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Abstract Lenalidomide (LEN) is widely used immunomodulatory drug (IMiD). Nonetheless, despite its efficacy, over time patients become resistant to LEN and relapse. Due to high clinical relevance, drug resistance in MM is being thoroughly investigated. However, less is known about predictors of good response to LEN-based treatment. The aim of this study was to identify molecular pathways associated with good and long response to LEN. The study included newly diagnosed MM patients (NDMM) and MM patients treated with first-line LEN and dexamethasone (RD) who achieved and least very good partial remission (VGPR). RNA was isolated from MM cells and new-generation sequencing was performed. Obtained results were validated with qRT-PCR. A global increase in gene expression was found in the RD group compared to NDMM, suggesting the involvement of epigenetic mechanisms. Moreover, upregulation of genes controlling the interaction within MM niche was detected. Next, genes controlling immune response were upregulated. In particular, the gene encoding the IL-17 receptor was overexpressed in the RD group which is a novel finding. This should be emphasized because IL-17-related signaling can potentially be targeted, providing the rationale for future research. Establishing the molecular background associated with long-lasting and profound response to LEN may improve LEN-based chemotherapy regimens and facilitate the development of adjuvant therapies to enhance its anti-MM activity.

The effects of Content and Language Integrated Learning (CLIL) on students' foreign language skill development have been overestimated by previous studies, as most studies needed to have considered selection and preparation effects appropriately. We used complete survey data from a 1996-2003 cohort to investigate English skill development of N = 332 German CLIL and N = 6,401 non-CLIL grammar school students from grade seven (M = 12.64, SD = 0.60) to grade eleven (M = 16.72, SD = 0.70). We found selection effects for prior achievement, sociodemographic variables, and cognitive abilities. After propensity score matching, data revealed significant preparation effects of additional English lessons for the CLIL students. When controlling selection and preparation effects, CLIL compensated for the assumed fading out-effect but did not contribute significant added value measured by a C-test. We commend to include selection and preparation effects when analyzing CLIL effects.

Multilingualism is often associated with advantages for acquiring additional languages. Theoretical approaches explain these advantages by assuming a Common Underlying Proficiency or a Metalinguistic Awareness. At the State Europe School in Berlin, students from different language backgrounds receive instruction in German and a partner language according to two-way immersion (TWI). It is unclear how this bilingual instruction affects the acquisition of a third language. We examined the English proficiency of N = 656 TWI sixth-grade students and N = 739 mainstream students via a C-test. Multiple regression analyses revealed that TWI students exhibited higher English proficiency than mainstream students despite having received less English instruction. The results showed additional effects of German- and partner-language reading skills. The findings support the assumption of TWI programs that the use of two languages of instruction fosters third language acquisition.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Abstract Chronic liver disease and cancer are global health challenges. The role of the circadian clock as a regulator of liver physiology and disease is well established in rodents, however, the identity and epigenetic regulation of rhythmically expressed genes in human disease is less well studied. Here we unravel the rhythmic transcriptome and epigenome of human hepatocytes using male human liver chimeric mice. We identify a large number of rhythmically expressed protein coding genes in human hepatocytes of male chimeric mice, which includes key transcription factors, chromatin modifiers, and critical enzymes. We show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer, perturbs the transcriptome by altering the rhythmicity of the expression of more than 1000 genes, and affects the epigenome, leading to an activation of critical pathways mediating metabolic alterations, fibrosis, and cancer. HCV-perturbed rhythmic pathways remain dysregulated in patients with advanced liver disease. Collectively, these data support a role for virus-induced perturbation of the hepatic rhythmic transcriptome and pathways in cancer development and may provide opportunities for cancer prevention and biomarkers to predict HCC risk.

Abstract Adaptation transcends scale in both natural and artificial systems, but delineating the causative factors of this phenomenon requires urgent clarification. Herein, we unravel the molecular requirements for adaptation and establish a link to rationalize adaptive behavior on a self-assembled level. These concepts are established by analyzing a model compound exhibiting both light- and pH-responsive units, which enable the combined or independent application of different stimuli. On a molecular level, adaptation arises from coupled stimuli, as the final outcome of the system depends on their sequence of application. However, in a self-assembled state, a single stimulus suffices to induce adaptation as a result of collective molecular behavior and the reversibility of non-covalent interactions. Our findings go beyond state-of-the-art (multi)stimuli-responsive systems and allow us to draw up design guidelines for adaptive behavior both at the molecular and supramolecular levels, which are fundamental criteria for the realization of intelligent matter.

Background: Migration-related factors, such as language barriers, can be relevant to the risk, healthcare and complications of type 2 diabetes in people with a history of migration. Diabetes-related data from people with selected citizenships were analysed on the basis of the nationwide survey German Health Update: Fokus (GEDA Fokus). Methods: The diabetes risk of persons without diabetes (n = 4,698, 18 – 79 years), key figures on healthcare and secondary diseases of persons with type 2 diabetes (n = 326, 45 – 79 years) and on concomitant diseases (n = 326 with type 2 diabetes compared to n = 2,018 without diabetes, 45 – 79 years) were stratified according to sociodemographic and migration-related characteristics. Results: Better German language proficiency is associated with a lower risk of diabetes. Diabetes-related organ complications are observed more frequently in persons who report experiences of discrimination in the health or care sector. Both persons with and without diabetes are more likely to have depressive symptoms when they reported experiences of discrimination. A stronger sense of belonging to the society in Germany is associated with reporting depressive symptoms less often in people without diabetes, but not in people with type 2 diabetes. Conclusions: The differences according to migration-related characteristics indicate a need for improvement in the prevention and care of type 2 diabetes. Migration-sensitive indicators should be integrated into the surveillance of diabetes.

Background: The nationwide study German Health Update (GEDA) 2021/2022-Diabetes was conducted to assess the current healthcare and health situation of adults with diabetes in Germany. Methods: GEDA 2021/2022-Diabetes comprises a sample of adults with diagnosed diabetes from the general population. The analysis focuses on adults aged 45 years and over with type 2 diabetes (N = 1,448) and provides selected indicators on diabetes care as well as mental, social and general health. Results: 87.5 % of participants aged 45 years and over with type 2 diabetes are treated with blood glucose-lowering medication. 36.5 % receive insulin alone or in combination with other antidiabetics; 0.7 % use an insulin pump. Almost 96 % had an HbA1c measurement in the last year and about two thirds each report annual foot and eye examinations, participation in a diabetes self-management education programme and self-monitoring of their feet and of blood glucose (12.0 % with continuous glucose monitoring). On average, the quality of diabetes care is perceived as moderate. 23.8 % rate their mental health as excellent/very good. More than a tenth each have anxiety or depressive symptoms and feelings of loneliness. Half rate their general health as very good/good. Conclusions: There is a potential for improvement in the quality of diabetes care and the mental and physical health of adults with type 2 diabetes.

Abstract Background Micro- and macrovascular diseases are common in patients with type 2 diabetes mellitus (T2D) and may be partly caused by nocturnal hypoxemia. The study aimed to characterize the composition of nocturnal hypoxemic burden and to assess its association with micro- and macrovascular disease in patients with T2D. Methods This cross-sectional analysis includes overnight oximetry from 1247 patients with T2D enrolled in the DIACORE (DIAbetes COhoRtE) study. Night-time spent below a peripheral oxygen saturation of 90% (T90) as well as T90 associated with non-specific drifts in oxygen saturation (T90non − specific), T90 associated with acute oxygen desaturation (T90desaturation) and desaturation depths were assessed. Binary logistic regression analyses adjusted for known risk factors (age, sex, smoking status, waist-hip ratio, duration of T2D, HbA1c, pulse pressure, low-density lipoprotein, use of statins, and use of renin-angiotensin-aldosterone system inhibitors) were used to assess the associations of such parameters of hypoxemic burden with chronic kidney disease (CKD) as a manifestation of microvascular disease and a composite of cardiovascular diseases (CVD) reflecting macrovascular disease. Results Patients with long T90 were significantly more often affected by CKD and CVD than patients with a lower hypoxemic burden (CKD 38% vs. 28%, p

Abstract Background Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy. Methods We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U‐13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level. Results The metabolomics analysis in myotubes revealed insulin‐like growth factor‐1 (IGF‐1)‐induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose‐5‐phosphate/ribulose‐5‐phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: −36.8%; P = 0.009). Like the hypertrophy stimulation with IGF‐1 in myotubes in vitro, the concentration of the dipeptide l‐carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose‐6‐phosphate, fructose‐6‐phosphate or glucose‐1‐phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF‐1‐stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U‐13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non‐essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Agricultural land use and management fundamentally impacts the condition of natural resources like waterbodies, soils, and biodiversity. Modelling the anthropogenic effects on those resources over time requires detailed knowledge of the temporal and spatial distribution of crops. However, currently available crop type maps for Europe either lack the required spatial resolution or the temporal and spatial coverage. We develop and apply a probabilistic, spatially explicit crop type mapping approach that is suitable for ex-post and ex-ante modelling. The approach allows to quantify epistemic and aleatoric uncertainty related to estimated crop shares by providing an ensemble of maps. We implement the method for the EU-28 for the years 2010 – 2020, distinguishing between 28 different crop types at 1 km resolution. Based on a model of the data generating process that conceptually links field-, grid cell- and region-level crop acreages, our approach considers soil, climate, and topography information, as well as administrative data. The validation with ground-truthing data for France indicates that the generated crop type maps are plausible. The provided uncertainty intervals capture differences in uncertainty across space and time and correctly identify grid cells and crops where estimations are less precise. The generated maps constitute a unique data product of high practical value, e.g., for agri-environmental modelling applications. We see additional potential in using the approach to disaggregate the regional or national predictions of socio-economic ex-ante prediction models.

Background: Per-and polyfluoroalkyl substances (PFAS) contamination may disrupt sleep through disrupted metabolic and immune functions. The study aims to investigate the association and potential mechanism between PFAS and sleep. Methods: We included 136 young adults recruited between 2014-2018 and 76 were re-assessed between 2020-2022. Additional 8 participants only had complete data between 2020-2022. Plasma PFAS (PFOS, PFOA, PFHxS, PFHpS, PFPeS, PFNA, PFDA) were measured at both visits using liquid-chromatography high-resolution mass spectrometry. Plasma proteins were measured by Olink® Explore 384 Cardiometabolic and Inflammation Panel I. Sleep duration was self-reported at both visits along with follow-up sleep disturbance and sleep-related impairment using validated instruments. We utilized multiple linear regression to explore the association between individual PFAS (in tertile) and these sleep outcomes. PFAS associated with sleep outcomes were subjected to computational toxicology analysis using the Comparative Toxicogenomics Database and Toxicology in the 21st Century database to identify potential genetic links between them. Mediation analysis using proteomic data was then performed to confirm the findings from computational toxicology analysis. Results: At baseline, one tertile increase in PFDA was associated with 0.39 (95 % CI: 0.05, 0.73) hours of shorter nightly sleep duration, and, at follow-up, PFHxS and PFOA were associated with 0.39 (95 % CI: 0.05, 0.72) and 0.32 (95 % CI: 0.01, 0.63) hours shorter sleep duration, respectively. One tertile increase in PFOS exposure was associated with a 2.99-point increase in sleep disturbance scores (95 % CI: 0.67, 5.31) and a 3.35-point increase in sleep-related impairment scores (95 % CI: 0.51, 6.20). Computational toxicology and mediation analyses identified potential mediating roles for several proteins in the PFAS-sleep associations, including 11-beta-dehydrogenase isozyme 1 (HSD11B1), cathepsin B (CTSB) and several immune system-related proteins. Conclusion: Future large scale epidemiological and mechanistic studies should confirm our findings and test effect measure modification of the associations by age.

Background & Aims: Chronic HBV infection is the leading cause of liver disease and of hepatocellular carcinoma. The improvement of antiviral therapy remains an unmet medical need. Capsid assembly modulators (CAMs) target the HBV core antigen (HBc) and inhibit HBV replication. Although CAM-A compounds are well-known inducers of aberrant viral capsid aggregates, their mechanisms of action in HBV-hepatocyte interactions are poorly understood. Recently, we demonstrated that CAM-A molecules lead to a sustained reduction of HBsAg in the serum of HBV replicating mice and induce HBc aggregation in the nucleus of HBc-expressing cells leading to cell death. Methods: The mechanism of action by which CAM-A compounds induce cell death was investigated using an HBV infection model, HBc-overexpressing HepG2-NTCP cells, primary human hepatocytes, and HBV replicating HepAD38 cells. Results: We first confirmed the decrease in HBsAg levels associated with CAM-A treatment and the induction of cell toxicity in HBV-infected differentiated HepaRG cells. Next, we showed that CAM-A-mediated nuclear aggregation of HBc was associated with cell death through the activation of apoptosis. Transcriptomic analysis was used to investigate the mechanism of action driving this phenotype. CAM-A-induced HBc nuclear aggregation led to the upregulation of ANXA1 expression, a documented driver of apoptosis. Finally, silencing of ANXA1 expression delayed cell death and apoptosis in CAM-A-treated cells, confirming its direct involvement in CAM-A-induced cell death. Conclusions: Our results unravel a previously undiscovered mechanism of action involving CAM-As and open the door to new therapeutic strategies involving CAM to achieve a functional cure in patients with chronic infections. Impact and implications:: Chronic HBV infection is a global health threat. To date, no treatment achieves viral clearance in chronically infected patients. In this study, we characterized a new mechanism of action of an antiviral molecule targeting the assembly of the viral capsid (CAM). The study demonstrated that a CAM subtype, CAM-A-induced formation of aberrant structures from HBV core protein aggregates in the nucleus leading to cell death by ANXA1-driven apoptosis. Thus, CAM-A treatment may lead to the specific elimination of HBV-infected cells by apoptosis, paving the way to novel therapeutic strategies for viral cure.

Abstract Chronic hepatitis B (CHB) is a major global health challenge. CHB can be controlled by antivirals but a therapeutic cure is lacking. CHB is characterized by limited HBV-specific T cell reactivity and functionality and expression of inhibitory receptors. The mechanisms driving these T cell phenotypes are only partially understood. Here, we created a single-cell RNA-sequencing dataset of HBV immune responses in patients to contribute to a better understanding of the dysregulated immunity. Blood samples of a well-defined cohort of 21 CHB and 10 healthy controls, including a subset of 5 matched liver biopsies, were collected. scRNA-seq data of total immune cells (55,825) plus sorted HBV-specific (1,963), non-naive (32,773) and PD1+ T cells (96,631) was generated using the 10X Genomics platform (186,123 cells) or the full-length Smart-seq2 protocol (1,069 cells). The shared transcript count matrices of single-cells serve as a valuable resource describing transcriptional changes underlying dysfunctional HBV-related T cell responses in blood and liver tissue and offers the opportunity to identify targets or biomarkers for HBV-related immune exhaustion.

Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

This article examines the extent to which normative beliefs on acculturation constitute (a) individual resources and risk factors for adolescents facing developmental tasks and (b) institutional norms that define developmental milieus in secondary schools. To what extent do egalitarianism, multiculturalism, assimilationism, and segregationism help or hinder academic and psychosocial adjustment in mid-adolescence? We examined how both individually endorsed beliefs and socially shared beliefs at the 10th-grade cohort level relate to students' academic performance, educational and occupational aspirations, motivational and emotional attachment to school, self-esteem, and life satisfaction. Data came from a random sample of 15- to 17-year-olds in Berlin, Germany, assessed at the end of Grades 9 and 10 (N = 1,992). Multivariate analyses identified egalitarianism and multiculturalism as the most prevalent acculturation beliefs, forming a combined belief pattern that pairs recognition of equality with respect for diversity. At the individual level, this belief pattern was positively related to academic and psychosocial adjustment. Assimilationism beliefs were associated with higher motivational and emotional attachment to school in both minority and majority students. Segregationism beliefs were associated with higher self-esteem in all adolescents regardless of background, but with lower levels of academic performance in immigrant youth. At the grade cohort level, a single bipolar factor (egalitarianism/multiculturalism vs. assimilationism/segregationism) described the institutional diversity culture. An environment characterized by egalitarianism/multiculturalism beliefs was positively associated with motivational and emotional attachment to school but not related to academic adjustment or psychological well-being.

Vocational education and training (VET) is a common form of upper secondary school tracking in countries around the world. There are ongoing debates regarding the effects of this differentiation on academic and labor market outcomes; however, evidence on civic outcomes is lacking. Using a unique cohort study in Germany (N = 2461) and a doubly robust weighting approach with a rich set of baseline covariates to address selection bias, we estimated the effects of VET (relative to academic upper secondary school) on political interest, internal political efficacy, and intent to vote across 15 years of late adolescence and early adulthood. We estimated negative effects of VET on these civic outcomes, particularly as participants grew older. Implications for future research and VET policy are discussed.

Yong Du,1 Jens Baumert,1 Stefan Damerow,1 Alexander Rommel,1 Hannelore Neuhauser,1,2 Christin Heidemann1 1Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin, Germany; 2German Centre for Cardiovascular Research (DZHK), Berlin, GermanyCorrespondence: Yong Du, Department of Epidemiology and Health Monitoring, Robert Koch Institute, General-Pape-Str. 62-66, Berlin, D-12101, Germany, Tel +49-30-18754 3199, Fax +49 − 30-18754 3211, Email duy@rki.dePurpose: Fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and lockdown measures may have an impact on health care utilization particularly for people with chronic diseases. We investigated changes in outpatient utilization behavior in pandemic phases among people with selected chronic diseases in Germany.Methods: The nationwide population-based telephone surveys German Health Update (GEDA) 2019/2020 (April 2019 to September 2020) and GEDA 2021 (July to December 2021) covered 4 out of 7 pandemic phases from the pre-pandemic to the 4th pandemic wave. Data on hypertension, diabetes and major cardiovascular diseases (CVD) in the past 12 months and visiting a general practitioner (GP) or a specialist (excluding dentist) in the past 4 weeks was collected using a standardized questionnaire. Proportions and odds ratios were derived from logistic regression models adjusted for age, sex, education and federal states.Results: Among 27,967 participants aged ≥ 16 years, 8,449, 2,497 and 1,136 individuals had hypertension, diabetes and major CVD. Participants with these chronic diseases visited a GP or specialist significantly more often than the overall study population, irrespective of pandemic phases. Compared to the pre-pandemic phase, a significant reduction in specialist-visiting was found in the first pandemic wave among people with hypertension (34.3% vs 24.1%), diabetes (39.5% vs 25.5%) and major CVD (41.9% vs 25.6%). GP-visiting was lower only among people with hypertension (53.0% vs 46.0%). No difference in GP or specialist visiting was found in the 4th pandemic wave compared to the pre-pandemic phase.Conclusion: The observed decrease particularly in specialist utilization among people with the selected chronic diseases at the beginning of the pandemic was not observed for the second half of 2021 despite the ongoing pandemic. Further studies are required to examine whether the temporary changes in the utilization of ambulatory health care have affected the disease management of people with chronic diseases.Keywords: health service utilization, outpatients, SARS-CoV-2, chronic disease, cardiometabolic diseases, diabetes, Germany

Abstract Aims This study aimed to assess the effectiveness of adaptive servo‐ventilation (ASV) for lowering hypoxaemic burden components in heart failure with reduced ejection fraction (HFrEF) patients. Methods and results Fifty‐six stable HFrEF patients with left ventricular ejection fraction ≤ 40 were randomized to receive either ASV (n = 27; 25 males) or optimal medical management or optimal medical management alone (n = 29; 26 males). Patients underwent overnight polysomnography at baseline and a 12 week follow‐up visit. We quantified hypoxaemic as time spent at