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Affect is known to be predictive of and enhanced by higher physical activity (PA) levels in the general population. This secondary analysis aimed to increase the understanding of the bi-directional relationship between PA and core affect (i.e. valence, energetic arousal, and calmness) among adults with higher body weight. Affect and PA were assessed in naturalistic settings via ecological momentary assessment using a mixed sampling scheme from 157 participants (body mass index: 32.99 ± 3.78 kg/m 2 ). Multilevel models revealed that being more physically active in the 15 minutes prior to the assessment predicted an increase in energetic arousal and a decrease in calmness. Subsequently, feeling more energetic and agitated was associated with increased PA within the following 15 minutes. Valence (i.e. pleasure-displeasure) was not associated with PA nor predictive of subsequent PA. Digital PA interventions may target the enhancement of feelings of energy and present psychoeducation about these distinct psychological benefits., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

C-reactive protein (CRP) apheresis has been introduced in ST-elevation myocardial infarction and cardiogenic shock. Here, we describe a first-in-man application in non-ST-elevation acute coronary syndrome (NSTE-ACS). Seven NSTE-ACS patients with high CRP levels (range 14.2-154 mg/L) were treated with CRP apheresis. Treatment was well-tolerated. Patients were discharged in good clinical condition., Competing Interests: AS was founder and shareholder of Pentracor GmbH. SM was employee of Pentracor GmbH. The remaining 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 authors 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., (© 2024 Torzewski, Mattecka, Esposito, Heigl, Fiedler and Sheriff.)

Previous studies indicate an implication of the terminal complement complex (TCC) in disc degeneration (DD). To investigate the functional role of TCC in trauma-induced DD in vivo, the model of endplate (EP) drilling was first applied in rabbits using a C6-deficient rabbit strain in which no TCC formation was possible. In parallel the model of needle puncture was investigated. Using a minimally invasive surgical intervention, lumbar rabbit intervertebral discs (IVDs) were treated with EP drilling or needle puncture. Degenerative effects of both surgical interventions were assessed by Pfirrmann grading and T2 quantification of the IVDs based on high-resolution MRI (11.7 T), as well as radiographic determination of disc height index. Pfirrmann grading indicated significant degenerative effects after EP drilling. Contrary to our assumption, no evidence was found that the absence of TCC formation in C6-deficient rabbits reduces the development of DD compared to C6-sufficient animals. EP drilling was proven to be suitable for application in rabbits. However, results of the present study do not provide clear evidence of a central functional role of TCC within DD and suggest that TCC deposition in DD patients may be primarily considered as a marker of complement activation during DD progression.

Various nonribosomal peptide synthetases (NRPSs) create structural and functional diversity by incorporating α-hydroxy acids into peptide backbones. Trigonic acid, an unusual cyclopropanol-substituted hydroxy acid, is the source of the molecular warhead of malleicyprol, a critical virulence factor of human and animal pathogens of the Burkholderia pseudomallei (BP) group. The process of selecting and loading this building block remained enigmatic as the NRPS module designated for this task is incomplete. Using a combination of bioinformatics, mutational analyses, targeted metabolomics, and in vitro biochemical assays, we show that two trans-acting enzymes are required to load this central building block onto the modular assembly line. An adenylation-thiolation didomain enzyme (BurJ) activates trigonic acid, followed by the translocation of the enzyme-bound α-hydroxy acid thioester by an FkbH-like protein with a mutated phosphatase domain (BurH). This specialized gateway is the first reported direct loading of an α-hydroxy acid onto a bona fide NRPS module in bacteria and expands the synthetic biology toolbox for the site-specific incorporation of non-canonical building blocks. Moreover, insight into the biochemical basis of virulence factor biosynthesis can provide a foundation for developing enzyme inhibitors as anti-virulence therapeutics against BP pathogen infections., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2is) in cardiovascular diseases have been extensively reported leading to the inclusion of these drugs in the treatment guidelines for heart failure. However, molecular actions especially on non-myocyte cells remain uncertain. We observed dose-dependent inhibitory effects of two SGLT2is, dapagliflozin (DAPA) and empagliflozin (EMPA), on inflammatory signaling in human umbilical vein endothelial cells. Proteomic analyses and subsequent enrichment analyses discovered profound effects of these SGLT2is on proteins involved in mitochondrial respiration and actin cytoskeleton. Validation in functional oxygen consumption measurements as well as tube formation and migration assays revealed strong impacts of DAPA. Considering that most influenced parameters played central roles in endothelial to mesenchymal transition (EndMT), we performed in vitro EndMT assays and identified substantial reduction of mesenchymal and fibrosis marker expression as well as changes in cellular morphology upon treatment with SGLT2is. In line, human cardiac fibroblasts exposed to DAPA showed less proliferation, reduced ATP production, and decelerated migration capacity while less extensive impacts were observed upon EMPA. Mechanistically, sodium proton exchanger 1 (NHE1) as well as sodium-myoinositol cotransporter (SMIT) and sodium-multivitamin cotransporter (SMVT) could be identified as relevant targets of SGLT2is in non-myocyte cardiovascular cells as validated by individual siRNA-knockdown experiments. In summary, we found comprehensive beneficial effects of SGLT2is on human endothelial cells and cardiac fibroblasts. The results of this study therefore support a distinct effect of selected SGLT2i on non-myocyte cardiovascular cells and grant further insights into potential molecular mode of action of these drugs., (© 2024. The Author(s).)

Background and Objectives: Endovascular treatment of cerebral aneurysms has tremendously advanced over the past decades. Nevertheless, aneurysm residual and recurrence remain challenges after embolization. The objective of this study was to elucidate the portion of embolized aneurysms requiring open surgery and evaluate whether newer endovascular treatments have changed the need for open surgery after failed embolization., Methods: All 15 cerebrovascular centers in Austria and the Czech Republic provided overall aneurysm treatment frequency data and retrospectively reviewed consecutive cerebral aneurysms treated with open surgical treatment after failure of embolization from 2000 to 2022. All endovascular modalities were included., Results: On average, 1362 aneurysms were treated annually in the 2 countries. The incidence increased from 0.006% in 2005 to 0.008% in 2020 in the overall population. Open surgery after failed endovascular intervention was necessary in 128 aneurysms (0.8%), a proportion that remained constant over time. Subarachnoid hemorrhage was the initial presentation in 70.3% of aneurysms. The most common location was the anterior communicating artery region (40.6%), followed by the middle cerebral artery (25.0%). The median diameter was 6 mm (2-32). Initial endovascular treatment included coiling (107 aneurysms), balloon-assist (10), stent-assist (4), intrasaccular device (3), flow diversion (2), and others (2). Complete occlusion after initial embolization was recorded in 40.6%. Seventy-one percent of aneurysms were operated within 3 years after embolization. In 7%, the indication for surgery was (re-)rupture and, in 88.3%, reperfusion. Device removal was performed in 16.4%. Symptomatic intraoperative and postoperative complications occurred in 10.2%. Complete aneurysm occlusion after open surgery was achieved in 94%., Conclusion: Open surgery remains a rare indication for cerebral aneurysms after failed endovascular embolization even in the age of novel endovascular technology, such as flow diverters and intrasaccular devices. Regardless, it is mostly performed for ruptured aneurysms initially treated with primary coiling that are in the anterior circulation., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Carbon quantum dots have become attractive in various applications, such as drug delivery, biological sensing, photocatalysis, and solar cells. Among these, pH sensing via luminescence lifetime measurements of surface-functionalized carbon dots is one application currently investigated for their long lifetime and autonomous operation. In this article, we explore the theoretical connection between excitation lifetimes and the pH value of the surrounding liquid via the protonation and deprotonation of functional groups. Example calculations applied to m-phenylenediamine, phloroglucinol, and tethered disperse blue 1 are shown by applying a separation approach treating the electronic wave function of functional groups separately from the internal electronic structure of the (large) carbon dot. The bulk of the carbon dot is treated as an environment characterized by its optical spectrum that shifts the transition rates of the functional group. A simple relationship between pH, pKa, and mixed fluorescence lifetime is derived from the transition rates of the protonated and deprotonated states. pH sensitivity improves when the difference in the transition rates is greatest between protonated and deprotonated species, with the greatest sensitivity found where the pKa is close to the pH region of interest. The introduced model can directly be extended to consider multicomponent liquids and multiple protonation states., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Oats (Avena sativa L.) provide unique nutritional benefits and contribute to sustainable agricultural systems. Breeding high-value oat varieties that meet milling industry standards is crucial for satisfying the demand for oat-based food products. Test weight, thins, and groat percentage are primary traits that define oat milling quality and the final price of food-grade oats. Conventional selection for milling quality is costly and burdensome. Multi-trait genomic selection (MTGS) combines information from genome-wide markers and secondary traits genetically correlated with primary traits to predict breeding values of primary traits on candidate breeding lines. MTGS can improve prediction accuracy and significantly accelerate the rate of genetic gain. In this study, we evaluated different MTGS models that used morphometric grain traits to improve prediction accuracy for primary grain quality traits within the constraints of a breeding program. We evaluated 558 breeding lines from the University of Illinois Oat Breeding Program across 2 years for primary milling traits, test weight, thins, and groat percentage, and secondary grain morphometric traits derived from kernel and groat images. Kernel morphometric traits were genetically correlated with test weight and thins percentage but were uncorrelated with groat percentage. For test weight and thins percentage, the MTGS model that included the kernel morphometric traits in both training and candidate sets outperformed single-trait models by 52% and 59%, respectively. In contrast, MTGS models for groat percentage were not significantly better than the single-trait model. We found that incorporating kernel morphometric traits can improve the genomic selection for test weight and thins percentage., (© 2024 The Authors. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Background: Numerous smartphone apps are targeting physical activity (PA) and healthy eating (HE), but empirical evidence on their effectiveness for the initialization and maintenance of behavior change, especially in children and adolescents, is still limited. Social settings influence individual behavior; therefore, core settings such as the family need to be considered when designing mobile health (mHealth) apps., Objective: The purpose of this study was to evaluate the effectiveness of a theory- and evidence-based mHealth intervention (called SMARTFAMILY [SF]) targeting PA and HE in a collective family-based setting., Methods: A smartphone app based on behavior change theories and techniques was developed, implemented, and evaluated with a cluster randomized controlled trial in a collective family setting. Baseline (t 0 ) and postintervention (t 1 ) measurements included PA (self-reported and accelerometry) and HE measurements (self-reported fruit and vegetable intake) as primary outcomes. Secondary outcomes (self-reported) were intrinsic motivation, behavior-specific self-efficacy, and the family health climate. Between t 0 and t 1 , families of the intervention group (IG) used the SF app individually and collaboratively for 3 consecutive weeks, whereas families in the control group (CG) received no treatment. Four weeks following t 1 , a follow-up assessment (t 2 ) was completed by participants, consisting of all questionnaire items to assess the stability of the intervention effects. Multilevel analyses were implemented in R (R Foundation for Statistical Computing) to acknowledge the hierarchical structure of persons (level 1) clustered in families (level 2)., Results: Overall, 48 families (CG: n=22, 46%, with 68 participants and IG: n=26, 54%, with 88 participants) were recruited for the study. Two families (CG: n=1, 2%, with 4 participants and IG: n=1, 2%, with 4 participants) chose to drop out of the study owing to personal reasons before t 0 . Overall, no evidence for meaningful and statistically significant increases in PA and HE levels of the intervention were observed in our physically active study participants (all P>.30)., Conclusions: Despite incorporating behavior change techniques rooted in family life and psychological theories, the SF intervention did not yield significant increases in PA and HE levels among the participants. The results of the study were mainly limited by the physically active participants and the large age range of children and adolescents. Enhancing intervention effectiveness may involve incorporating health literacy, just-in-time adaptive interventions, and more advanced features in future app development. Further research is needed to better understand intervention engagement and tailor mHealth interventions to individuals for enhanced effectiveness in primary prevention efforts., Trial Registration: German Clinical Trials Register DRKS00010415; https://drks.de/search/en/trial/DRKS00010415., International Registered Report Identifier (irrid): RR2-10.2196/20534., (©Kathrin Wunsch, Janis Fiedler, Sebastian Hubenschmid, Harald Reiterer, Britta Renner, Alexander Woll. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 26.04.2024.)

Cardiomyopathies encompass a spectrum of heart disorders with diverse causes and presentations. Fibrosis stands out as a shared hallmark among various cardiomyopathies, reflecting a common thread in their pathogenesis. This prevalent fibrotic response is intricately linked to the consequences of dysregulated extracellular matrix (ECM) remodeling, emphasizing its significance in the development and progression the disease. This review explores the ECM involvement in various cardiomyopathies and its impact on myocardial stiffness and fibrosis. Additionally, we discuss the potential of ECM fragments as early diagnosis, prognosis, and risk stratification. Biomarkers deriving from turnover of collagens and other ECM proteins hold promise in clinical applications. We outline current clinical management, future directions, and the potential for personalized ECM-targeted therapies with specific focus on microRNAs. In summary, this review examines the role of the fibrosis in cardiomyopathies, highlighting the potential of ECM-derived biomarkers in improving disease management with implications for precision medicine., Competing Interests: Declaration of Competing Interest EA was funded by the Danish Research Foundation and has a shared affiliation with the University of Copenhagen and Nordic Bioscience, Herlev, Denmark, as a PhD fellow. MJ, MO, and JF were funded by the Bundesamt für Strahlenschutz, Z4/AG-R-08313/3621S32210 and supported by Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD). MJ kindly acknowledges support by Hannover Biomedical Research School (HBRS). FG and MK are full-time employees and shareholders at Nordic Bioscience, Herlev, Denmark. SDS participated in PRACTIS, a Clinician Scientist Program supported and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 3696/3 and Hannover Medical School. SDS was supported by internal project funding (HiLF) of the Hannover Medical School (MHH) and was funded by the German Cardiac Society Research Stipend (Deutsche Gesellschaft für Kardiologie, DGK, no. DGK06/2023). TT is founder and shareholder of Cardior Pharmaceuticals. TT has filed and licensed multiple patents about diagnostic and therapeutic use of noncoding RNAs. We acknowledge funding by the ERC Advanced Grant REVERSE (to TT)., (Copyright © 2024. Published by Elsevier B.V.)

Optical whispering gallery mode biosensors are able to detect single molecules through effects of their polarizability. We address the factors that affect the polarizability of amino acids, which are the building blocks of life, via electronic structure theory. Amino acids are detected in aqueous environments, where their polarizability is different compared to the gasphase due to solvent effects. Solvent effects include structural changes, protonation and the local field enhancement through the solvent (water). We analyse the impact of these effects and find that all contribute to an increased effective polarizability in the solvent. We also address the excess polarizability relative to the displaced water cavity and develop a hybrid quantum-classical model that is in good agreement with self-consistent calculations. We apply our model to calculate the excess polarizability of 20 proteinogenic amino acids and determine the minimum resolution required to distinguish the different molecules and their ionised conformers based on their polarizability.

Background : The effectiveness of knee orthoses as part of conservative treatment for patients with medial knee osteoarthritis has not been fully explored. The purpose of this study was to evaluate the effects of a novel semi-rigid knee orthosis on pain, physical activity, and functional capacity. Methods : Pain levels, physical activity, and functional capacity were assessed in 24 participants experiencing symptomatic medial knee osteoarthritis one week before (i.e., pretest) initiating a six-week orthosis intervention and again during the final week of the intervention (i.e., post-test). Results : Night pain, pain during walking, pain during stair climbing, and pain during sitting consistently decreased by 41% to 48% while wearing the knee orthosis. Device-based measured physical activity showed a 20.2-min increase in vigorous physical activity during the post-test, while light and moderate physical activity did not show significant changes. After six weeks of orthosis application, there was a 5% increased distance for the six-minute walk test, and participants reported fewer limitations both in everyday and athletic activities, as well as an enhanced quality of life. Conclusions : These findings highlight the potential effectiveness of a semi-rigid knee orthosis to enhancing functional capacity and quality of life. More extensive and longer clinical trials are needed to improve confidence in these findings and understand their impact on disease progression.

Modular polyketide synthases (PKSs) are giant assembly lines that produce an impressive range of biologically active compounds. However, our understanding of the structural dynamics of these megasynthases, specifically the delivery of acyl carrier protein (ACP)-bound building blocks to the catalytic site of the ketosynthase (KS) domain, remains severely limited. Using a multipronged structural approach, we report details of the inter-domain interactions after C-C bond formation in a chain-branching module of the rhizoxin PKS. Mechanism-based crosslinking of an engineered module was achieved using a synthetic substrate surrogate that serves as a Michael acceptor. The crosslinked protein allowed us to identify an asymmetric state of the dimeric protein complex upon C-C bond formation by cryo-electron microscopy (cryo-EM). The possible existence of two ACP binding sites, one of them a potential "parking position" for substrate loading, was also indicated by AlphaFold2 predictions. NMR spectroscopy showed that a transient complex is formed in solution, independent of the linker domains, and photochemical crosslinking/mass spectrometry of the standalone domains allowed us to pinpoint the interdomain interaction sites. The structural insights into a branching PKS module arrested after C-C bond formation allows a better understanding of domain dynamics and provides valuable information for the rational design of modular assembly lines., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Introduction: Emotions consist of different components such as the emotional experience, physiological reactions, action tendencies, or emotional expressions. Assessing the relation of these components may help to better understand the role of emotions in sport competitions. Based on the component process model of emotions, the goal of the present study was to assess the relation between emotional experiences and emotional expressions., Methods: Twenty tennis players (7 female) with an average age of 23.10 (SD = 4.88) were taped during competitive tennis matches. Thereafter, in individual meetings, after having watched themselves on the footage at pre-selected points, the players had to indicate whether, immediately after the end of a rally, they had a positive or a negative emotional experience and, in case they had one, rate its intensity. Moreover, based on their observable behavior, the players were also asked to state whether they could recognize a positive or a negative emotional expression and, in case they recognized one, rate its intensity. The occurrence of emotional expressions was additionally rated by two external coders. Using multilevel models, separate analyses were conducted for positive emotions after won points and negative emotions after lost points., Results and Discussion: For both positive and negative emotions, the results indicated a positive correlation between emotional experiences and emotional expressions. Moreover, the intensity of emotional experiences could predict the occurrence of an emotional expression rated by both the players or external coders. These insights into the relation between emotional experiences and emotional expressions may help players to more effectively regulate their emotions., 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 © 2024 Fritsch, Fiedler, Hatzigeorgiadis and Jekauc.)

Objective: This study aims to evaluate the usage and implementation of video remote (VR) interpreting and telephone remote (TR) interpreting in primary healthcare settings., Design: This publication forms part of a larger three-pronged study in which we compared both remote interpreting modalities to each other and to a control group. This paper conveys the findings of the qualitative evaluation of the implementation and usage of both remote interpreting solutions. The quantitative evaluation of the 6-month intervention period (September 2018-February 2019) has been reported previously. After this period, we conducted focus groups with the healthcare professionals involved. The focus groups were recorded, transcribed verbatim and analysed using the structured qualitative content analysis., Setting: We provided either VR or TR tools to 10 different primary healthcare practices (general medicine, gynaecology and paediatrics) in the city of Hamburg, Germany., Participants: Three physicians and two physician's assistants took part in the TR focus group. The VR focus group consisted of four physicians., Results: The main topics identified were the importance of communication for diagnostic and therapeutic processes, previous solutions to language barriers, as well as advantages and disadvantages of the two remote interpreting solutions. Advantages included the possibility to adequately communicate with language discordant patients and the high quality of the interpreting. Disadvantages included the habituation time required for new technology as well as time constraints., Conclusion: Our evaluation found that these solutions were highly appreciated, if not considered indispensable, for the delivery of appropriate medical care to language-discordant patients. Differences between the two modalities were named and concrete suggestions for improvement were made. Policy-makers should consider providing VR or TR as an adequate and safe interpreting service alternative when professional in-person interpreters are not available or too expensive., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to demonstrate the behavior of different complexes using IR spectroelectrochemistry (SEC), a technique that combines IR spectroscopy with electrochemistry. Four different Mn and Re catalysts for electrochemical CO 2 reduction were studied in dry acetonitrile. In the case of Mn(apbpy)(CO) 3 Br (apbpy = 4(4-aminophenyl)-2,2'-bipyridine), SEC suggested that a very slow catalytic reduction of CO 2 also occurs in acetonitrile in the absence of proton donors, but at rather negative potentials. In contrast, the corresponding Re(apbpy)(CO) 3 Br clearly demonstrated slow catalytic conversion at the first reduction potential. Switching to saturated CO 2 solutions in a mixture of acetonitrile and 5% water as a proton donor, the SEC of Mn(apbpy)(CO) 3 Br displayed a faster catalytic behavior.

Background & Aims: Body composition (BC) changes with age and is associated with morbidity and mortality. A physically active lifestyle influences BC and represents an important predictor of successful aging. To emphasize this, the World Health Organization established activity recommendations for all age groups. We describe BC during adulthood using a cross-sectional sample from a German community and investigate the associations between physical activity (PA), physical fitness (PF), and BC., Methods: Data from 329 men and women aged 35 to 86 years were analyzed. PA was measured by questionnaire and classified into sport activity and habitual activity. PF was measured through physical performance tests and BC by bioelectrical impedance analysis. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated to represent height-adjusted BC. Associations between PA, PF, and BC were analyzed using linear regression models., Results: For both sexes, strength was positively associated with FFMI (♂: ß = 0.313; ♀: ß = 0.213) and phase angle (♂: ß = 0.357; ♀: ß = 0.409). For FMI, a significant negative association with strength was found only in women (ß = -0.189). Cardiorespiratory fitness showed a negative association with FMI (ß = -0.312) and FFMI (ß = -0.201) for men, while in women a positive association was found for FFMI (ß = 0.186). For coordination, a significant association with FMI was observed only in women (ß = -0.190). Regarding PA only one significant relationship between sport activity and FMI among women (ß = -0.170) was found., Conclusions: In our sample, PF was closer related to BC than PA. Strength and cardiorespiratory fitness were the strongest predictors for BC. This supports the World Health Organization's activity recommendations to include both resistance and endurance training in the weekly sports program to maintain a healthy BC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Schilling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The conserved multiple PDZ-domain containing protein PATJ stabilizes the Crumbs-Pals1 complex to regulate apical-basal polarity and tight junction formation in epithelial cells. However, the molecular mechanism of PATJ's function in these processes is still unclear. In this study, we demonstrate that knockout of PATJ in epithelial cells results in tight junction defects as well as in a disturbed apical-basal polarity and impaired lumen formation in three-dimensional cyst assays. Mechanistically, we found PATJ to associate with and inhibit histone deacetylase 7 (HDAC7). Inhibition or downregulation of HDAC7 restores polarity and lumen formation. Gene expression analysis of PATJ-deficient cells revealed an impaired expression of genes involved in cell junction assembly and membrane organization, which is rescued by the downregulation of HDAC7. Notably, the function of PATJ regulating HDAC7-dependent cilia formation does not depend on its canonical interaction partner, Pals1, indicating a new role of PATJ, which is distinct from its function in the Crumbs complex. By contrast, polarity and lumen phenotypes observed in Pals1- and PATJ-deficient epithelial cells can be rescued by inhibition of HDAC7, suggesting that the main function of this polarity complex in this process is to modulate the transcriptional profile of epithelial cells by inhibiting HDAC7., (© 2023. The Author(s).)

Background and Aim: In-stent restenosis (ISR) belongs to an infrequent but potentially serious complication after carotid angioplasty and stenting in patients with severe carotid stenosis. Some of these patients might be contraindicated to repeat percutaneous transluminal angioplasty with or without stenting (rePTA/S). The purpose of the study is to compare the safety and effectiveness of carotid endarterectomy with stent removal (CEASR) and rePTA/S in patients with carotid ISR., Methods: Consecutive patients with carotid ISR (≥80%) were randomly allocated to the CEASR or rePTA/S group. The incidence of restenosis after intervention, stroke, transient ischaemic attack myocardial infarction and death 30 days and 1 year after intervention and restenosis 1 year after intervention between patients in CEASR and rePTA/S groups were statistically evaluated., Results: A total of 31 patients were included in the study; 14 patients (9 males; mean age 66.3±6.6 years) were allocated to CEASR and 17 patients (10 males; mean age 68.8±5.6 years) to the rePTA/S group. The implanted stent in carotid restenosis was successfully removed in all patients in the CEASR group. No clinical vascular event was recorded periproceduraly, 30 days and 1 year after intervention in both groups. Only one patient in the CEASR group had asymptomatic occlusion of the intervened carotid artery within 30 days and one patient died in the rePTA/S group within 1 year after intervention. Restenosis after intervention was significantly greater in the rePTA/S group (mean 20.9%) than in the CEASR group (mean 0%, p=0.04), but all stenoses were <50%. Incidence of 1-year restenosis that was ≥70% did not differ between the rePTA/S and CEASR groups (4 vs 1 patient; p=0.233)., Conclusion: CEASR seems to be effective and save procedures for patients with carotid ISR and might be considered as a treatment option., Trial Registration Number: NCT05390983., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease characterized by an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue inflammation and damage is not known. In lupus nephritis, we previously identified an inflammatory gene program in kidney-infiltrating T cells that is dependent on HIF-1, a transcription factor critical for the cellular and developmental response to hypoxia as well as inflammation-associated signals. In our present studies using a mouse model of lupus skin disease, we find that skin-infiltrating CD4+ and CD8+ T cells also express high levels of HIF-1. Skin-infiltrating T cells demonstrated a strong cytotoxic signature at the transcript and protein levels, and HIF-1 inhibition abrogated skin and systemic diseases in association with decreased T cell cytotoxic activity. We also demonstrate in human CLE tissue that the T cell-rich inflammatory infiltrate exhibited increased amounts of HIF-1 and a cytotoxic signature. Granzyme B-expressing T cells were concentrated at sites of skin tissue damage in CLE, suggesting relevance of this pathway to human disease.

Bacterial pathogens of the Burkholderia pseudomallei (BP) group cause life-threatening infections in both humans and animals. Critical for the virulence of these often antibiotic-resistant pathogens is the polyketide hybrid metabolite malleicyprol, which features two chains, a short cyclopropanol-substituted chain and a long hydrophobic alkyl chain. The biosynthetic origin of the latter has remained unknown. Here, we report the discovery of novel overlooked malleicyprol congeners with varied chain lengths and identify medium-sized fatty acids as polyketide synthase (PKS) starter units that constitute the hydrophobic carbon tails. Mutational and biochemical analyses show that a designated coenzyme A-independent fatty acyl-adenylate ligase (FAAL, BurM) is essential for recruiting and activating fatty acids in malleicyprol biosynthesis. In vitro reconstitution of the BurM-catalyzed PKS priming reaction and analysis of ACP-bound building blocks reveal a key role of BurM in the toxin assembly. Insights into the function and role of BurM hold promise for the development of enzyme inhibitors as novel antivirulence therapeutics to combat infections with BP pathogens.

Despite the importance of functional outcome, only a few scoring systems exist to predict neurologic outcome in meningioma surgery. Therefore, our study aims to identify preoperative risk factors and develop the receiver operating characteristics (ROC) models estimating the risk of a new postoperative neurologic deficit and a decrease in Karnofsky performance status (KPS). A multicentric study was conducted in a cohort of 552 consecutive patients with skull base meningiomas who underwent surgical resection from 2014 to 2019. Data were gathered from clinical, surgical, and pathology records as well as radiological diagnostics. The preoperative predictive factors of functional outcome (neurologic deficit, decrease in KPS) were analyzed in univariate and multivariate stepwise selection analyses. Permanent neurologic deficits were present in 73 (13.2%) patients and a postoperative decrease in KPS in 84 (15.2%). Surgery-related mortality was 1.3%. A ROC model was developed to estimate the probability of a new neurologic deficit (area 0.74; SE 0.0284; 95% Wald confidence limits (0.69; 0.80)) based on meningioma location and diameter. Consequently, a ROC model was developed to predict the probability of a postoperative decrease in KPS (area 0.80; SE 0.0289; 95% Wald confidence limits (0.74; 0.85)) based on the patient's age, meningioma location, diameter, presence of hyperostosis, and dural tail. To ensure an evidence-based therapeutic approach, treatment should be founded on known risk factors, scoring systems, and predictive models. We propose ROC models predicting the functional outcome of skull base meningioma resection based on the age of the patient, meningioma size, and location and the presence of hyperostosis and dural tail., (© 2023. The Author(s).)

Background: Despite all the gains that have been achieved with endovascular mechanical thrombectomy revascularization and intravenous thrombolysis logistics since 2015, there is still a subgroup of patients with salvageable brain tissue for whom persistent emergent large vessel occlusion portends a catastrophic outcome., Objective: To test the safety and efficacy of emergent microsurgical intervention in patients with acute ischemic stroke and symptomatic middle cerebral artery occlusion after failure of mechanical thrombectomy., Methods: A prospective two-center cohort study was conducted. Patients with acute ischemic stroke and middle cerebral artery occlusion for whom recanalization failed at center 1 were randomly allocated to the microsurgical intervention group (MSIG) or control group 1 (CG1). All similar patients at center 2 were included in the control group 2 (CG2) with no surgical intervention. Microsurgical embolectomy and/or extracranial-intracranial bypass was performed in all MSIG patients at center 1., Results: A total of 47 patients were enrolled in the study: 22 at center 1 (12 allocated to the MSIG and 10 to the CG1) and 25 patients at center 2 (CG2). MSIG group patients showed a better clinical outcome on day 90 after the stroke, where a modified Rankin Scale score of 0-2 was reached in 7 (58.3%) of 12 patients compared with 1/10 (10.0%) patients in the CG1 and 3/12 (12.0%) in the CG2., Conclusions: This study demonstrated the potential for existing microsurgical techniques to provide good outcomes in 58% of microsurgically treated patients as a third-tier option., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gas hydrates (GHs) in water close to freezing temperatures can be stabilised via the formation of ice layers. In a recent work [Boström et al. , Astron. Astrophys. , A54 , 650, 2021], it was found that a surface region with partial gas dilution could be essential for obtaining nano- to micron-sized anomalously stabilizing ice layers. In this paper, it is demonstrated that the Casimir-Lifshitz free energy in multi-layer systems could induce thinner, but more stable, ice layers in cavities than those found for gas hydrates in a large reservoir of cold water. The thickness and stability of such ice layers in a pore filled with cold water could influence the leakage of gas molecules. Additional contributions, e.g. from salt-induced stresses, can also be of importance, and are briefly discussed.

Nanocomposite materials consist of nanometer-sized quantum objects such as atoms, molecules, voids or nanoparticles embedded in a host material. These quantum objects can be exploited as a super-structure, which can be designed to create material properties targeted for specific applications. For electromagnetism, such targeted properties include field enhancements around the bandgap of a semiconductor used for solar cells, directional decay in topological insulators, high kinetic inductance in superconducting circuits, and many more. Despite very different application areas, all of these properties are united by the common aim of exploiting collective interaction effects between quantum objects. The literature on the topic spreads over very many different disciplines and scientific communities. In this review, we present a cross-disciplinary overview of different approaches for the creation, analysis and theoretical description of nanocomposites with applications related to electromagnetic properties.

Key Message: We identified and integrated the novel FHB-resistant Fhb7 The2 allele into wheat B genome and made it usable in both common and durum wheat breeding programs without yellow flour linkage drag. A novel tall wheatgrass-derived (Thinopyrum elongatum, genome EE) Fhb7 allele, designated Fhb7 The2 , was identified and integrated into the wheat B genome through a small 7B-7E translocation (7BS·7BL-7EL) involving the terminal regions of the long arms. Fhb7 The2 conditions significant Type II resistance to Fusarium head blight (FHB) in wheat. Integration of Fhb7 The2 into the wheat B genome makes this wild species-derived FHB resistance gene usable for breeding in both common and durum wheat. By contrast, other Fhb7 introgression lines involving wheat chromosome 7D can be utilized only in common wheat breeding programs, not in durum wheat. Additionally, we found that Fhb7 The2 does not have the linkage drag of the yellow flour pigment gene that is tightly linked to the decaploid Th. ponticum-derived Fhb7 allele Fhb7 Thp . This will further improve the utility of Fhb7 The2 in wheat breeding. DNA sequence analysis identified 12 single nucleotide polymorphisms (SNPs) in Fhb7 The2 , Fhb7 Thp , and another Th. elongatum-derived Fhb7 allele Fhb7 The1 , which led to seven amino acid conversions in Fhb7 The2 , Fhb7 Thp , and Fhb7 The1 , respectively. However, no significant variation was observed in their predicted protein configuration as a glutathione transferase. Diagnostic DNA markers were developed specifically for Fhb7 The2 . The 7EL segment containing Fhb7 The2 in the translocation chromosome 7BS·7BL-7EL exhibited a monogenic inheritance pattern in the wheat genetic background. This will enhance the efficacy of marker-assisted selection for Fhb7 The2 introgression, pyramiding, and deployment in wheat germplasm and varieties., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Major depressive disorder (MDD) constitutes a main risk factor for suicide. Suicide risk in psychiatric patients is primarily determined by often unreliable, self-reported information. We assessed serum levels of three microRNAs (miRNAs), previously demonstrated to be dysregulated in post-mortem brain samples of suicide victims, as potential peripheral biomarkers for suicidality., Methods: All study participants were diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria. Suicidality, defined as acute suicide risk or suicide attempt within one week prior to study entry, was assessed by clinical interview. Relative serum levels of miR-30a, miR-30e, and miR-200a, normalized to U6, were measured by quantitative real-time PCR in MDD inpatients with (MDD/SI, N = 19) and without (MDD, N = 31) acute suicide risk. Median age and gender distribution were comparable in both groups., Results: Levels of miR-30a, miR-30e, and miR-200a were significantly elevated in MDD/SI compared to MDD. Subgroup analysis of the MDD/SI group showed that levels of miR-30e and miR-200a were significantly higher and miR-30a was increased by trend in patients admitted following a suicide attempt ( N = 7) compared to patients with acute suicide risk but without recent suicide attempt ( N = 12). Additionally, use of two databases for in silico transcription factor-miRNA interaction prediction indicated early growth response protein (EGR) 1 as potential transcriptional regulator for all three miRNAs., Conclusion: This study demonstrates suicide risk in MDD patients to be associated with increased levels of miR-30a, miR-30e, and miR-200a. Thus, these miRNAs might constitute potential biomarkers to predict suicidal behavior in MDD patients., Competing Interests: KK received speaker honoraria by Janssen, Otsuka, Neuraxpharm, EliLilly, Schwabe, Servier, and Trommsdorff/Ferrer; he received an unrestricted grant by Ferrer, ADDISCA. TT was founder and shareholder of Cardior Pharmaceuticals GmbH. TT filed and licensed patents regarding noncoding RNAs. TT received speaker honoraria and/or was in advisory boards by/of Takeda, Boehringer Ingelheim, Novo Nordisk, Sanofi-Genzyme, Amicus Therapeutics, Ksilink. The remaining 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 Stapel, Xiao, Gorinski, Schmidt, Pfanne, Fiedler, Richter, Vollbrecht, Thum, Kahl and Ponimaskin.)

Objectives: Fluctuations of physical performance and biological responses during a repetitive daily 24-h cycle are known as circadian rhythms. These circadian rhythms can influence the optimal time of day for endurance performance and related parameters which can be crucial in a variety of sports disciplines. The current study aimed to evaluate the daytime variations in endurance running performance in a 3.000-m field run and endurance running performance, blood lactate levels, and heart rate in an incremental treadmill test in adolescent soccer players., Results: In this study, 15 adolescent male soccer players (age: 18.0 ± 0.6 years) performed a 3.000-m run and an incremental treadmill test at 7:00-8:00 a.m. and 7:00-8:00 p.m. in a randomized cross-over manner. No significant variations after a Bonferroni correction were evident in endurance running performance, perceived exertion, blood lactate levels, and heart rates between the morning and the evening. Here, the largest effect size was observed for maximal blood lactate concentration (9.15 ± 2.18 mmol/l vs. 10.64 ± 2.30 mmol/l, p = .110, ES = 0.67). Therefore, endurance running performance and physiological responses during a field-based 3.000-m run and a laboratory-based test in young male soccer players indicated no evidence for daytime variations., (© 2022. The Author(s).)

We study the impact of an environment on the electromagnetic responses of a molecule in the presence of a dielectric medium. By applying the dipole-dipole coupling between the molecule's and the environment's degrees of freedom, we can reduce the complex system into its components and predict excitation lifetimes of single and few molecules attached to a dielectric surface by knowing the entire quantum-mechanical properties of the molecules, such as transition energies and dipole moments. The derived theory allows for the description of superradiance between two molecules depending on the geometric arrangement between both concerning their separation and orientation with respect to each other. We analyze the possibility of superradiance between two molecules bound to a dielectric sphere and determine a change in the relevant length scale where the usually considered wavelength in free space is replaced with the binding distance, drastically reducing the length scales at which collective effects can take place.

Background: During the COVID-19 pandemic there has been a strong interest in forecasts of the short-term development of epidemiological indicators to inform decision makers. In this study we evaluate probabilistic real-time predictions of confirmed cases and deaths from COVID-19 in Germany and Poland for the period from January through April 2021., Methods: We evaluate probabilistic real-time predictions of confirmed cases and deaths from COVID-19 in Germany and Poland. These were issued by 15 different forecasting models, run by independent research teams. Moreover, we study the performance of combined ensemble forecasts. Evaluation of probabilistic forecasts is based on proper scoring rules, along with interval coverage proportions to assess calibration. The presented work is part of a pre-registered evaluation study., Results: We find that many, though not all, models outperform a simple baseline model up to four weeks ahead for the considered targets. Ensemble methods show very good relative performance. The addressed time period is characterized by rather stable non-pharmaceutical interventions in both countries, making short-term predictions more straightforward than in previous periods. However, major trend changes in reported cases, like the rebound in cases due to the rise of the B.1.1.7 (Alpha) variant in March 2021, prove challenging to predict., Conclusions: Multi-model approaches can help to improve the performance of epidemiological forecasts. However, while death numbers can be predicted with some success based on current case and hospitalization data, predictability of case numbers remains low beyond quite short time horizons. Additional data sources including sequencing and mobility data, which were not extensively used in the present study, may help to improve performance., (© 2022. The Author(s).)

Key Message: We mapped three adult plant resistance (APR) loci on oat chromosomes 4D and 6C and developed flanking KASP/PACE markers for marker-assisted selection and gene pyramiding. Using sequence orthology search and the available oat genomic and transcriptomic data, we surveyed these genomic regions for genes that may control disease resistance. Sources of durable disease resistance are needed to minimize yield losses in cultivated oat caused by crown rust (Puccinia coronata f. sp. avenae). In this study, we developed five oat recombinant inbred line mapping populations to identify sources of adult plant resistance from crosses between five APR donors and Otana, a susceptible variety. The preliminary bulk segregant mapping based on allele frequencies showed two regions in linkage group Mrg21 (Chr4D) that are associated with the APR phenotype in all five populations. Six markers from these regions in Chr4D were converted to high-throughput allele specific PCR assays and were used to genotype all individuals in each population. Simple interval mapping showed two peaks in Chr4D, named QPc.APR-4D.1 and QPc.APR-4D.2, which were detected in the OtanaA/CI4706-2 and OtanaA/CI9416-2 and in the Otana/PI189733, OtanaD/PI260616, and OtanaA/CI8000-4 populations, respectively. These results were validated by mapping two entire populations, Otana/PI189733 and OtanaA/CI9416, genotyped using Illumina HiSeq, in which polymorphisms were called against the OT3098 oat reference genome. Composite interval mapping results confirmed the presence of the two quantitative trait loci (QTL) located on oat chromosome 4D and an additional QTL with a smaller effect located on chromosome 6C. This mapping approach also narrowed down the physical intervals to between 5 and 19 Mb, and indicated that QPc.APR-4D.1, QPc.APR-4D.2, and QPc.APR-6C explained 43.4%, 38.5%, and 21.5% of the phenotypic variation, respectively. In a survey of the gene content of each QTL, several clusters of disease resistance genes that may contribute to APR were found. The allele specific PCR markers developed for these QTL regions would be beneficial for marker-assisted breeding, gene pyramiding, and future cloning of resistance genes from oat., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Loss of MHC I expression is a tumoral escape mechanism, part of the process of immunoediting. MHC expression patterns and their prognostic and predictive value have not been studied in urothelial carcinoma of the bladder (UC) so far., Objective: To correlate the expression of MHC I and MHC II with prognosis after curative treatment, response to chemotherapy and checkpoint inhibition., Patients and Methods: We analyzed different patient cohorts for their expression of MHC I(HLA-A/B/C) and II (HLA-DR/DP/DQ) and examined potential correlations with prognosis and response to cisplatin-based chemotherapy or PD-1/PD-L1 directed immunotherapy., Results and Limitations: Overall, MHC expression was analyzed in 246 patients, and complete MHC I loss was seen in 29.7% of patients. In 35% of patients aberrant tumoral expression of MHC II was observed. In a homogeneous cohort of 149 patients with cystectomy with curative intent there were no significant differences in survival between the MHC expression groups. MHC I+ and MHC II+ patients had higher infiltration densities with CD8+ T effector cells.An analysis of 77 additional patients (cohort II) with neoadjuvant chemotherapy revealed no associations of MHC status with response defined as < pT2 pN0 in the cystectomy specimen. Lastly, we analyzed 26 patients with metastatic disease treated with PD-1/PD-L1 directed immunotherapy (cohort III, best response: 11 PD, 5 SD, 10 OR) and observed responses exclusively in MHC I+ patients (10/19 patients, 52.6). All four MHC I+ /MHC II+ /PD-L1+ patients had a progression-free interval of at least 12 months., Conclusions: Tumoral MHC I expression is frequently lost in UC. We found no association with prognosis or response to cisplatin-based chemotherapy but response to checkpoint inhibitors was limited to MHC I+ patients., Competing Interests: Nawroth R. is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Slotta-Huspenina J.: none Schwamborn K.: lecture honoraria and advisory board participation for Roche, BMS, MSD, Merck Steiger K.: none Simon R.: none Kirchhoff F.: none Büchler J.: none Fiedler J.: none Retz M.: lecture honoraria from BMS Ritschel C.: none Gschwend J.: lecture honoraria from Amgen, Astellas, Bayer, Janssen, Merck, Roche, consultant for AAA, Amgen, Bayer, BMS, Janssen, MSD, Merck, Pfizer, Roche Horn T.: lecture honoraria from Merck, medac GmbH and Pfizer, advisory board participation Merck and Bayer, (© 2022 – The authors. Published by IOS Press.)

Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th-April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017-2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017-2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria., (© 2022. The Author(s).)

Aims: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS., Methods and Results: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects., Conclusion: miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Constant supply of oxygen is crucial for multicellular tissue homeostasis and energy metabolism in cardiac tissue. As a first response to acute hypoxia, endothelial cells (ECs) promote recruitment and adherence of immune cells to the dysbalanced EC barrier by releasing inflammatory mediators and growth factors, whereas chronic hypoxia leads to the activation of a transcription factor (TF) battery, that potently induces expression of growth factors and cytokines including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). We report a hypoxia-minded, targeted bioinformatics approach aiming to identify and validate TFs that regulate angiogenic signaling., Results: A comprehensive RNA-Seq dataset derived from human ECs subjected to normoxic or hypoxic conditions was selected to identify significantly regulated genes based on (i) fold change (normoxia vs. hypoxia) and (ii) relative abundancy. Transcriptional regulation of this gene set was confirmed via qPCR in validation experiments where HUVECs were subjected to hypoxic conditions for 24 h. Screening the promoter and upstream regulatory elements of these genes identified two TFs, KLF5 and SP1, both with a potential binding site within these regions of selected target genes. In vitro , siRNA experiments confirmed SP1- and KLF5-mediated regulation of identified hypoxia-sensitive endothelial genes. Next to angiogenic signaling, we also validated the impact of TFs on inflammatory signaling, both key events in hypoxic sensing. Both TFs impacted on inflammatory signaling since endogenous repression led to increased NF-κB signaling. Additionally, SP1 silencing eventuated decreased angiogenic properties in terms of proliferation and tube formation., Conclusion: By detailed in silico analysis of promoter region and upstream regulatory elements for a list of hypoxia-sensitive genes, our bioinformatics approach identified putative binding sites for TFs of SP or KLF family in vitro . This strategy helped to identify TFs functionally involved in human angiogenic signaling and therefore serves as a base for identifying novel RNA-based drug entities in a therapeutic setting of vascularization., Competing Interests: TT has filed and licensed patents regarding non-coding RNAs in CVD. TT is founder and shareholder of Cardior Pharmaceuticals GmbH. The remaining 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 Schmidt, Fuchs, Stojanović, Liang, Schmidt, Jung, Xiao, Weusthoff, Just, Pfanne, Distler, Dandekar, Fiedler, Thum and Kunz.)

Objective: The clinical outcome of surgical extracranial internal carotid artery (eICA) recanalization may be adversely affected by intraoperative ischemia. Median nerve somatosensory evoked potential (SEP) amplitude correlates well with cerebral blood flow. Our study presents the value of intraoperative SEP and selective shunting in the prevention of intraoperative ischemia development during urgent eICA recanalization., Methods: Prospective recruitment of patients with acute unilateral eICA occlusion. All underwent surgical recanalization with intraoperative monitoring of scalp median SEPs. Preoperative clinical findings, cerebral collaterals, and 3 month functional outcome were evaluated., Results: The cohort consisted of 33 patients. Intraoperative SEP amplitude decreased significantly in 6 (18.2%). An intraluminal shunt was inserted twice (6.1%), surgical complications occurred in 6 (18.2%), intracerebral hemorrhage was not found. Favorable outcome 3 months after surgery according to the modified Rankin scale (mRS 0-2) was achieved in 28 (84.8%), 3 patients died (9.1%)., Conclusions: Intraoperative SEP during urgent eICA recanalization seems to be beneficial. Thanks to the effective measure based on the intraoperative SEP changes, the clinical outcome in four(12.1%) could be positively affected., Significance: The results suggest that selective shunting based on intraoperative median SEPs may prevent intraoperative ischemia and may improve overall outcome of urgent eICA recanalization., 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 © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Children and adolescents increasingly do not meet physical activity (PA) recommendations. Hence, insufficient PA (IPA) and sedentary behavior (SB) among children and adolescents are relevant behavior change domains for using individualized mobile health (mHealth) interventions., Objective: This review and meta-analysis investigated the effectiveness of mHealth interventions on IPA and SB, with a special focus on the age and level of individualization., Methods: PubMed, Scopus, Web of Science, SPORTDiscus, and Cochrane Library were searched for randomized controlled trials published between January 2000 and March 2021. mHealth interventions for primary prevention in children and adolescents addressing behavior change related to IPA and SB were included. Included studies were compared for content characteristics and methodological quality and summarized narratively. In addition, a meta-analysis with a subsequent exploratory meta-regression examining the moderating effects of age and individualization on overall effectiveness was performed., Results: On the basis of the inclusion criteria, 1.3% (11/828) of the preliminary identified studies were included in the qualitative synthesis, and 1.2% (10/828) were included in the meta-analysis. Trials included a total of 1515 participants (mean age (11.69, SD 0.788 years; 65% male and 35% female) self-reported (3/11, 27%) or device-measured (8/11, 73%) health data on the duration of SB and IPA for an average of 9.3 (SD 5.6) weeks. Studies with high levels of individualization significantly decreased insufficient PA levels (Cohen d=0.33; 95% CI 0.08-0.58; Z=2.55; P=.01), whereas those with low levels of individualization (Cohen d=-0.06; 95% CI -0.32 to 0.20; Z=0.48; P=.63) or targeting SB (Cohen d=-0.11; 95% CI -0.01 to 0.23; Z=1.73; P=.08) indicated no overall significant effect. The heterogeneity of the studies was moderate to low, and significant subgroup differences were found between trials with high and low levels of individualization (χ 2 1 =4.0; P=.04; I 2 =75.2%). Age as a moderator variable showed a small effect; however, the results were not significant, which might have been because of being underpowered., Conclusions: Evidence suggests that mHealth interventions for children and adolescents can foster moderate reductions in IPA but not SB. Moreover, individualized mHealth interventions to reduce IPA seem to be more effective for adolescents than for children. Although, to date, only a few mHealth studies have addressed inactive and sedentary young people, and their quality of evidence is moderate, these findings indicate the relevance of individualization on the one hand and the difficulties in reducing SB using mHealth interventions on the other., Trial Registration: PROSPERO CRD42020209417; https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=209417., (©Hannes Baumann, Janis Fiedler, Kathrin Wunsch, Alexander Woll, Bettina Wollesen. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 11.05.2022.)

Chromosomal instability (CIN) can be a driver of tumorigenesis but is also a promising therapeutic target for cancer associated with poor prognosis such as triple negative breast cancer (TNBC). The treatment of TNBC cells with defects in DNA repair genes with poly(ADP-ribose) polymerase inhibitor (PARPi) massively increases CIN, resulting in apoptosis. Here, we identified a previously unknown role of microRNA-449a in CIN. The transfection of TNBC cell lines HCC38, HCC1937 and HCC1395 with microRNA-449a mimics led to induced apoptosis, reduced cell proliferation, and reduced expression of genes in homology directed repair (HDR) in microarray analyses. EME1 was identified as a new target gene by immunoprecipitation and luciferase assays. The reduced expression of EME1 led to an increased frequency of ultrafine bridges, 53BP1 foci, and micronuclei. The induced expression of microRNA-449a elevated CIN beyond tolerable levels and induced apoptosis in TNBC cell lines by two different mechanisms: (I) promoting chromatid mis-segregation by targeting endonuclease EME1 and (II) inhibiting HDR by downregulating key players of the HDR network such as E2F3 , BIRC5 , BRCA2 and RAD51 . The ectopic expression of microRNA-449a enhanced the toxic effect of PARPi in cells with pathogenic germline BRCA1 variants. The newly identified role makes microRNA-449a an interesting therapeutic target for TNBC.

Changes in hydration status influence plasma volume (PV) which is associated with post-exercise parasympathetic reactivation. The present study hypothesized that, after dehydrating cycling exercise in the heat (DE), stimulation of PV expansion with sodium citrate (CIT) supplementation would promote heart rate variability (HRV) recovery in endurance-trained men. Twelve participants lost 4% of body mass during DE. During subsequent 16-h recovery, participants consumed water ad libitum (CIT =5.5-L, PLC =5.1-L) and ate prescribed food supplemented with CIT or placebo in a randomized, double-blind, crossover manner. Relative changes in PV were assessed across DE and 16-h recovery. HRV was analyzed before and 16 h after DE in three conditions for altogether four 5-min periods: supine in a thermoneutral environment, supine in the heat (32°C, 46% relative humidity; 2 periods), and standing in the heat. A larger expansion of PV across 16-h recovery occurred in CIT compared to placebo trial (p < 0.0001). However, no between-trial differences appeared in HRV parameters (lnRMSSD, lnSDNN, lnLF/HF) in any 5-min period analyzed before or 16 h after DE (in all cases p > 0.05). Increases in HR (p < 0.001) and lnLF/HF (p = 0.005) and decreases in lnRMSSD (p < 0.001) and lnSDNN (p < 0.001) occurred following DE in both trials. Larger PV expansion induced by CIT supplementation after DE does not improve recovery of HRV at rest and has no influence on HRV responsiveness in endurance-trained men., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Cardiac fibroblasts constitute the major cell type of the murine and human heart. Once activated, they contribute to an excessive deposition of extracellular matrix (ECM) leading to cardiac fibrosis and subsequently organ dysfunction. With the exception of the pulmonary drugs, nintedanib and pirfenidone, drugs specifically targeting anti-fibrotic pathways are scarce. We recently performed large library screenings of natural occurring compounds and identified first lead structures with anti-fibrotic properties in vitro and in vivo. In line, we now aimed to improve efficacy of these anti-fibrotic lead structures by combining in vitro validation studies and in silico prediction. Next to this combined approach, we performed large OMICs-multi-panel-based mechanistic studies. Applying human cardiac fibroblasts (HCF), we analysed 26 similars of the initially identified anti-fibrotic lead molecules bufalin and lycorine and determined anti-proliferative activity and potential toxicity in an array of in vitro and ex vivo studies. Of note, even at lower concentrations, certain similars were more effective at inhibiting HCF proliferation than nintedanib and pirfenidone. Additionally, selected similars showed low cytotoxicity on human iPS-derived cardiomyocytes and anti-fibrotic gene regulation in human ex vivo living myocardial slices. Further, array and RNA sequencing studies of coding and non-coding RNAs in treated HCFs revealed strong anti-fibrotic properties, especially with the lycorine similar lyco-s (also known as homoharringtonine), that led to a nearly complete shutdown of ECM production at concentrations 100-fold lower than the previously identified anti-fibrotic compound lycorine without inducing cellular toxicity. We thus identified a new natural compound similar with strong anti-fibrotic properties in human cardiac fibroblasts and human living heart tissue potentially opening new anti-fibrotic treatment strategies., (© 2022. The Author(s).)

Stress-related disorders display differences at multiple levels according to sex. While most studies have been conducted in male rodents, less is known about comparable outcomes in females. In this study, we found that the chronic restraint stress model (2.5 h/day for 14 days) triggers different somatic responses in male and female adult rats. Chronic restraint produced a loss in sucrose preference and novel location preference in male rats. However, chronic restraint failed to produce loss of sucrose preference in females, while it improved spatial performance. We then characterized the molecular responses associated with these behaviors in the hippocampus, comparing the dorsal and ventral poles. Notably, sex- and hippocampal pole-specific transcriptional signatures were observed, along with a significant concordance between the female ventral and male dorsal profiles. Functional enrichment analysis revealed both shared and specific terms associated with each pole and sex. By looking into signaling pathways that were associated with these terms, we found an ample array of sex differences in the dorsal and, to a lesser extent, in the ventral hippocampus. These differences were mainly present in synaptic TrkB signaling, Akt pathway, and glutamatergic receptors. Unexpectedly, the effects of stress on these pathways were rather minimal and mostly dissociated from the sex-specific behavioral outcomes. Our study suggests that female rats are resilient and males susceptible to the restraint stress exposure in the sucrose preference and object location tests, while the activity of canonical signaling pathways is primarily determined by sex rather than stress in the dorsal and ventral hippocampus., Competing Interests: None., (© 2022 The Authors. Published by Elsevier Inc.)

An efficient and safe drug development process is crucial for the establishment of new drugs on the market aiming to increase quality of life and life-span of our patients. Despite technological advances in the past decade, successful launches of drug candidates per year remain low. We here give an overview about some of these advances and suggest improvements for implementation to boost preclinical and clinical drug development with a focus on the cardiovascular field. We highlight advantages and disadvantages of animal experimentation and thoroughly review alternatives in the field of three-dimensional cell culture as well as preclinical use of spheroids and organoids. Microfluidic devices and their potential as organ-on-a-chip systems, as well as the use of living animal and human cardiac tissues are additionally introduced. In the second part, we examine recent gold standard randomized clinical trials and present possible modifications to increase lead candidate throughput: adaptive designs, master protocols, and drug repurposing. In silico and N-of-1 trials have the potential to redefine clinical drug candidate evaluation. Finally, we briefly discuss clinical trial designs during pandemic times., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

To improve the efficiency of high-density genotype data storage and imputation in bread wheat (Triticum aestivum L.), we applied the Practical Haplotype Graph (PHG) tool. The Wheat PHG database was built using whole-exome capture sequencing data from a diverse set of 65 wheat accessions. Population haplotypes were inferred for the reference genome intervals defined by the boundaries of the high-quality gene models. Missing genotypes in the inference panels, composed of wheat cultivars or recombinant inbred lines genotyped by exome capture, genotyping-by-sequencing (GBS), or whole-genome skim-seq sequencing approaches, were imputed using the Wheat PHG database. Though imputation accuracy varied depending on the method of sequencing and coverage depth, we found 92% imputation accuracy with 0.01× sequence coverage, which was slightly lower than the accuracy obtained using the 0.5× sequence coverage (96.6%). Compared to Beagle, on average, PHG imputation was ∼3.5% (P-value < 2 × 10-14) more accurate, and showed 27% higher accuracy at imputing a rare haplotype introgressed from a wild relative into wheat. We found reduced accuracy of imputation with independent 2× GBS data (88.6%), which increases to 89.2% with the inclusion of parental haplotypes in the database. The accuracy reduction with GBS is likely associated with the small overlap between GBS markers and the exome capture dataset, which was used for constructing PHG. The highest imputation accuracy was obtained with exome capture for the wheat D genome, which also showed the highest levels of linkage disequilibrium and proportion of identity-by-descent regions among accessions in the PHG database. We demonstrate that genetic mapping based on genotypes imputed using PHG identifies SNPs with a broader range of effect sizes that together explain a higher proportion of genetic variance for heading date and meiotic crossover rate compared to previous studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Objectives: This paper sought to evaluate the occurrence of decompression sickness (DCS) after the application of a patent foramen ovale (PFO) screening and risk stratification strategy., Background: PFO is associated with an increased risk of DCS. Recently, transcatheter closure was reported to reduce DCS occurrence in divers with a high-grade shunt. However, to date, there are no data regarding the effectiveness of any PFO screening and risk stratification strategy for divers., Methods: A total of 829 consecutive divers (age 35.4 ± 10.0 years, 81.5% men) were screened for PFO by means of transcranial color-coded sonography in the DIVE-PFO (Decompression Illness Prevention in Divers with a Patent Foramen Ovale) registry. Divers with a high-grade PFO were offered either catheter-based PFO closure (the closure group) or advised conservative diving (high grades). Divers with a low-grade shunt were advised conservative diving (low grades), whereas those with no PFO continued unrestricted diving (controls). A telephone follow-up was performed. To study the effect of the screening and risk stratification strategy, DCS occurrence before enrollment and during the follow-up was compared., Results: Follow-up was available for 748 (90%) divers. Seven hundred and 2 divers continued diving and were included in the analysis (mean follow-up 6.5 ± 3.5 years). The DCS incidence decreased significantly in all groups, except the controls. During follow-up, there were no DCS events in the closure group; DCS incidence was similar to the controls in the low-grade group (HR: 3.965; 95% CI: 0.558-28.18; P = 0.169) but remained higher in the high-grade group (HR: 26.170; 95% CI: 5.797-118.160; P < 0.0001)., Conclusions: The screening and risk stratification strategy using transcranial color-coded sonography was associated with a decrease in DCS occurrence in divers with PFO. Catheter-based PFO closure was associated with a DCS occurrence similar to the controls; the conservative strategy had a similar effect in the low-grade group, but in the high-grade group the DCS incidence remained higher than in all other groups., Competing Interests: Funding Support and Author Disclosures This research was supported by the project for conceptual development of research organization (grant number 00064203) and the AZV Grant, Ministry of Health, Czech Republic (grant number 15-34904A) and was partially supported by the long-term strategic development financing of the Institute of Computer Science (Czech Republic RVO 67985807) and the Ministry of Education, Youth and Sports of the Czech Republic (Large RI Project LM2018129 Czech-BioImaging). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Global migration trends have led to a more diverse population in health care services everywhere, which in turn has set off a paradigm shift away from medical paternalism toward more patient autonomy. Consequently, physicians need to provide a more precise patient-centred healthcare. Professional interpreting appears to play a crucial part in tackling the challenges of language barriers adequately. The aim of this study was to conduct process evaluation through the implementing of video remote interpreting (VR) and telephone remote interpreting (TR) within primary care facilities in the northern German metropolis of Hamburg., Methods: We conducted a three-armed exploratory pilot trial, which compared VR to TR and to a control group (CG) in different primary care settings. We assessed feasibility of implementation, as well as the acceptance of interpreting tools among their users. In addition, we compared the quality of communication as perceived by patients and physicians, as well as the enabling of patient-centred medicine over all three study groups using quantitative questionnaires., Results: 13 practices (7 GPs, 3 Gynaecologists, 3 Paediatricians) took part in this trial. 183 interpreting calls were documented, 178 physicians as well as 127 patients answered their respective questionnaires. The implementation of the VR- und TR-tools went smoothly and they were broadly accepted by their users. However, the tools were used significantly less often than we had anticipated. With regards to quantitative questionnaires, VR scored significantly better than the control group in terms of the perceived quality of communication by both, patients and physicians and enabled of patient-centred medicine., Conclusion: Our main findings were the discrepancy between the assumed high demand of professional interpreting solutions on the one hand and the low willingness of practices to participate on the other. The rather low utilisation rates were also noteworthy. This discrepancy indicates a lack of awareness concerning the adverse effects of using informal or no interpreter in medical settings, which needs to be rectified. Due to the small sample size, all statistical results must be viewed with caution. However, our results show that remote interpreting represents a promising approach to tackling language barriers in primary care settings., (© 2022. The Author(s).)

Spot form net blotch (SFNB), caused by the necrotrophic fungal pathogen Pyrenophora teres f. maculata (Ptm), is a foliar disease of barley that results in significant yield losses in major growing regions worldwide. Understanding the host-parasite interactions between pathogen virulence/avirulence genes and the corresponding host susceptibility/resistance genes is important for the deployment of genetic resistance against SFNB. Two recombinant inbred mapping populations were developed to characterize genetic resistance/susceptibility to the Ptm isolate 13IM8.3, which was collected from Idaho (ID). An Illumina Infinium array was used to produce a genome-wide marker set. Quantitative trait loci (QTL) analysis identified ten significant resistance/susceptibility loci, with two of the QTL being common to both populations. One of the QTL on 5H appears to be novel, while the remaining loci have been reported previously. Single nucleotide polymorphisms (SNPs) closely linked to or delimiting the significant QTL have been converted to user-friendly markers. Loci and associated molecular markers identified in this study will be useful in genetic mapping and deployment of the genetic resistance to SFNB in barley., (Published by Oxford University Press on behalf of Genetics Society of America 2021.)