandin E 2 (PGE 2 ) attenuates efficient resolution of inflammation. PGE 2 levels during later stages of the inflammatory process further correlate with expression of the hyaluronan (HA) receptor Lyve1 in peritoneal macrophages. In the present study, we therefore aimed to understand if PGE 2 might contribute to the regulation of Lyve1 and how this might impact inflammatory responses. In line with our in vivo findings, PGE 2 synergized with dexamethasone to enhance Lyve1 expression in bone marrow-derived macrophages, while expression of the predominant hyaluronan receptor CD44 remained unaltered. PGE 2 -mediated Lyve1 upregulation was strictly dependent on PGE 2 receptor EP2 signaling. While PGE 2 /dexamethasone-treated macrophages, despite their enhanced Lyve1 expression, did not show inflammatory responses upon stimulation with low (LMW) or high-molecular-weight hyaluronan (HMW)-HA, they were sensitized towards LMW-HA-dependent augmentation of lipopolysaccharide (LPS)-induced inflammatory responses. Thus, Lyve1-expressing macrophages emerged as a subpopulation of macrophages integrating inflammatory stimuli with extracellular matrix-derived signals.

Bread forms an integral part of the daily diet in many cultures worldwide. At the same time, a significant number of people try to avoid wheat-based products for either health reasons or due to personal preferences. The absence of a protein network in gluten free bread affects its structure, taste, texture and shelf-life. This paper suggests a technological solution to this issue that uses a pre-foamed mass of gluten free raw materials which is mixed with the bread's ingredients, then kneaded and baked to form a high quality gluten free bread. To survive the high shear stresses during kneading and temperature increase during baking, the foam requires exceptional stability. This stability was achieved through particle stabilisation of the bubble interfaces. Both of the tested foams (with and without particles) exhibited thermal stability up to 80 °C. However, resistance to shear stresses was higher in the particle stabilised foams. Of all the tested particles, linseed press cake and banana powder led to the best results. In conclusion, particle stabilised foams seem very well suited to applications in gluten free baked goods. Further application potential is seen for vegan foamed desserts., Competing Interests: Conflicts of interestNone., (© The Author(s) 2023.)

Background: Pain in early life may impact on development and risk of chronic pain. We developed an optogenetic Cre/loxP mouse model of "early-life-pain" (ELP) using mice with transgenic expression of channelrhodopsin-2 (ChR2) under control of the Advillin (Avil) promoter, which drives expression of transgenes predominantly in isolectin B4 positive non-peptidergic nociceptors in postnatal mice. Avil-ChR2 (Cre +) and ChR2-flfl control mice were exposed to blue light in a chamber once daily from P1-P5 together with their Cre-negative mother., Results: ELP caused cortical hyperexcitability at P8-9 as assessed via multi-electrode array recordings that coincided with reduced expression of synaptic genes (RNAseq) including Grin2b, neurexins, piccolo and voltage gated calcium and sodium channels. Young adult (8-16 wks) Avil-ChR2 mice presented with nociceptive hypersensitivity upon heat or mechanical stimulation, which did not resolve up until one year of age. The persistent hypersensitivy to nociceptive stimuli was reflected by increased calcium fluxes in primary sensory neurons of aged mice (1 year) upon capsaicin stimulation. Avil-ChR2 mice behaved like controls in maze tests of anxiety, social interaction, and spatial memory but IntelliCage behavioral studies revealed repetitive nosepokes and corner visits and compulsive lickings. Compulsiveness at the behavioral level was associated with a reduction of sphingomyelin species in brain and plasma lipidomic studies. Behavioral studies were done with female mice., Conclusion: The results suggest that ELP may predispose to chronic "pain" and compulsive psychopathology in part mediated by alterations of sphingolipid metabolism, which have been previously described in the context of addiction and psychiatric diseases., (© 2023. Society of Chinese Bioscientists in America (SCBA).)

Purpose: The aim of this systematic review was to investigate tendon-specific microRNAs (miRNAs) as biomarkers for the detection of tendinopathies or degenerative tendon ruptures. Also, their regulatory mechanisms within the tendon pathophysiology were summarized., Methods: A systematic literature research was performed using the PRISMA guidelines. The search was conducted in the Pubmed database. The SIGN checklist was used to assess the study quality of the included original studies. To determine the evidence and direction of the miRNA expression rates, a best-evidence synthesis was carried out, whereby only studies with at least a borderline methodological quality were considered for validity purposes., Results: Three thousand three hundred seventy studies were reviewed from which 22 fulfilled the inclusion criteria. Moderate evidence was found for miR-140-3p and miR-425-5p as potential biomarkers for tendinopathies as well as for miR-25-3p, miR-29a-3p, miR-140-3p, and miR-425-5p for the detection of degenerative tendon ruptures. This evidence applies to tendons at the upper extremity in elderly patients. All miRNAs were associated with inflammatory cytokines as interleukin-6 or interleukin-1ß and tumor necrosis factor alpha., Conclusions: Moderate evidence exists for four miRNAs as potential biomarkers for tendinopathies and degenerative tendon ruptures at the upper extremity in elderly patients. The identified miRNAs are associated with inflammatory processes., (© 2023. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Hypoxia contributes to numerous pathophysiological conditions including inflammation-associated diseases. We characterized the impact of hypoxia on the immunometabolic cross-talk between cholesterol and interferon (IFN) responses. Specifically, hypoxia reduced cholesterol biosynthesis flux and provoked a compensatory activation of sterol regulatory element-binding protein 2 (SREBP2) in monocytes. Concomitantly, a broad range of interferon-stimulated genes (ISGs) increased under hypoxia in the absence of an inflammatory stimulus. While changes in cholesterol biosynthesis intermediates and SREBP2 activity did not contribute to hypoxic ISG induction, intracellular cholesterol distribution appeared critical to enhance hypoxic expression of chemokine ISGs. Importantly, hypoxia further boosted chemokine ISG expression in monocytes upon infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Mechanistically, hypoxia sensitized toll-like receptor 4 (TLR4) signaling to activation by SARS-CoV-2 spike protein, which emerged as a major signaling hub to enhance chemokine ISG induction following SARS-CoV-2 infection of hypoxic monocytes. These data depict a hypoxia-regulated immunometabolic mechanism with implications for the development of systemic inflammatory responses in severe cases of coronavirus disease-2019 (COVID-19)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bauer, Meyer, Raue, Palmer, Guerrero Ruiz, Cardamone, Rösser, Heffels, Roesmann, Wilhelm, Lütjohann, Zarnack, Fuhrmann, Widera, Schmid and Brüne.)

Introduction: Artificial intelligence (AI) is increasingly used in healthcare. AI-based chatbots can act as automated conversational agents, capable of promoting health and providing education at any time. The objective of this study was to develop and evaluate a user-friendly medical chatbot (prostate cancer communication assistant (PROSCA)) for provisioning patient information about early detection of prostate cancer (PC)., Methods: The chatbot was developed to provide information on prostate diseases, diagnostic tests for PC detection, stages, and treatment options. Ten men aged 49 to 81 years with suspicion of PC were enrolled in this study. Nine of ten patients used the chatbot during the evaluation period and filled out the questionnaires on usage and usability, perceived benefits, and potential for improvement., Results: The chatbot was straightforward to use, with 78% of users not needing any assistance during usage. In total, 89% of the chatbot users in the study experienced a clear to moderate increase in knowledge about PC through the chatbot. All study participants who tested the chatbot would like to re-use a medical chatbot in the future and support the use of chatbots in the clinical routine., Conclusions: Through the introduction of the chatbot PROSCA, we created and evaluated an innovative evidence-based health information tool in the field of PC, allowing targeted support for doctor-patient communication and offering great potential in raising awareness, patient education, and support. Our study revealed that a medical chatbot in the field of early PC detection is readily accepted and benefits patients as an additional informative tool., (© The Author(s) 2023.)

The cranial neural crest plays a fundamental role in orofacial development and morphogenesis. Accordingly, mutations with impact on the cranial neural crest and its development lead to orofacial malformations such as cleft lip and palate. As a pluripotent and dynamic cell population, the cranial neural crest undergoes vast transcriptional and epigenomic alterations throughout the formation of facial structures pointing to an essential role of factors regulating chromatin state or transcription levels. Using CRISPR/Cas9-guided genome editing and conditional mutagenesis in the mouse, we here show that inactivation of Kat5 or Ep400 as the two essential enzymatic subunits of the Tip60/Ep400 chromatin remodeling complex severely affects carbohydrate and amino acid metabolism in cranial neural crest cells. The resulting decrease in protein synthesis, proliferation and survival leads to a drastic reduction of cranial neural crest cells early in fetal development and a loss of most facial structures in the absence of either protein. Following heterozygous loss of Kat5 in neural crest cells palatogenesis was impaired. These findings point to a decisive role of the Tip60/Ep400 chromatin remodeling complex in facial morphogenesis and lead us to conclude that the orofacial clefting observed in patients with heterozygous KAT5 missense mutations is at least in part due to disturbances in the cranial neural crest., (© 2023. The Author(s).)

The importance of biologically active lipid mediators, such as prostanoids, leukotrienes, and specialized pro-resolving mediators, in the regulation of inflammation is well established. While the relevance of cholesterol in the context of atherosclerosis is also widely accepted, the role of cholesterol and its biosynthetic precursors on inflammatory processes is less comprehensively described. In the present mini-review, we summarize the current understanding of the inflammation-regulatory properties of cholesterol and relevant biosynthetic intermediates taking into account the implications of different subcellular distributions. Finally, we discuss the inflammation-regulatory effect of cholesterol homeostasis in the context of SARS-CoV-2 infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bauer, Brüne and Schmid.)

5-Lipoxygenase (5-LO), the central enzyme in the biosynthesis of leukotrienes, is frequently expressed in human solid malignancies even though the enzyme is not present in the corresponding healthy tissues. There is little knowledge on the consequences of this expression for the tumor cells regarding gene expression and cellular function. We established a knockout (KO) of 5-LO in different cancer cell lines (HCT-116, HT-29, U-2 OS) and studied the consequences on global gene expression using next generation sequencing. Furthermore, cell viability, proliferation, migration and multicellular tumor spheroid (MCTS) formation were studied in these cells. Our results show that 5-LO influences the gene expression and cancer cell function in a cell type-dependent manner. The enzyme affected genes involved in cell adhesion, extracellular matrix formation, G protein signaling and cytoskeleton organization. Furthermore, absence of 5-LO elevated TGFβ 2 expression in HCT-116 cells while MCP-1, fractalkine and platelet-derived growth factor expression was attenuated in U-2 OS cells suggesting that tumor cell-derived 5-LO shapes the tumor microenvironment. In line with the gene expression data, KO of 5-LO had an impact on cell proliferation, motility and MCTS formation. Interestingly, pharmacological inhibition of 5-LO only partly mimicked the KO suggesting that also noncanonical functions are involved., (© 2022. The Author(s).)

Objectives: Lacerations comprise 5.6-33.6% of skiing/snowboarding related injuries. This study aimed to investigate the mechanism of injury and the location of these lacerations and propose preventive measures., Methods: After our state ethics committee approval, we retrospectively reviewed the medical records and surgical protocols of 46 patients (mean age (±SD) 34.6 (±15.3); 71.4% men) treated for severe skiing/snowboarding lacerations at our level-1 trauma centre between 2016 and 2021. Patients were asked to answer a questionnaire on their skiing experience, equipment used and the circumstances of the accident., Results: Lacerations around the hip, thigh, and knee accounted for 94%. The latter was the most common location (45%). Although 91.3% of patients wore appropriate clothing and full standard protection equipment, it did not offer any extra-resistance against skiing/snowboarding's edges. Skiers were more affected (91.3%) than snowboarders (8.7%). The most common mechanism of injury was inadvertent release of the bindings (52.2%), followed by insufficient ski level for the slope (21.7%) and collisions (17.4%). Long-term trends demonstrated an increasing incidence., Conclusion: Identification of body areas at risk and the mechanisms of injury were the most significant findings of this work. These data encourage the development of specific injury prevention programs as the occurrence of these lesions tended to increase over the last few years. To reduce their incidence, we propose skiers to have their bindings regularly adjusted and manufacturers to develop cut-resistant skiwear., Level of Evidence: IV., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The discussed comparative analyses of Roman Imperial pigment balls and fragmentary murals unearthed in the ancient cities of Aventicum and Augusta Raurica (Switzerland) by means of Raman microspectroscopy pertain to a predecessor study on trace compounds in Early Medieval Egyptian blue (St. Peter, Gratsch, South Tyrol, Northern Italy). The plethora of newly detected associated minerals of the raw materials surviving the synthesis procedure validate the use of quartz sand matching the composition of sediments transported by the Volturno river into the Gulf of Gaeta (Campania, Southern Italy) with a roasted sulphidic copper ore and a mixed-alkaline plant ash as fluxing agent. Thus, the results corroborate a monopolised pigment production site located in the northern Phlegrean Fields persisting over the first centuries A.D., this in line with statements of the antique Roman writers Vitruvius and Pliny the Elder and recent archaeological evidences. Beyond that, Raman spectra reveal through gradual peak shifts and changes of band width locally divergent process conditions and compositional inhomogeneities provoking crystal lattice disorder in the chromophoric cuprorivaite as well as the formation of a copper-bearing green glass phase, the latter probably in dependency of the concentration of alkali flux, notwithstanding that otherwise solid-state reactions predominate the synthesis., (© 2022. The Author(s).)

Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, besides its canonical function as an arachidonic acid metabolizing enzyme, is a regulator of gene expression associated with euchromatin. By Crispr-Cas9-mediated 5-LO knockout (KO) in MonoMac6 (MM6) cells and subsequent RNA-Seq analysis, we identified 5-LO regulated genes which could be clustered to immune/defense response, cell adhesion, transcription and growth/developmental processes. Analysis of differentially expressed genes identified cyclooxygenase-2 (COX2, PTGS2) and kynureninase (KYNU) as strongly regulated 5-LO target genes. 5-LO knockout affected MM6 cell adhesion and tryptophan metabolism via inhibition of the degradation of the immunoregulator kynurenine. By subsequent FAIRE-Seq and 5-LO ChIP-Seq analyses, we found an association of 5-LO with euchromatin, with prominent 5-LO binding to promoter regions in actively transcribed genes. By enrichment analysis of the ChIP-Seq results, we identified potential 5-LO interaction partners. Furthermore, 5-LO ChIP-Seq peaks resemble patterns of H3K27ac histone marks, suggesting that 5-LO recruitment mainly takes place at acetylated histones. In summary, we demonstrate a noncanonical function of 5-LO as transcriptional regulator in monocytic cells., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Sorafenib constitutes a suitable treatment alternative for patients with advanced hepatocellular carcinoma (HCC) in whom atezolizumab + bevacizumab therapy is contraindicated. The aim of the study was the identification of a miRNA signature in liquid biopsy related to sorafenib response., Methods: miRNAs were profiled in hepatoblastoma HepG2 cells and tested in animal models, extracellular vesicles (EVs), and plasma from HCC patients., Results: Sorafenib altered the expression of 11 miRNAs in HepG2 cells. miR-200c-3p and miR-27a-3p exerted an anti-tumoral activity by decreasing cell migration and invasion, whereas miR-122-5p, miR-148b-3p, miR-194-5p, miR-222-5p, and miR-512-3p exerted pro-tumoral properties by increasing cell proliferation, migration, or invasion, or decreasing apoptosis. Sorafenib induced a change in EVs population with an increased number of larger EVs, and promoted an accumulation of miR-27a-3p, miR-122-5p, miR-148b-3p, miR-193b-3p, miR-194-5p, miR-200c-3p, and miR-375 into exosomes. In HCC patients, circulating miR-200c-3p baseline levels were associated with increased survival, whereas high levels of miR-222-5p and miR-512-3p after 1 month of sorafenib treatment were related to poor prognosis. The RNA sequencing revealed that miR-200c-3p was related to the regulation of cell growth and death, whereas miR-222-5p and miR-512-3p were related to metabolic control., Conclusions: The study showed that Sorafenib regulates a specific miRNA signature in which miR-200c-3p, miR-222-5p, and miR-512-3p bear prognostic value and contribute to treatment response.

Bats have evolved behavioral specializations that are unique among mammals, including self-propelled flight and echolocation. However, areas of motor cortex that are critical in the generation and fine control of these unique behaviors have never been fully characterized in any bat species, despite the fact that bats compose ∼25% of extant mammalian species. Using intracortical microstimulation, we examined the organization of motor cortex in Egyptian fruit bats (Rousettus aegyptiacus), a species that has evolved a novel form of tongue-based echolocation. 1 , 2 We found that movement representations include an enlarged tongue region containing discrete subregions devoted to generating distinct tongue movement types, consistent with their behavioral specialization generating active sonar using tongue clicks. This magnification of the tongue in motor cortex is comparable to the enlargement of somatosensory representations in species with sensory specializations. 3-5 We also found a novel degree of coactivation between the forelimbs and hindlimbs, both of which are involved in altering the shape and tension of wing membranes during flight. Together, these findings suggest that the organization of motor cortex has coevolved with peripheral morphology in bats to support the unique motor demands of flight and echolocation., Competing Interests: Declaration of interests The authors have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Conductive intracardiac communication (CIC) has been demonstrated as a promising concept for the synchronization of multi-chamber leadless cardiac pacemakers (LLPMs). To meet the 2-5 μW power budget of a LLPM, highly specialized CIC-transceivers, which make optimal use of the cardiac communication channel, need to be developed. However, a detailed investigation of the optimal communication parameters for CIC-based LLPM synchronization is missing so far. This work analyzes the intracardiac communication performance of two low-power modulation techniques, namely On-Off-Keying (OOK) and Manchester-encoded baseband transmission (BB-MAN), as a function of the transmitted bit-energy. The bit error rate (BER) of a prototype dual-chamber LLPM was determined both in simulation and in-vitro experiments on porcine hearts. A BER of 1e -4 was achieved with a median bit-energy in the range of 3-16 pJ (interquartile range: 4-15 pJ) for data rates from 75-500 kbps and a receiver input noise density of 7 nV/ √{Hz}. Both modulation schemes showed comparable performance, with BB-MAN having a slight bit-energy advantage (1-2 dB at 150-500 kbps) under equalized transceiver characteristics. This study demonstrates that reliable CIC-based LLPM synchronization is feasible at transmitted power levels 10 nW under realistic channel conditions and receiver noise performance. Therefore, modulation techniques such, as BB-MAN or OOK, are preferable over recently proposed alternatives, such as pulse position modulation or conductive impulse signaling, since they can be realized with fewer hardware resources and smaller bandwidth requirements. Ultimately, a baseband communication approach might be favored over OOK, due to the more efficient cardiac signal transmission and reduced transceiver complexity.

Previous studies towards reduced oxygen availability have mostly focused on changes in total mRNA expression, neglecting underlying transcriptional and post-transcriptional events. Therefore, we generated a comprehensive overview of hypoxia-induced changes in total mRNA expression, global de novo transcription, and mRNA stability in monocytic THP-1 cells. Since hypoxic episodes often persist for prolonged periods, we further compared the adaptation to acute and chronic hypoxia. While total mRNA changes correlated well with enhanced transcription during short-term hypoxia, mRNA destabilization gained importance under chronic conditions. Reduced mRNA stability not only added to a compensatory attenuation of immune responses, but also, most notably, to the reduction in nuclear-encoded mRNAs associated with various mitochondrial functions. These changes may prevent the futile production of new mitochondria under conditions where mitochondria cannot exert their full metabolic function and are indeed actively removed by mitophagy. The post-transcriptional mode of regulation might further allow for the rapid recovery of mitochondrial capacities upon reoxygenation. Our results provide a comprehensive resource of functional mRNA expression dynamics and underlying transcriptional and post-transcriptional regulatory principles during the adaptation to hypoxia. Furthermore, we uncover that RNA stability regulation controls mitochondrial functions in the context of hypoxia.

A new hetero-bimetallic polyoxometalate (POM) nano-ring was synthesized in a one-pot procedure. The structure consists of tetrameric units containing four bismuth-substituted monolacunary Keggin anions including distorted [BiO 8 ] cubes. The nano-ring is formed via self-assembly from metal precursors in aqueous acidic medium. The compound (NH 4 ) 16 [(BiPMo 11 O 39 ) 4 ] ⋅ 22 H 2 O; (P 4 Bi 4 Mo 44 ) was characterized by single-crystal X-ray diffraction, extended X-ray absorption fine structure spectroscopy (EXAFS), Raman spectroscopy, matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF), and thermogravimetry/differential scanning calorimetry mass spectrometry (TG-DSC-MS). The formation of the nano-ring in solution was studied by time-resolved in situ small- and wide-angle X-ray scattering (SAXS/WAXS) and in situ EXAFS measurements at the Mo-K and the Bi-L 3 edge indicating a two-step process consisting of condensation of Mo-anions and formation of Bi-Mo-units followed by a rapid self-assembly to yield the final tetrameric ring structure., (© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Local antibiotic therapy is increasingly being recognised for its role in preventing and treating orthopaedic device-related infection (ODRI). A bioresorbable, injectable gentamicin-loaded hydrogel has been developed to deliver local antibiotics at the time of surgery with potential for both prevention and treatment of ODRI. In a prophylaxis model, the antibiotic hydrogel was compared with systemic perioperative antibiotic prophylaxis alone in twelve sheep (six per group) at the time of intramedullary (IM) nail insertion to the tibia, which was inoculated with methicillin-sensitive Staphylococcus aureus (MSSA). In a treatment model of single-stage revision surgery, adjunctive antibiotic-loaded hydrogel was compared with systemic antibiotics alone in a single stage revision of MSSA infection associated with a tibia intramedullary nail in eleven sheep (five/six per group). The primary endpoint was quantitative microbiological results of soft tissue, bone and sonicate fluid from explanted hardware at the time of euthanasia. At euthanasia, the control sheep that received no local antibiotics in the prophylaxis model were all culture-positive (median 1x10 8 , range 7x10 6 -3x10 8 colony forming units, CFU) while only two of six sheep receiving local gentamicin had any culture positive biopsies (median 1x10 1 , range 0 - 1x10 5 CFU). For the treatment model, sheep receiving only systemic antibiotics were all culture-positive (median 8x10 5 , range 2x10 3 - 9x10 6 CFU) while only two of six sheep treated with gentamicin-loaded hydrogel had any culture positive biopsies (median 3x10 2 , range 0 - 7x10 4 CFU). Local gentamicin concentrations measured in extracellular fluid in the tibial canal show a burst release of gentamicin from the hydrogel. Serum gentamicin concentrations peaked in both models at one day post application and were below detection limit thereafter. This study has demonstrated the effective use of a locally delivered antibiotic hydrogel for both the prevention and treatment of ODRI that is superior to that of systemic antibiotics alone. Future studies will endeavour to translate from preclinical to clinical research trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boot, Foster, Guillaume, Eglin, Schmid, D’Este, Zeiter, Richards and Moriarty.)

An altered lipidome in tumors may affect not only tumor cells themselves but also their microenvironment. In this study, a lipidomics screen reveals increased amounts of phosphatidylserine (PS), particularly ether-PS (ePS), in murine mammary tumors compared with normal tissue. PS was produced by phosphatidylserine synthase 1 (PTDSS1), and depletion of Ptdss1 from tumor cells in mice reduced ePS levels accompanied by stunted tumor growth and decreased tumor-associated macrophage (TAM) abundance. Ptdss1-deficient tumor cells exposed less PS during apoptosis, which was recognized by the PS receptor MERTK. Mammary tumors in macrophage-specific Mertk-/- mice showed similarly suppressed growth and reduced TAM infiltration. Transcriptomic profiles of TAMs from Ptdss1-knockdown tumors and Mertk-/- TAMs revealed that macrophage proliferation was reduced when the Ptdss1/Mertk pathway was targeted. Moreover, PTDSS1 expression correlated positively with TAM abundance but negatively with breast carcinoma patient survival. PTDSS1 thus may be a target to modify tumor-promoting inflammation., Significance: This study shows that inhibiting the production of ether-phosphatidylserine by targeting phosphatidylserine synthase PTDSS1 limits tumor-associated macrophage expansion and breast tumor growth., (©2022 American Association for Cancer Research.)

Medication organization devices (MODs) are widely used among home care nursing services. However, current practices such as the responsibility for filling MODs, different MOD types used and requirements of home care nursing services are largely unknown. The study aimed at analyzing home care nursing services' current practices regarding MOD use, investigating their requirements and determining whether different practices met these requirements. A survey was administered online to German home care nursing services in February 2021. The importance of requirements and the extent of satisfaction were measured using a five-point scale. Attitudes towards disposable, pharmacy-filled MODs were recorded as free text. In total, 690 nursing services responded (67.5% privately owned and 34.5% based in large cities), 92.2% filled MODs themselves and used predominantly reusable, rigid MODs. Pharmacies filling MODs used primarily disposable MODs. Satisfaction with current practices was generally high. Respondents filling MODs themselves were more satisfied with nurses' medication knowledge, but less satisfied with cost effectiveness than those who had pharmacies fill MODs. Of all respondents filling MODs themselves who expressed an opinion on disposable, pharmacy-filled MODs, 50.9% were skeptical, primarily due to fear of losing flexibility. However, no difference in satisfaction with flexibility was found between respondents filling MODs themselves and those using pharmacy-filled MODs. In conclusion, employment of MODs in the professional care setting is a complex task with nursing services as key constituents. There is potential for improvement in the inter-professional collaboration between pharmacies and home care nursing services on the use of MODs. Measures for improvement have to address home care nursing services' requirements with respect to flexibility and medication knowledge.

We present data collected for the research article "Advances in Spiral fMRI: A High-resolution Study with Single-shot Acquisition" (Kasper et al. 2022). All data was acquired on a 7T ultra-high field MR system (Philips Achieva), equipped with a concurrent magnetic field monitoring setup based on 16 NMR probes. For task-based fMRI, a visual quarterfield stimulation paradigm was employed, alongside physiological monitoring via peripheral recordings. This data collection contains different datasets pertaining to different purposes: (1) Measured magnetic field dynamics (k 0 , spiral k-space trajectories, 2nd order spherical harmonics, concomitant fields) during ultra-high field fMRI sessions from six subjects, as well as concurrent temperature curves of the gradient coil, to explore MR system and subject-induced variability of field fluctuations and assess the impact of potential correction methods. (2) MR Raw Data, i.e., coil and concurrent encoding magnetic field (trajectory) data, of a single subject, as well as nominal spiral gradient waveforms, precomputed B 0 and coil sensitivity maps, to enable testing of alternative image reconstruction approaches for spiral fMRI data. (3) Reconstructed image time series of the same subject alongside behavioral and physiological logfiles, to reproduce the fMRI preprocessing and analysis, as well as figures presented in the research article related to this article, using the published analysis code repository. All data is provided in standardized formats for the respective research area. In particular, ISMRMRD (HDF5) is used to store raw coil data and spiral trajectories, as well as measured field dynamics. Likewise, the NIfTI format is used for all imaging data (anatomical MRI and spiral fMRI, B 0 and coil sensitivity maps)., Competing Interests: At the time of submission, Christoph Barmet and Bertram J. Wilm are employees of Skope Magnetic Resonance Technologies. Klaas P. Pruessmann holds a research agreement with and receives research support from Philips. He is a shareholder of Gyrotools LLC. Rest authors have no conflicts of interest to declare., (© 2022 The Author(s). Published by Elsevier Inc.)

Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN.

Purpose: To investigate driving ability (brake reaction time, BRT) after right-sided hernia repair. It was assumed that postoperatively BRT would be impaired as compared to the preoperative reference and healthy controls., Methods: BRT was prospectively collected from 30 patients undergoing hernia repair [Lichtenstein or total extraperitoneal endoscopic procedure (TEP)]. BRT was measured with a driving simulator preoperatively and on postoperative days 2 and 14. After receiving a visual stimulus, the patients had to apply the brake pedal with 160 N. The average of ten runs was used as the patient's BRT value., Results: Thirty patients completed all measurements. In the Lichtenstein group, BRT was significantly impaired as compared to the patient's preoperative values (p = 0.021). Two weeks after surgery BRT had returned to the preoperative level (p = 0.859). BRT in the Lichtenstein group was also significantly impaired 2 days postoperatively as compared to the BRT of 60 healthy controls (p = 0.001). In the TEP group, no impaired BRT was detected., Conclusions: Based on our finding of significantly impaired BRT in patients following right-sided Lichtenstein hernia repair, it seems wise to recommend that such patients refrain from driving for 2 weeks after surgery. No such impairment was found in patients following TEP surgery. Consequently, it is deemed safe for them to resume driving 2 days after the procedure., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Compression sonography has been introduced for non-invasive measurement of compartment compressibility and possible diagnostic tool for acute or chronic compartment syndrome in studies using human cadavers and animal models. To date, standard values in healthy subjects are not yet defined. The aim was to define standard compartment compressibility values in healthy human subjects and to assess the reliability of this measurement method., Methods: In 60 healthy volunteers, using ultrasound, the diameter of the tibial anterior compartment was measured while applying no pressure, 10mbar and 80mbar of external pressure. A pressure manometer on the ultrasound head was used to monitor the externally applied pressure. Compartment compressibility ratio (R 0-80 , respectively R 10-80 ) was calculated as following: The delta of the compartment diameter with high and low external pressure, divided through the diameter with low external pressure. In 10 volunteers, two examinators conducted each two measurements to assess the reliability., Results: Mean compartment compressibility ratio R 10-80 was 15.9% ±3.6 (range: 7.2 - 22.2). Mean compartment compressibility ratio R 0-80 was 18.2% ±5.0 (3.0 - 32.1). There was no significant correlation with lower leg circumference, height, weight, BMI, gender, hours of sport per week and type of sport (e.g. weightlifting/ cardio). For R 10-80 , intraobserver ICC 2.1 was 0.89 for an experienced observer and 0.79 for a non-experienced observer. Interobserver ICC 2.1 was 0.78. For R 0-80 , intraobserver ICC 2.1 was 0.71 for the experienced and 0.56 for the unexperienced observer. Interobserver ICC 2.1 was 0.59., Discussion: In healthy volunteers between 18 and 50 years of age, mean compartment compressibility ratio R 10-80 was 15.9% ±3.6, independent of demographic factors and sport activity. Application of 10mbar instead of 0mbar increased image quality. Subsequently, R 10-80 showed lower standard deviation and both higher intraobserver and interobserver reliability than R 0-80 . Using R 10-80 , this measurement method is reliable with very high intra- and interobserver correlation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Spiral fMRI has been put forward as a viable alternative to rectilinear echo-planar imaging, in particular due to its enhanced average k-space speed and thus high acquisition efficiency. This renders spirals attractive for contemporary fMRI applications that require high spatiotemporal resolution, such as laminar or columnar fMRI. However, in practice, spiral fMRI is typically hampered by its reduced robustness and ensuing blurring artifacts, which arise from imperfections in both static and dynamic magnetic fields. Recently, these limitations have been overcome by the concerted application of an expanded signal model that accounts for such field imperfections, and its inversion by iterative image reconstruction. In the challenging ultra-high field environment of 7 Tesla, where field inhomogeneity effects are aggravated, both multi-shot and single-shot 2D spiral imaging at sub-millimeter resolution was demonstrated with high depiction quality and anatomical congruency. In this work, we further these advances towards a time series application of spiral readouts, namely, single-shot spiral BOLD fMRI at 0.8 mm in-plane resolution. We demonstrate that high-resolution spiral fMRI at 7 T is not only feasible, but delivers both excellent image quality, BOLD sensitivity, and spatial specificity of the activation maps, with little artifactual blurring. Furthermore, we show the versatility of the approach with a combined in/out spiral readout at a more typical resolution (1.5 mm), where the high acquisition efficiency allows to acquire two images per shot for improved sensitivity by echo combination., Competing Interests: Declaration of Competing Interest At the time of submission, Christoph Barmet and Bertram J. Wilm are employees of Skope Magnetic Resonance Technologies. Klaas P. Pruessmann holds a research agreement with and receives research support from Philips. He is a shareholder of Gyrotools LLC., (Copyright © 2021. Published by Elsevier Inc.)

Background: The mobile subtalar joint (STJ) may compensate for supra- and inframalleolar deformities and counteract the effect of realigning calcaneal or distal tibial osteotomies. The purpose of this study was to evaluate the compensatory effect of the mobile STJ after supramalleolar osteotomy (SMOT) and calcaneus osteotomy (COT) and whether the extent of the compensation correlates with STJ shape and orientation., Methods: In 10 human lower leg cadavers without evidence of deformity or prior trauma 700 Newton load were applied as a simulated standing pose. The center of force (COF) migration, maximum pressure (Pmax), and the area loaded were measured with high-resolution sensors in the ankle before and after 10-mm varus/valgus sliding COT and 10-degree varus / valgus SMOT. A computed tomographic evaluation of subtalar anatomy was conducted to correlate posterior facet curvature, its varus/valgus orientation in the coronal plane, and the effect on COF, Pmax, and area loaded., Results: The COF migration was significant for both varus and valgus SMOTs (varus SMOT: 1.78 mm, P = .0029; valgus SMOT: 1.85 mm, P = .0018) but not for COT (varus COT: 0.45 mm, P = .85; valgus COT: 1.15 mm, P = .11). Pmax and area loaded changed but not significantly. The radius of the posterior STJ surface showed a moderate correlation (varus SMOT: r = 0.61, P = .063; valgus SMOT: r = 0.28, P = .43, varus COT: r = -0.61, P = .063; valgus COT: r = 0.13, P = .38) and the axis a weak inverse correlation (varus SMOT: r = -0.51, P = .013; valgus SMOT: r = 0.58, P = .079; varus COT: r = -0.51, P = .14; valgus COT: r = 0.38, P = .28) with the COF migration after the osteotomies., Conclusion: The compensatory capacity of a mobile STJ is relatively small but appears to limit the effect of COT more than SMOT. The COT is less effective in influencing ankle joint pressure for realignment purposes than SMOT in mobile STJ and clinically more consistent in stiff STJ. Correlations are moderate to weak, whereas the curvature more than orientation of posterior facet inversely correlates with osteotomy's effects., Level of Evidence: Level IV, biomechanical cadaver study.

Aims: Parkinson's disease (PD) is frequently associated with a prodromal sensory neuropathy manifesting with sensory loss and chronic pain. We have recently shown that PD-associated sensory neuropathy in patients is associated with high levels of glucosylceramides. Here, we assessed the underlying pathology and mechanisms in Pink1 -/- SNCA A53T double mutant mice., Methods: We studied nociceptive and olfactory behaviour and the neuropathology of dorsal root ganglia (DRGs), including ultrastructure, mitochondrial respiration, transcriptomes, outgrowth and calcium currents of primary neurons, and tissue ceramides and sphingolipids before the onset of a PD-like disease that spontaneously develops in Pink1 -/- SNCA A53T double mutant mice beyond 15 months of age., Results: Similar to PD patients, Pink1 -/- SNCA A53T mice developed a progressive prodromal sensory neuropathy with a loss of thermal sensitivity starting as early as 4 months of age. In analogy to human plasma, lipid analyses revealed an accumulation of glucosylceramides (GlcCer) in the DRGs and sciatic nerves, which was associated with pathological mitochondria, impairment of mitochondrial respiration, and deregulation of transient receptor potential channels (TRPV and TRPA) at mRNA, protein and functional levels in DRGs. Direct exposure of DRG neurons to GlcCer caused transient hyperexcitability, followed by a premature decline of the viability of sensory neurons cultures upon repeated GlcCer application., Conclusions: The results suggest that pathological GlcCer contribute to prodromal sensory disease in PD mice via mitochondrial damage and calcium channel hyperexcitability. GlcCer-associated sensory neuron pathology might be amenable to GlcCer lowering therapeutic strategies., (© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell- and T cell-dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1-refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells. SIGNIFICANCE: Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy. This article is highlighted in the In This Issue feature, p. 2659 ., (©2021 The Authors; Published by the American Association for Cancer Research.)