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Error detection in typing is crucial for assessing the adequacy of ongoing actions, leveraging both predictive mechanisms for early detection and sensory feedback for late detection. Neurophysiological studies have supported the anticipation of errors through predictive models. This research extends the understanding of error detection in typing, focusing on the neurocognitive mechanisms underlying errors in transparent and intransparent German words. Thirty-six volunteer students typed out aurally presented words, classified as either orthographically transparent or intransparent, on a computer keyboard without the possibility of correction. Because of poor spelling or excessive artifacts, the final sample comprised 27 participants. Event-related potentials (ERPs) were obtained time-locked to key presses, and behavioral data on typing correctness and speed were collected. A higher error rate and longer latency for intransparent words compared to transparent ones were found, suggesting the complexity of spelling impacts typing correctness. Post-error slowing was observed, aligning with increased cognitive control following errors. ERPs revealed a negative component akin to the error-related negativity (ERN) for typing errors, with a pronounced ERN-like negativity preceding erroneous key-presses, particularly for intransparent words. The study provides evidence of the cognitive and neural mechanisms underlying typing errors, highlighting the impact of orthographic transparency. The detection of an ERN-like negativity before erroneous key-presses, especially in typing intransparent words, underscores the brain's use of predictive mechanisms for error detection.

Abstract Magnetic vortices are topological spin structures frequently found in ferromagnets, yet novel to antiferromagnets. By combining experiment and theory, it is demonstrated that in a nanostructured antiferromagnetic‐ferromagnetic NiO(111)‐Fe(110) bilayer, a magnetic vortex is naturally stabilized by magnetostatic interactions in the ferromagnet and is imprinted onto the adjacent antiferromagnet via interface exchange coupling. Micromagnetic simulations are used to construct a corresponding phase diagram of the stability of the imprinted antiferromagnetic vortex state. The in‐depth analysis reveals that the interplay between interface exchange coupling and the antiferromagnet magnetic anisotropy plays a crucial role in locally reorienting the Néel vector out‐of‐plane in the prototypical in‐plane antiferromagnet NiO and thereby stabilizing the vortices in the antiferromagnet.

Abstract Although often located at a distance from their target gene promoters, enhancers are the primary genomic determinants of temporal and spatial transcriptional specificity in metazoans. Since the discovery of the first enhancer element in simian virus 40, there has been substantial interest in unraveling the mechanism(s) by which enhancers communicate with their partner promoters to ensure proper gene expression. These research efforts have benefited considerably from the application of increasingly sophisticated sequencing- and imaging-based approaches in conjunction with innovative (epi)genome-editing technologies; however, despite various proposed models, the principles of enhancer–promoter interaction have still not been fully elucidated. In this review, we provide an overview of recent progress in the eukaryotic gene transcription field pertaining to enhancer–promoter specificity. A better understanding of the mechanistic basis of lineage- and context-dependent enhancer–promoter engagement, along with the continued identification of functional enhancers, will provide key insights into the spatiotemporal control of gene expression that can reveal therapeutic opportunities for a range of enhancer-related diseases.

**Background:** Individuals with type 2 diabetes (T2D) show high risk of heart failure (HF). Left ventricular ejection fraction is a major factor for disease progression. In Germany, no recent longitudinal data are available. **Objectives:** To (1) measure the proportion of individuals with T2D who acquire HF over 2 years and (2) categorize ejection fraction using routine data and an algorithm, and (3) understand progression of HF in 5-year follow-up. **Methods:** This descriptive, retrospective study used longitudinal data from German statutory health insurance claims. A model using coded data classified the patients with HF into ejection fraction (EF) categories. Individuals were selected during 2013, with an inclusion period from 2014 to 2015 and a follow-up from 2016 to 2020. Baseline characteristics included demographic data, disease stage, comorbidities, and risk factors. Follow-up criteria included major adverse cardiac events (MACEs), EF category, and mortality. Disease progression was visualized by Sankey plots. **Results:** Among the 173 195 individuals with T2D identified in 2013, 6725 (median age, 74 years) developed HF in 2014 or 2015. 34.4% of individuals had MACEs, and 42.9% died over 5 years. Myocardial infarction (42%) was the most common event, followed by stroke (32%) and hospitalization (28%). A total of 5282 (78.54%) patients were classified into preserved EF and 1443 (21.46%) into reduced EF. Survival after 5 years was 71% in HF for preserved EF patients, and 29% in the HF for those with reduced EF. **Conclusion:** Heart failure is relevant in individuals with diabetes. A high number of patients may likely not survive a 5-year period. Validation of the model with German data is highly desirable. New ways of close monitoring could help improve outcomes.

Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α, β) with differential tissue distribution. Thyroid hormone recepto r β (TRβ) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the β form of the receptor (pituitary, liver). This study seeks to i dentify the effects of mutant TRβ on pituitary size. Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHβ in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one ne uroscientist). Results: Patients with mutant TRβ (resistance to thyroid hormone β, RTHβ) showed elevated free tri-iodothyronine/thyroxine levels with normal thyroid-stimulating hormone levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHβ patients in comparison to healthy controls (F(1,35) = 7.05, P = 0.012, partial η2 = 0.17). Conclusion: RTHβ subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.

Late‐stage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via post‐translational modifications (PTMs). While the relevance of p53 C‐terminal acetylation for transcriptional regulation is well defined, it is unknown whether this PTM controls mitochondrially mediated apoptosis directly. We used wild‐type p53 or p53‐negative human CRC cells, cells with acetylation‐defective p53, transformation assays, CRC organoids, and xenograft mouse models to assess how p53 acetylation determines cellular stress responses. The topoisomerase‐1 inhibitor irinotecan induces acetylation of several lysine residues within p53. Inhibition of histone deacetylases (HDACs) with the class I HDAC inhibitor entinostat synergistically triggers mitochondrial damage and apoptosis in irinotecan‐treated p53‐positive CRC cells. This specifically relies on the C‐terminal acetylation of p53 by CREB‐binding protein/p300 and the presence of C‐terminally acetylated p53 in complex with the proapoptotic BCL2 antagonist/killer protein. This control of C‐terminal acetylation by HDACs can mechanistically explain why combinations of irinotecan and entinostat represent clinically tractable agents for the therapy of p53‐proficient CRC.

BackgroundPredicting complications associated with pulmonary hypertension (PH) after cardiac transplantation is an important factor when considering cardiac transplantation. The transpulmonary gradient (TPG) is recommended to quantify PH in transplant candidates. Nonetheless, PH remains a common driver of mortality. The diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) can differentiate post- from combined pre- and post-capillary PH and may improve estimation of PH-associated risks. We used a large European cohort of transplant candidates to assess whether the pulmonary pulsatility index (PAPi), improves prediction of graft failure and mortality compared to DPG and PVR.MethodsOut of all patients undergoing heart transplantation between 2009 and 2019 in Eurotransplant member states (n = 10,465), we analyzed the impact of PH (mPAP > 25 mmHg) and right heart catheter hemodynamic data on graft failure and mortality within 1–5 years.ResultsIn 1,407 heart transplant patients with PH (79% male, median age 54 years, IQR 39–69 years), the median PVR was 2.5 WU (IQR 1.6 WU) with a median mPAP (pulmonary arterial pressure) of 32 mmHg (IQR 9 mmHg). Patients with low (< 3 mmHg) DPG had a better 5 year survival than those with higher DPG (log rank p = 0.023). TPG, mPAP, PAPi, and PVR did not improve prediction of survival. Low PAPi (OR = 2.24, p < 0.001) and high PVR (OR = 2.12, p = 0.005) were associated with graft failure.ConclusionPAPI and PVR are associated with graft failure in patients with PH undergoing cardiac transplantation. DPG is associated with survival in this cohort.

Abstract Background Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPα) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies. Case presentation and literature review A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed. Conclusion Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can co-occur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPα antibodies and longitudinal extensive myelitis with anti-MOG antibodies.

Abstract Objectives To determine the feasibility of eliciting utilities with a standard gamble self-completion questionnaire that uses a single-item approach in melanoma patients. Methods 150 patients with low-risk melanoma completed a paper standard gamble questionnaire. Six scenarios described the adjuvant treatment of high-risk melanoma with interferon alfa-2b with varied side effects. Patients were asked to directly state the maximum death risk they would accept to prevent these health states. Methods were the same as in a study by Kilbridge et al. (J Clin Oncol 19(3):812–823, 2021. https://doi.org/10.1200/JCO.2001.19.3.812 ), except that they used computerised interviews and an iterative risk variation (Ping–Pong method) to elicit utilities. Results The rate of missing values in the standard gamble was 1.0%. The percentage of patients who misordered scenarios was very similar to the reference study (11.3% vs. 11.2%). Mean utilities were also similar with a maximum difference of 0.02 points, but median utilities were not (between 0.21 points below and 0.05 points above the reference study). Conclusions One-item utility elicitation with questionnaires might be a feasible alternative to computerised face-to-face interviews to conduct a standard gamble in melanoma patients.

Abstract Background Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is common and associated with worse outcome. Prediction of RHF remains challenging. Our study aims to assess predictors of RHF focusing on clinical manifestations. Methods We retrospectively analyzed clinical, echocardiographic and hemodynamic parameters of 112 patients undergoing LVAD implantation. Pre-operative, early (ERHF, day 7 and 14) and late postoperative RHF (LRHF, after 1, 3, 6 and 12 months) were assessed. Results In the total study population (87.5% men, mean age 55 years), early RHF was frequent (47% on day 7 and 30% on day 14). Prevalence of late RHF and death from RHF was high after 3, 6 and 12 months (23, 24 and 17%). Pre-existing RHF was only associated with early RHF and persistent, but not for new onset late RHF. Early RHF was associated with lower INTERMACS level (p

Aims: There is no gold standard to predict outcome in acute decompensated heart failure (ADHF). Several scores for mortality prediction of patients with ADHF have been developed and mostly consist of complex regression models. None of these models has been widely adopted by clinicians. The quick SOFA score (qSOFA) is a simple score including three parameters (systolic blood pressure ≤ 100 mmHg, respiratory rate ≥22 breathes/min, and GCS

Representative, actively collected surveillance data on asymptomatic SARS-CoV-2 infections in primary schoolchildren remain scarce. We evaluated the feasibility of a saliva mass screening concept and assessed infectious activity in primary schools. During a 10-week period from 3 March to 21 May 2021, schoolchildren and staff from 17 primary schools in Munich participated in the sentinel surveillance, cohort study. Participants were tested using the Salivette® system, testing was supervised by trained school staff, and samples were processed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). We included 4433 participants: 3752 children (median age, 8 [range, 6–13] years; 1926 girls [51%]) and 681 staff members (median age, 41 [range, 14–71] years; 592 women [87%]). In total, 23,905 samples were processed (4640 from staff), with participants representing 8.3% of all primary schoolchildren in Munich. Only eight cases were detected: Five out of 3752 participating children (0.13%) and three out of 681 staff members (0.44%). There were no secondary cases. In conclusion, supervised Salivette® self-sampling was feasible, reliable, and safe and thus constituted an ideal method for SARS-CoV-2 mass screenings in primary schoolchildren. Our findings suggest that infectious activity among asymptomatic primary schoolchildren and staff was low. Primary schools appear to continue to play a minor role in the spread of SARS-CoV-2 despite high community incidence rates.

ObjectivesSalinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer.MethodsPrimary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin. TICs were injected subcutaneously into NOD/SCID mice to induce a patient-derived mouse xenograft model of colorectal cancer. Animals were treated either with salinomycin, FOLFOX regimen, or salinomycin and FOLFOX. Human colorectal cancer cells were used to delineate an underlying molecular mechanism of salinomycin in this tumor entity.ResultsApplying TICs isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment. Consistently, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer. Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species. These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment.ConclusionCollectively, the results of this pre-clinical study indicate that salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.

Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.

There is legitimate interest in the effects of recombinant human activated protein C (rhAPC) on various organs and individual patients, but the specific effects on organ tissues during early sepsis remain unknown. Differences in the levels of organ damage may influence responses to drug therapy. We aimed to investigate whether rhAPC induces organ-specific effects on inflammation and apoptosis using randomized, experimental trials with male NMRI mice. Animals underwent caecal ligation and puncture, and after 12 h, sepsis inflammation and apoptosis were assessed by plasma cytokines, gene expression ratios and immunohistochemistry (IHC). RhAPC-treated animals exhibited increased physical activity and decreased cytokine release compared to untreated animals (interleukin-6 reduction 58%, P < 0.001). CD14 expression was higher in the heart and liver and decreased upon rhAPC application in the heart (−35%), liver and kidney (both −60%). Macrophage inflammatory protein 2 (MIP2) expression decreased in the heart (−58%) but not in the liver or kidney. IHC revealed decreased cleaved caspase-3 in the heart and kidney due to rhAPC intervention. Preservation of the endothelial PC receptor was significant only in the heart during sepsis ( P = 0.007). In early polymicrobial sepsis, inflammation was more pronounced in the heart and liver compared to the kidney. RhAPC exhibited protective effects, especially in the heart tissue, and led to reduced plasma levels of pro-inflammatory cytokines and improved physical activity.

A promising route to novel quantum technologies are hybrid quantum systems, which combine the advantages of several individual quantum systems. We have realized a hybrid atomic-mechanical experiment consisting of a Si _3 N _4 membrane oscillator cryogenically precooled to 500 mK and optically coupled to a cloud of laser cooled ^87 Rb atoms. Here, we demonstrate active feedback cooling of the oscillator to a minimum mode occupation of ${\bar{n}}_{{\rm{m}}}=16\pm 1$ corresponding to a mode temperature of T _min ≈ 200 μ K. Furthermore, we characterize in detail the coupling of the membrane to the atoms by means of sympathetic cooling. By simultaneously applying both cooling methods we demonstrate the possibility of preparing the oscillator near the motional ground state while it is coupled to the atoms. Realistic modifications of our setup will enable the creation of a ground state hybrid quantum system, which opens the door for coherent quantum state transfer, teleportation and entanglement as well as quantum enhanced sensing applications.

ApoE deficiency in mice (Apoe-/-) results in severe hypercholesterolemia and atherosclerosis. In diet-induced obesity, Apoe-/- display steatohepatitis but reduced accumulation of triacylglycerides and enhanced insulin sensitivity in white adipose tissue (WAT). Although the vast majority of apoE is expressed by hepatocytes apoE is also abundantly expressed in WAT. As liver and adipose tissue play important roles for metabolism, this study aims to outline functions of both hepatocyte- and adipocyte-derived apoE separately by investigating a novel mouse model of tissue-specific apoE deficiency. Therefore we generated transgenic mice carrying homozygous floxed Apoe alleles. Mice lacking apoE either in hepatocytes (ApoeΔHep) or in adipose tissue (ApoeΔAT) were fed experimental diets. ApoeΔHep exhibited slightly higher body weights, adiposity and liver weights on diabetogenic high fat diet (HFD). Accordingly, hepatic steatosis and markers of inflammation were more pronounced compared to controls. Hypercholesterolemia evoked by lipoprotein remnant accumulation was present in ApoeΔHep mice fed a Western type diet (WTD). Lipidation of VLDL particles and tissue uptake of VLDL were disturbed in ApoeΔHep while the plasma clearance rate remained unaltered. ApoeΔAT did not display any detectable phenotype, neither on HFD nor on WTD. In conclusion, our novel conditional apoE deletion model has proven here the role of hepatocyte apoE for VLDL production and diet-induced dyslipidemia. Specific deletion of apoE in adipocytes cannot reproduce the adipose phenotype of global Apoe-/- mice, suggesting that apoE produced in other cell types than hepatocytes or adipocytes explains the lean and insulin-sensitive phenotype described for Apoe-/- mice.

Memory performance in everyday life is often far from perfect and therefore needs to be monitored and controlled by metamemory evaluations, such as judgments of learning (JOLs). JOLs support monitoring for goal-directed modification of learning. Behavioral studies suggested retrieval processes as providing a basis for JOLs. Previous functional imaging research on JOLs found a dissociation between processes underlying memory prediction, located in the medial prefrontal cortex (mPFC), and actual encoding success, located in the medial temporal lobe. However, JOL-specific neural correlates could not be identified unequivocally, since JOLs were given simultaneously with encoding. Here, we aimed to identify the neurocognitive basis of JOLs, i.e., the cognitive processes and neural correlates of JOL, separate from initial encoding. Using functional magnetic resonance imaging (fMRI), we implemented a face-name paired associative design. In general, we found that actual memory success was associated with increased brain activation of the hippocampi bilaterally, whereas predicted memory success was accompanied by increased activation in mPFC, orbital frontal and anterior cingulate cortices. Masking brain activation during predicted memory success with activation during retrieval success revealed BOLD increases of the mPFC. Our findings indicate that JOLs actually incorporate retrieval processes.