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Highlights
• Currently, China has the most publications, ahead of the USA and European countries.
• Research focuses are strictly separated into ecological and material science topics.
• Russia and Ukraine are among the frontrunners with a clear focus on materials science.
• The focus in PFAS research is shifting toward ecological issues.
• A national imbalance can be observed that leaves the low economies behind.
Abstract
The European Commission's current efforts to launch the largest proposal to restrict per- and polyfluoroalkyl substances (PFAS) in history reflect the dire global plight of PFAS accumulation in the environment and their health impacts. While there are existing studies on PFAS research, there is a lack of comprehensive analysis that both covers the entire research period and provides deep insights into global research patterns, incentives, and barriers based on various parameters. We have been able to demonstrate the increasing interest in PFAS research, although citation numbers are declining prematurely. Policy regulations based on proving and establishing the toxicity of PFASs have stimulated research in developed countries and vice versa, with increasing emphasis on ecological aspects. China, in particular, is investing increasingly in PFAS research, but without defining or implementing regulations - with devastating effects. The separation of industrial and environmental research interests is clear, with little involvement of developing countries, even though their exposure to PFAS is devastating. It, therefore, requires increased globally networked and multidisciplinary approaches to address PFAS contamination challenges.
Highlights
• High resolution profile of C. pipiens' sugar diet has been obtained using UHPLC-MS.
• Artificial feeding using ornamental plants provides similar sugar profiles as observed in field collected mosquitoes.
• Metabolomic profiling found secondary metabolites and pollutants of anthropogenic use.
Abstract: Culex pipiens (Linnaeus, 1758) mosquitoes search plant sources of sugars to cope with the energetic demand of various physiological processes. The crop as part of the digestive system is devoted to the storage of sugar-based meal obtained from various nectars sources. The profiling of sugars and metabolites in the Culex pipiens’ crop is scarce, and only few studies used Liquid Chromatography – Mass Spectrometry (LC-MS), which provides broad detection for biomonitoring environmental substances and even contaminants in the sugar diet of mosquitoes populations.
Therefore, sugar and metabolite profiling were performed on crops obtained from mosquitoes exposed to plant nectar under laboratory or natural conditions by Ultra High-Performance LC-MS (UHPLC-MS). This method allowed us a precise quantitative and qualitative identification of sugar diet and associated environmental compounds in the crop of the mosquito C. pipiens. Under laboratory condition, mosquitoes were allowed to feed on either glucose solution, commercially-available flowers or field collected flowers. In addition, we collected mosquitoes from the field to compare those crop metabolomes with metabolome patterns occurring after nectar feeding in the lab.
The sugar quantities and quality obtained from the crops of mosquitoes collected in the field were similar to those crops obtained from mosquitoes that fed on commercially-available flowers and from field collected flowers with a limit of detection of 10 μg/L for sucrose, glucose and sucrose. Next to sugar compounds, we identified 2 types of amino acids, 12 natural products, and 9 pesticides.
Next to the diversity of sugar compounds, we could confirm that secondary metabolites and environmental pollutants are typically up taken from floral nectar sources by C. pipiens. The in-depth knowledge on mosquito–plant interactions may inspire the development and further optimization of mosquito trap systems and arboviral surveillance systems.
We provide in this paper a comprehensive comparison of various transfer learning strategies and deep learning architectures for computer-aided classification of adult-type diffuse gliomas. We evaluate the generalizability of out-of-domain ImageNet representations for a target domain of histopathological images, and study the impact of in-domain adaptation using self-supervised and multi-task learning approaches for pretraining the models using the medium-to-large scale datasets of histopathological images. A semi-supervised learning approach is furthermore proposed, where the fine-tuned models are utilized to predict the labels of unannotated regions of the whole slide images (WSI). The models are subsequently retrained using the ground-truth labels and weak labels determined in the previous step, providing superior performance in comparison to standard in-domain transfer learning with balanced accuracy of 96.91% and F1-score 97.07%, and minimizing the pathologist's efforts for annotation. Finally, we provide a visualization tool working at WSI level which generates heatmaps that highlight tumor areas; thus, providing insights to pathologists concerning the most informative parts of the WSI.
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
Highlights
• TAM polarization induces CP RNA.
• CP RNA expression is regulated by HIF-2 and STAT1.
• CP RNA is transferred from TAMs to HT1080 cells.
• CP RNA is translated by HT1080 cells and protects from ferroptosis.
• Co-cultured HT1080 cells decrease iron and lipid peroxidation.
Abstract
Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
Beyond well-established difficulties with working memory in individuals with attention deficit hyperactivity disorder (ADHD), evidence is emerging that other memory processes may also be affected. We investigated, first, which memory processes show differences in adults and adolescents with ADHD in comparison to control participants, focusing on working and short-term memory, initial learning, interference, delayed and recognition memory. Second, we investigated whether ADHD severity, co-occurring depressive symptoms, IQ and physical fitness are associated with the memory performance in the individuals with ADHD.
We assessed 205 participants with ADHD (mean age 25.8 years, SD 7.99) and 50 control participants (mean age 21.1 years, SD 5.07) on cognitive tasks including the digit span forward (DSF) and backward (DSB), the Rey Auditory Verbal Learning Test (RAVLT), and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Participants with ADHD were additionally assessed on ADHD severity, depression symptoms and cardiorespiratory fitness. A series of regressions were run, with sensitivity analyses performed when variables were skewed.
ADHD-control comparisons were significant for DSF, DSB, delayed and recognition memory, with people with ADHD performing less well than the control participants. The result for recognition memory was no longer significant in sensitivity analysis. Memory performance was not associated with greater ADHD or depression symptoms severity. IQ was positively associated with all memory variables except DSF. Cardiorespiratory fitness was negatively associated with the majority of RAVLT variables.
Individuals with ADHD showed difficulties with working memory, short-term memory and delayed memory, as well as a potential difficulty with recognition memory, despite preserved initial learning.
Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based protein degraders has evolved over the past two decades and has now established molecular tags that are already in clinical use, as well as chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for the two E3 ligases CRBN and VHL. The large size of the human E3 ligase family suggests that PROTACs can be developed by targeting a large diversity of E3 ligases, some of which have restricted expression patterns with the potential to design disease- or tissue-specific degraders. Indeed, many new E3 ligands have been published recently, confirming the druggability of E3 ligases. This review summarises recent data on E3 ligases and highlights the challenges in developing these molecules into efficient PROTACs rivalling the established degrader systems.
PET probes targeting fibroblasts are frequently used for varying applications in oncology. In recent years, the clinical spectrum has been expanded towards cardiovascular medicine, e.g., after myocardial infarction, in aortic stenosis or as a non-invasive read-out of atherosclerosis. We herein provide a brief overview of the current status of this PET radiotracer in the context of cardiovascular disease, including translational and clinical evidence. In addition, we will also briefly discuss future applications, e.g., the use of fibroblast-targeting PET to investigate bilateral organ function along the cardiorenal axis.
Highligthts
• Marburg virus infects and replicates in primary human proximal tubular cells (PTC).
• Transcriptome analyses at multiple time points revealed a profound inflammatory response by IFNα, -y and TNFα signaling.
• Among the strongly downregulated gene sets were targets of the transcription factors MYC and E2F, the G2M checkpoint, as well as oxidative phosphorylation.
• Importantly, the downregulated factors comprise PGC-1α, a key factor in mitochondrial biogenesis and renal energy homeostasis, to be substantially downregulated in MARV-infected PTC.
• Our results suggest inflammation-induced changes in tubular energy metabolism as a possible factor in MARV-associated tubular dysfunction.
Abstract
Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90 %. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 h post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response.
Background: Urachal cancer (UrC) is a rare disease with limited availability of representative incidence and clinical data. Although, the prevalence is accounting for less than 1% of bladder tumors, the 5-year survival rate is around only 50% for patients with resectable tumors, and even worse for patients with metastatic disease. Due to the lack of comprehensive prospective studies, our current knowledge of UrC is still limited.
Objective: The present study aimed to summarize the available registry-based studies with unselected UrC patients to evaluate its incidence and clinicopathological characteristics.
Material and methods: We conducted a systematic literature search of registry-based UrC publications on the 15th of May 2023 in 5 databases, which identified 4,748 publications. After duplicate removal and selection by 2 independent investigators, 6 publications proved to be appropriate for the final meta-analysis. Estimated incidence and clinicopathological parameters were extracted.
Results: Estimated incidence ranged between 0.022 and 0.060/ 100.000 person-years, with the highest occurrence in Japan and the lowest in Canada, while the random effect model calculated an overall incidence rate of 0.04 (95%CI: 0.03–0.05) 100.000 person-years. The median age at first diagnosis was 60 years (range: 58–64). The female to male ratio was 2:3. Lymph node or distant metastases were present in 9% and 14% of patients. The predominant tumour type was adenocarcinoma (86%) followed by urothelial carcinoma (12%) and squamous cell carcinoma (2%). The 5-year survival rate was 51.0% with 95%CI: 45.2–57.4.
Conclusions: Our study provides an up-to-date comparison of estimated incidence rates between 6 countries of 3 continents based on rigorously selected registry-based studies. The results suggest low incidence rates for UrC with considerable geographic differences. The present meta-analysis provides unbiased registry-based data on the incidence, clinicopathological parameters and survival of UrC.
Understanding the underlying mechanisms that link psychopathology and physical comorbidities in schizophrenia is crucial since decreased physical fitness and overweight pose major risk factors for cardio-vascular diseases and decrease the patients’ life expectancies. We hypothesize that altered reward anticipation plays an important role in this. We implemented the Monetary Incentive Delay task in a MR scanner and a fitness test battery to compare schizophrenia patients (SZ, n = 43) with sex- and age-matched healthy controls (HC, n = 36) as to reward processing and their physical fitness. We found differences in reward anticipation between SZs and HCs, whereby increased activity in HCs positively correlated with overall physical condition and negatively correlated with psychopathology. On the other handy, SZs revealed stronger activity in the posterior cingulate cortex and in cerebellar regions during reward anticipation, which could be linked to decreased overall physical fitness. These findings demonstrate that a dysregulated reward system is not only responsible for the symptomatology of schizophrenia, but might also be involved in physical comorbidities which could pave the way for future lifestyle therapy interventions.
Highlights
• CD62p + exosomes were significantly increased in septic polytrauma-patients, while CD40+, as well as CD49e + exosomes were diminished.
• Exosomal IL-6 concentration in septic patients reflects the systemic IL-6.
• Exosomal IL-10 concentration seemed to be constant in patients and healthy controls.
• Decrease of miR-21 in exosomes was associated with the development of sepsis, while exosomal miR-93, miR-155 and miR-92a were not specifically altered.
Abstract
Sepsis as a severe systemic inflammation leads oftentimes to organ dysfunction and subsequently to death. In polytrauma patients, septic complications represent with 45% the predominant cause of late death and are responsible for extremely high costs in the healthcare system. Therefore, clinicians have to detect as early as possible the begin of sepsis to improve the patient's outcome. One new promising diagnostic tool to diagnose septic complications in polytraumatized patients are exosomes.
Plasma samples from polytraumatized patients (Injury Severity Score (ISS) ≥16) which developed sepsis (n = 10) and without sepsis (n = 10), were collected at emergency room (ER), 24h and 5 days after trauma. The EVs subpopulations were investigated by a bead-based multiplex flow cytometry measurement of surface epitopes and were compared with plasma EVs from healthy controls (n = 10). Moreover, exosomal cytokine concentrations were measured via high-sensitive ELISA and were correlated with systemic concentrations. For miRNA cargo analysis, we analysed the miRNAs miR-1298-5p, miR-1262, miR-125b-5p, miR-92a-3p, miR-93-5p, miR-155-5p and miR-21-5p and compared their exosomal concentrations by means of RT-qPCR.
CD62p + exosomes were significantly increased in septic polytrauma-patients (p ≤ 0.05), while CD40+exosomes, as well as CD49e + exosomes were diminished (p ≤ 0.05). Furthermore, we observed that the exosomal IL-6 concentration reflects the systemic IL-6 concentration (r2 = 0.63) and did not significantly alter between patients with and without sepsis. The exosomal IL-10 concentration seemed to be constant in all patients and healthy controls. We observed that a decrease of miR-21-5p in exosomes was associated with the development of sepsis (p ≤ 0.05), while exosomal miR-93-5p, miR-155-5p and miR-92a-3p were not specifically altered in septic patients.
Taken together, the present study in polytraumatized patients demonstrated that the development of sepsis is associated with an increase of CD62p + exosomes. Furthermore, the exosomal cargo was changed in septic patients: miR-21-5p was diminished.
Highlights
• Artificial intelligence systems for mechanically ventilated patients are increasing.
• The clinical and financial impact of these models are often unexamined.
• We developed a generic health-economic model for artificial intelligence systems.
• This model assesses the cost-effectiveness for many different scenarios.
• The developed framework is easily adjustable to other (clinical) situations.
Abstract
Purpose: The health and economic consequences of artificial intelligence (AI) systems for mechanically ventilated intensive care unit patients often remain unstudied. Early health technology assessments (HTA) can examine the potential impact of AI systems by using available data and simulations. Therefore, we developed a generic health-economic model suitable for early HTA of AI systems for mechanically ventilated patients.
Materials and methods: Our generic health-economic model simulates mechanically ventilated patients from their hospitalisation until their death. The model simulates two scenarios, care as usual and care with the AI system, and compares these scenarios to estimate their cost-effectiveness.
Results: The generic health-economic model we developed is suitable for estimating the cost-effectiveness of various AI systems. By varying input parameters and assumptions, the model can examine the cost-effectiveness of AI systems across a wide range of different clinical settings.
Conclusions: Using the proposed generic health-economic model, investors and innovators can easily assess whether implementing a certain AI system is likely to be cost-effective before an exact clinical impact is determined. The results of the early HTA can aid investors and innovators in deployment of AI systems by supporting development decisions, informing value-based pricing, clinical trial design, and selection of target patient groups.
Background: Trauma-related guilt and shame are crucial for the development and maintenance of PTSD (posttraumatic stress disorder). We developed an intervention combining cognitive techniques with loving-kindness meditations (C-METTA) that specifically target these emotions. C-METTA is an intervention of six weekly individual treatment sessions followed by a four-week practice phase.
Objective: This study examined C-METTA in a proof-of-concept study within a randomized wait-list controlled trial.
Method: We randomly assigned 32 trauma-exposed patients with a DSM-5 diagnosis to C-METTA or a wait-list condition (WL). Primary outcomes were clinician-rated PTSD symptoms (CAPS-5) and trauma-related guilt and shame. Secondary outcomes included psychopathology, self-criticism, well-being, and self-compassion. Outcomes were assessed before the intervention phase and after the practice phase.
Results: Mixed-design analyses showed greater reductions in C-METTA versus WL in clinician-rated PTSD symptoms (d = −1.09), guilt (d = −2.85), shame (d = −2.14), psychopathology and self-criticism.
Conclusion: Our findings support positive outcomes of C-METTA and might contribute to improved care for patients with stress-related disorders. The study was registered in the German Clinical Trials Register (DRKS00023470).
HIGHLIGHTS
C-METTA is an intervention that addresses trauma-related guilt and shame and combines cognitive interventions with loving-kindness meditations.
A proof-of-concept study was conducted examining C-METTA in a wait-list randomized controlled trial
C-METTA led to reductions in trauma-related guilt and shame and PTSD symptoms.
Background: Despite known clinical benefits, guideline-recommended heart rate (HR) control is not achieved for a significant proportion of patients with HF with reduced ejection fraction. The wearable cardioverter-defibrillator (WCD) provides continuous HR monitoring and alerts that could aid medication titration.
Objective: This study sought to evaluate sex differences in achieving guideline-recommended HR control during a period of WCD use.
Methods: Data from patients fitted with a WCD from 2015 to 2018 were obtained from the manufacturer’s database (ZOLL). The proportion of patients with adequate nighttime resting HR control at the beginning of use (BOU) and at the end of use (EOU) were compared by sex. Adequate HR control was defined as having a nighttime median HR <70 beats/min.
Results: A total of 21,440 women and a comparative sample of 17,328 men (median 90 [IQR 59–116] days of WCD wear) were included in the final dataset. Among patients who did not receive a shock, over half had insufficient HR control at BOU (59% of women, 53% of men). Although the proportion of patients with resting HR ≥70 beats/min improved by EOU, 43% of women and 36% of men did not achieve guideline-recommended HR control.
Conclusion: A significant proportion of women and men did not achieve adequate HR control during a period of medical therapy optimization. Compared with men, a greater proportion of women receiving WCD shocks had insufficiently controlled HR in the week preceding ventricular tachyarrhythmia/ventricular fibrillation and 43% of nonshocked women, compared with 36% of men, did not reach adequate HR control during the study period. The WCD can be utilized as a remote monitoring tool to record HR and inform adequate uptitration of beta-blockers, with particular focus on reducing the treatment gap in women.
Evidence-based and comprehensible health information is a key element of evidence-based medicine and public health. The goal is informed decision-making based on realistic estimations of health risks and accurate expectations about benefits and harms of interventions. In Germany, standards of evidence-based risk information were poorly followed during the COVID-19 pandemic. Frequently, public information was biased, fragmentary and misleading. Pandemic-related threat scenarios induced emotional distress and unnecessary anxiety. A systematic and comprehensive evaluation of the pandemic measures is crucial, but still pending in Germany. A critical analysis of risk communication by experts, politicians and the media during the pandemic should be a key element of the evaluation process. Evaluation of decision making and media reporting during the pandemic should improve preparedness for future crises.
The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification. Main problem in this context is that compounds with very low solubility and slow intrinsic dissolution in the intestinal environment will cause significant bioavailability problems if their solid oral dosage forms are emptied from the stomach undisintegrated. Also very low plasma profiles may result under these circumstances. Such cases can occur accidentally and are not resultant of non-compliance. Thus, limitation for one case per study only as suggested in the guideline is not justified.
Lifestyle factors—such as diet, physical activity (PA), smoking, and alcohol consumption—have a significant impact on mortality as well as healthcare costs. Moreover, they play a crucial role in the development of type 2 diabetes mellitus (DM2). There also seems to be a link between lifestyle behaviours and insulin resistance, which is often a precursor of DM2. This study uses an enhanced Healthy Living Index (HLI) integrating accelerometric data and an Ecological Momentary Assessment (EMA) to explore differences in lifestyle between insulin-sensitive (IS) and insulin-resistant (IR) individuals. Moreover, it explores the association between lifestyle behaviours and inflammation. Analysing data from 99 participants of the mPRIME study (57 women and 42 men; mean age 49.8 years), we calculated HLI scores—ranging from 0 to 4— based on adherence to specific low-risk lifestyle behaviours, including non-smoking, adhering to a healthy diet, maximally moderate alcohol consumption, and meeting World Health Organization (WHO) PA guidelines. Insulin sensitivity was assessed using a Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) levels were used as a proxy for inflammation. Lifestyle behaviours, represented by HLI scores, were significantly different between IS and IR individuals (U = 1529.0; p = 0.023). The difference in the HLI score between IR and IS individuals was mainly driven by lower adherence to PA recommendations in the IR group. Moreover, reduced PA was linked to increased CRP levels in the IR group (r = −0.368, p = 0.014). Our findings suggest that enhancing PA, especially among individuals with impaired insulin resistance, holds significant promise as a preventive strategy.
Highlights
• NCoR1 is the most highly expressed endothelial corepressor.
• Loss of NCoR1 promotes angiogenic function in endothelial cells.
• Loss of NCoR1 promotes a tip cell position during angiogenic sprouting.
Abstract
Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCOR1 promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCOR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
Highlights
• Since there is only a low level of evidence, it is difficult to agree on state-of-the-art standards or to provide recommendations and guidelines.
• The value of combining several monitoring devices for dual or triple guidance must be challenged.
• The principle of fascial plane blocks is suitable to avoid traumatic needle-to-nerve contact. However, local toxicity must be regarded as a possible mechanism for nerve injuries.
• Block procedures might be conducted during sedation or general anesthesia when considering the individual patients' clinical situations and the expertise of the anesthesiologist.
• The quality of ultrasound equipment and education provided by the corresponding anesthesia department is highly relevant
Highlights
• Out of the six edible pumpkin seeds found in Cameroonian C. sativus showed most potent anti-proliferative effects on prostate cells.
• Its oil conserved almost all the effects of raw seeds and prevented benign prostatic hyperplasia (BPH).
• It exhibited potent anti-inflammatory activities in rat with BPH.
Abstract
Pumpkin seeds are claimed to treat prostate tumour/cancer. The in vitro (ability to inhibit cell growth through MTT assay) and in vivo (ability to prevent testosterone-induced BPH in rats at the doses of 125, 250, 500 and 1000 mg/kg BW) of six edible pumpkin seeds found in Cameroonian were assessed. The endpoints were cell growth arrest, prostate mass and volume, prostatic epithelium height, prostatic proteins, prostate specific antigen (PSA) and inflammatory cytokines. In vitro, C. sativus seeds exhibited the most potent antiproliferative effects on DU145 and PC3 prostate cancer cells and its oil conserved almost all the effects of raw seeds. Further, it prevented the increased of prostate relative mass and volume, prostate epithelium height, PSA and testosterone dose-dependently compared to normal rats. This effect is thought to be mediated through antiandrogenic, estrogenic and anti-inflammatory activities, evidenced by a decreased in IL-1β, IL-6 and TNFα level. Overall, this results justify its traditional use.
Viruses that carry a positive-sense, single-stranded (+ssRNA) RNA translate their genomes soon after entering the host cell to produce viral proteins, with the exception of retroviruses. A distinguishing feature of retroviruses is reverse transcription, where the +ssRNA genome serves as a template to synthesize a double-stranded DNA copy that subsequently integrates into the host genome. As retroviral RNAs are produced by the host cell transcriptional machinery and are largely indistinguishable from cellular mRNAs, we investigated the potential of incoming retroviral genomes to directly express proteins. Here we show through multiple, complementary methods that retroviral genomes are translated after entry. Our findings challenge the notion that retroviruses require reverse transcription to produce viral proteins. Synthesis of retroviral proteins in the absence of productive infection has significant implications for basic retrovirology, immune responses and gene therapy applications.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Rationale and Objectives: Lumbar disk degeneration is a common condition contributing significantly to back pain. The objective of the study was to evaluate the potential of dual-energy CT (DECT)-derived collagen maps for the assessment of lumbar disk degeneration.
Patients and Methods: We conducted a retrospective analysis of 127 patients who underwent dual-source DECT and MRI of the lumbar spine between 07/2019 and 10/2022. The level of lumbar disk degeneration was categorized by three radiologists as follows: no/mild (Pfirrmann 1&2), moderate (Pfirrmann 3&4), and severe (Pfirrmann 5). Recall (sensitivity) and accuracy of DECT collagen maps were calculated. Intraclass correlation coefficient (ICC) was used to evaluate inter-reader reliability. Subjective evaluations were performed using 5-point Likert scales for diagnostic confidence and image quality.
Results: We evaluated a total of 762 intervertebral disks from 127 patients (median age, 69.7 (range, 23.0–93.7), female, 56). MRI identified 230 non/mildly degenerated disks (30.2%), 484 moderately degenerated disks (63.5%), and 48 severely degenerated disks (6.3%). DECT collagen maps yielded an overall accuracy of 85.5% (1955/2286). Recall (sensitivity) was 79.3% (547/690) for the detection of no/mild lumbar disk degeneration, 88.7% (1288/1452) for the detection of moderate disk degeneration, and 83.3% (120/144) for the detection of severe disk degeneration (ICC = 0.9). Subjective evaluations of DECT collagen maps showed high diagnostic confidence (median 4) and good image quality (median 4).
Conclusion: The use of DECT collagen maps to distinguish different stages of lumbar disk degeneration may have clinical significance in the early diagnosis of disk-related pathologies in patients with contraindications for MRI or in cases of unavailability of MRI.
Rationale and Objectives: Bone non-union is a serious complication of distal radius fractures (DRF) that can result in functional limitations and persistent pain. However, no accepted method has been established to identify patients at risk of developing bone non-union yet. This study aimed to compare various CT-derived metrics for bone mineral density (BMD) assessment to identify predictive values for the development of bone non-union.
Materials and Methods: CT images of 192 patients with DRFs who underwent unenhanced dual-energy CT (DECT) of the distal radius between 03/2016 and 12/2020 were retrospectively identified. Available follow-up imaging and medical health records were evaluated to determine the occurrence of bone non-union. DECT-based BMD, trabecular Hounsfield unit (HU), cortical HU and cortical thickness ratio were measured in normalized non-fractured segments of the distal radius.
Results: Patients who developed bone non-union were significantly older (median age 72 years vs. 54 years) and had a significantly lower DECT-based BMD (median 68.1 mg/cm3 vs. 94.6 mg/cm3, p < 0.001). Other metrics (cortical thickness ratio, cortical HU, trabecular HU) showed no significant differences. ROC and PR curve analyses confirmed the highest diagnostic accuracy for DECT-based BMD with an area under the curve (AUC) of 0.83 for the ROC curve and an AUC of 0.46 for the PR curve. In logistic regression models, DECT-based BMD was the sole metric significantly associated with bone non-union.
Conclusion: DECT-derived metrics can accurately predict bone non-union in patients who sustained DRF. The diagnostic performance of DECT-based BMD is superior to that of HU-based metrics and cortical thickness ratio.
We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52–0.67) and 0.56 (95% CI 0.43–0.68). The relapse rate was high (PP 0.33, 95% CI 0.27–0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and “symptomatic” etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48–0.89) or corticosteroids (PP 0.72, 95% CI 0.54–0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02–0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.
Key points
* Systematic review resulting in low to moderately solid evidence on the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroid treatment in children with epilepsy other than infantile spasms.
* Meta-analysis based on aggregate data from 2 controlled prospective, 5 uncontrolled prospective, and 31 retrospective studies.
* Pooled data showing a seizure response in 60% and electroencephalography (EEG) response in 56% of patients, with no major differences between drugs. However, 30%–40% of patients relapse after the cessation of treatment.
* The most frequent adverse effects are obesity and Cushing's syndrome, occurring in 70% of patients under continuous treatment for some weeks, but in less than 10% undergoing pulsed, intermittent regimens.
* More prospective, randomized-controlled studies are needed to improve the level of evidence and define the optimal doses and treatment duration.
Abstract
The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer’s disease, bipolar disorder, and Tourette’s syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.
Highlights
Local genetic correlations found even in the absence of global correlations.
Both positive and negative local correlations found for IR-neuropsychiatric pairs.
Enrichment for immune, and insulin signalling pathways, among others.
Pinpointed shared likely causal variants within 10 genomic regions.
Identified therapeutic targets, e.g., SLC39A8 and HLA-DRB1, for drug repurposing.
Background: Dual-energy CT (DECT)-derived bone mineral density (BMD) of the distal radius and other CT-derived metrics related to bone health have been suggested for opportunistic osteoporosis screening and risk evaluation for sustaining distal radius fractures (DRFs).
Methods: The distal radius of patients who underwent DECT between 01/2016 and 08/2021 was retrospectively analyzed. Cortical Hounsfield Unit (HU), trabecular HU, cortical thickness, and DECT-based BMD were acquired from a non-fractured, metaphyseal area in all examinations. Receiver-operating characteristic (ROC) analysis was conducted to determine the area under the curve (AUC) values for predicting DRFs based on DECT-derived BMD, HU values, and cortical thickness. Logistic regression models were then employed to assess the associations of these parameters with the occurrence of DRFs.
Results: In this study, 263 patients (median age: 52 years; interquartile range: 36–64; 132 women; 192 fractures) were included. ROC curve analysis revealed a higher area under the curve (AUC) value for DECT-derived BMD compared to cortical HU, trabecular HU, and cortical thickness (0.91 vs. 0.61, 0.64, and 0.69, respectively; p <.001). Logistic regression models confirmed the association between lower DECT-derived BMD and the occurrence of DRFs (Odds Ratio, 0.83; p <.001); however, no influence was observed for cortical HU, trabecular HU, or cortical thickness.
Conclusions: DECT can be used to assess the BMD of the distal radius without dedicated equipment such as calibration phantoms to increase the detection rates of osteoporosis and stratify the individual risk to sustain DRFs. In contrast, assessing HU-based values and cortical thickness does not provide clinical benefit.
Highlights
• Single nucleotide variants (SNVs) may affect transcription factor (TF) binding
• Fast statistical approach to assess significance of differential TF binding for SNVs
• Validate new approach on in vitro and in vivo TF binding assays
• Applications on GWAS SNVs and large eQTL studies illustrate utility
Summary
Non-coding variants located within regulatory elements may alter gene expression by modifying transcription factor (TF) binding sites, thereby leading to functional consequences. Different TF models are being used to assess the effect of DNA sequence variants, such as single nucleotide variants (SNVs). Often existing methods are slow and do not assess statistical significance of results. We investigated the distribution of absolute maximal differential TF binding scores for general computational models that affect TF binding. We find that a modified Laplace distribution can adequately approximate the empirical distributions. A benchmark on in vitro and in vivo datasets showed that our approach improves upon an existing method in terms of performance and speed. Applications on eQTLs and on a genome-wide association study illustrate the usefulness of our statistics by highlighting cell type-specific regulators and target genes. An implementation of our approach is freely available on GitHub and as bioconda package.
MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3’ untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
Key Points:
* Deep profiling identifies novel targets of miR-181 associated with global gene regulation.
* miR-181 MREs in repeat elements in the coding sequence act through translational inhibition.
* High-resolution analysis reveals an alternative seed match in functional MREs.
Background: Novel treatments are needed to control refractory status epilepticus (SE). This study aimed to assess the potential effectiveness of fenfluramine (FFA) as an acute treatment option for SE. We present a summary of clinical cases where oral FFA was used in SE.
Methods: A case of an adult patient with Lennox–Gastaut syndrome (LGS) who was treated with FFA due to refractory SE is presented in detail. To identify studies that evaluated the use of FFA in SE, we performed a systematic literature search.
Results: Four case reports on the acute treatment with FFA of SE in children and adults with Dravet syndrome (DS) and LGS were available. We report in detail a 30-year-old woman with LGS of structural etiology, who presented with generalized tonic and dialeptic seizures manifesting at high frequencies without a return to clinical baseline constituting the diagnosis of SE. Treatment with anti-seizure medications up to lacosamide 600 mg/d, brivaracetam 300 mg/d, valproate 1,600 mg/d, and various benzodiazepines did not resolve the SE. Due to ongoing refractory SE and following an unremarkable echocardiography, treatment was initiated with FFA, with an initial dose of 10 mg/d (0.22 mg/kg body weight [bw]) and fast up-titration to 26 mg/d (0.58 mg/kg bw) within 10 days. Subsequently, the patient experienced a resolution of SE within 4 days, accompanied by a notable improvement in clinical presentation and regaining her mobility, walking with the assistance of physiotherapists. In the three cases reported in the literature, DS patients with SE were treated with FFA, and a cessation of SE was observed within a few days. No treatment-emergent adverse events were observed during FFA treatment in any of the four cases.
Conclusions: Based on the reported cases, FFA might be a promising option for the acute treatment of SE in patients with DS and LGS. Observational data show a decreased SE frequency while on FFA, suggesting a potentially preventive role of FFA in these populations.
Key points
* We summarize four cases of refractory status epilepticus (SE) successfully treated with fenfluramine.
* Refractory SE resolved after 4–7 days on fenfluramine.
* Swift fenfluramine up-titration was well-tolerated during SE treatment.
* Treatment-emergent adverse events on fenfluramine were not observed.
* Fenfluramine might be a valuable acute treatment option for SE in Dravet and Lennox–Gastaut syndromes.
Background: The Association of the Scientific Medical Societies in Germany (AWMF) clinical practice guideline on cochlear implant (CI) treatment, which was updated in 2020, defined the entire process of CI care for the first time. In the present study, the feasibility and results of very early rehabilitation were examined.
Materials and methods: The intervention group (IG) comprised 54 patients in whom rehabilitation was initiated within 14 (maximally 28) days after implantation. Patients with a significantly longer waiting time were included in the control group (CG, n = 21). In addition to the start and duration of rehabilitation, the speech intelligibility achieved with CI was recorded at different timepoints within a 12-month period. In addition, questionnaires were used to assess the effort of fitting the CI processor and the patients’ satisfaction with the outcome as well as the timing of the start of rehabilitation.
Results: Median waiting time between implantation and start of rehabilitation was 14 days in the IG and 106 days in the CG; 92.6% of IG patients were able to start rehabilitation within 14 days. The effect of rehabilitation in the IG was 35 and in the CG 25 percentage points (Freiburg monosyllabic test). After 6 and 12 months of CI use, both groups showed comparable results in the test condition in quiet (IG/CG 6 months: 70%/70%; 12 months: 70%/60%, Freiburg monosyllabic test) and in noise (IG/CG 6 months: −1.1 dB SNR/–0.85 dB SNR; 12 months: −0.65 dB SNR/+0.3 dB SNR, Oldenburg sentence test). Hearing quality assessment scores collected by SSQ (Speech, Spatial and Qualities of Hearing Scale) questionnaire showed better scores in the IG at 6 months, which converged to CG scores at 12 months. The IG was significantly more satisfied with the timing of the start of rehab than the CG. All other data obtained from questionnaires showed no differences between the two groups.
Conclusion: A very early start of inpatient rehabilitation after cochlear implantation was successfully implemented. The rehabilitation was completed within 7 weeks of CI surgery. Comparison of speech recognition test results before and after rehabilitation showed a significant improvement. A clear rehabilitation effect can therefore be demonstrated. Inclusion of CI rehabilitation in the German catalog of follow-up treatments is thus scientifically justified and therefore strongly recommended.
There has been a growing awareness of the need for scientific research to focus on somatic and mental comorbidities in recent years due to the emerging evidence showing their substantial overlap at numerous levels. In this special issue, initiated by members of the EU-funded PRIME consortium (“Prevention and Remediation of Insulin Multimorbidity in Europe; www.prime-study.eu), the focus is on the comorbidities of metabolic disturbances, especially related to insulin signalling dysregulation and mental and neurological disorders. Thus, while obesity, type 2 diabetes, and metabolic syndrome are commonly known to be insulin-related disorders, the last decades have shown that neurodegenerative disorders, such as Alzheimer’s disease, as well as neurodevelopment disorders, such as obsessive-compulsive disorder (OCD), autism spectrum disorders (ASDs) and attention deficit / hyperactivity disorder (ADHD) also fall into this category. The special issue draws together a series of basic and clinical review articles that describe the current knowledge and future perspectives regarding insulin comorbidities across a multidisciplinary group of experts
Inflammation is a regulated reaction of the body to control a threat such as infection or injury. An efficient resolution of inflammation is critical to prevent the development of chronic inflammation and to restore tissue homeostasis. Macrophages (Mf) play a crucial role in the onset, but also in the resolution of inflammation, because they phagocytose and eliminate pathogens and tissue debris. Efficient efferocytosis, i.e. the engulfment of apoptotic cells, represents an important trigger for the onset of the resolution response and contributes to the pro-resolving reprogramming of Mf. Despite the importance of post- transcriptional modes of regulation during the resolution phase and translational control as a key node modulating gene expression in immune cells, relevant translational alterations remain largely elusive.
In the present study, I aimed to identify translationally regulated targets in inflammatory primary murine Mf upon resolution-promoting efferocytosis. To this end, I used total RNA-sequencing as well as de novo proteomics analyses to determine global transcriptional and translational changes. Sequencing data confirmed that efferocytosis induced a pro-resolution signature in inflammatory Mf and pointed towards translational regulation because the related integrated stress response was enriched upon efferocytosis. While changes of gene expression between efferocytic and non-efferocytic Mf appeared rather small at the transcriptional level, I observed considerable differences at the level of de novo synthesized proteins. This finding suggests a regulation at the level of translation. Furthermore, the tight connection between translational and metabolic changes was confirmed by enriched metabolism-associated terms of targets upregulated by efferocytosis at both RNA and de novo protein level. Interestingly, analysis of translationally regulated targets in response to inflammatory stimulation showed reduced translation for most targets, with only little impact of efferocytosis. Among those targets, I identified pro-resolving matrix metallopeptidase 12 (Mmp12) as a novel candidate, which showed translational repression during early inflammation and translational increase during the resolution phase. Noteworthy, a first indicator for a potential translation regulatory component of Mmp12 were the extremely high mRNA levels and not overly high de novo protein levels. Validation experiments recapitulated a slight elevation of Mmp12 mRNA expression and a significant downregulation of MMP12 intracellular protein levels in inflammatory Mf, as observed in the RNA-seq and de novo proteomics datasets. To investigate whether the discrepancy in mRNA and protein expression were due to changes in translation, I applied polysomal fractionation analysis to determine the translational status of Mmp12. Inflammatory Mf displayed a significantly lower relative Mmp12 mRNA abundance in the late polysomes compared to naïve Mf, suggesting reduced translational efficiency upon inflammatory stimulation. Consequently, extracellular MMP12 levels in the supernatant of inflammatory Mf decreased, although with a slight delay.
The functional impact of attenuated Mmp12 translation upon inflammatory stimulation was assessed in migration assays. While siRNA-mediated knockdown of Mmp12 did not alter Mf migration on uncoated plates, it increased migration 3-fold on matrigel/elastin-coated plates. Importantly, the increase in migrated distance driven by siMmp12 could be lowered by the addition of exogenous recombinant MMP12 protein. In line with reduced Mmp12 translation and MMP12 protein in inflammatory Mf, I observed a significant increase in cell migration on matrigel/elastin-coated plates, while it remained unaltered on uncoated plates. Consequently, Mf elastase MMP12 degrades elastin, thereby cell migration along elastin fibers is diminished. In inflammatory Mf, Mmp12 is translationally downregulated, thereby enhancing the migratory capacity.
In summary, the present study identifies a substantial contribution of translational regulation in the course of inflammation shown by high changes between inflammatory naïve and efferocytic Mf at the de novo proteomic level. Specifically, I was able to determine the translational regulation of pro-resolving Mmp12, which is repressed during early inflammation and recovers during the resolution phase. Functionally, translational control of MMP12 emerged as a strategy to alter the migratory properties of Mf, enabling enhanced, matrix- dependent migration of Mf during the early inflammatory phase, while restricting migration during the resolution phase.
Although, during the past decades, substantial advances emerged in identifying major local and systemic factors contributing to initiation and progression of osteoarthritis (OA), some neuroendocrine mechanisms are still not understood or even neglected when thinking about novel therapeutic options. One of which is the sympathetic nervous system that exhibits various OA-promoting effects in different tissues of the joint. Interestingly, the β2-adrenoceptor (AR) mediates the majority of these effects as demonstrated by several in vitro, in vivo as well as in clinical studies. This review article does not only summarize studies of the past two decades demonstrating that the β2-AR plays an OA-promoting role in different tissues of the joint but also aims to encourage the reader to think about next-level research to discover novel and innovative preventive and/or therapeutic strategies targeting the β2-AR in OA.
Highlights
• Constrictional structures range from dome-and-basin folds to coeval folds and boudins.
• Under bulk constriction, the competent layer rotates slower than a passive plane.
• Extension-parallel and –perpendicular folds grow simultaneously.
• Extension-perpendicular folds affect previous boudins.
Abstract
We conducted scaled analogue modelling to show the influence of varying single layer initial orientation on the geometry of folds and boudins in a bulk constrictional strain field. The initial angle between the plane of shortening and the competent layer (θZ(i)) was incrementally increased from 0° to 90° by multiples of 11.25°. While the amount of layer thickening decreased with increasing θZ(i), the deformation structures produced range from pure dome-and-basin folds to coeval folds and boudins. Based on the attitude of fold axes, there are extension-parallel (FEPR) and extension-perpendicular (FEPP) folds, with axes subparallel and subperpendicular to the principal stretching axis (X), respectively. Coeval growth of FEPR folds and boudins occurred when θZ(i) > ca. 25°. The FEPP folds can be subdivided into a first type which affect the entire layer (if θZ(i) ranges between 11.25 and 78.75°) and a second type, referred to as FBEPP folds, which are affecting pre-existing boudins if θZ(i) > 45°. The interlimb angle of all types of folds increases with increasing θZ(i). Folds and boudins similar to the ones produced in this study can be found in salt domes and in tectonites of subduction zones.
The human immune system is determined by the functionality of the human lymph node. With the use of high-throughput techniques in clinical diagnostics, a large number of data is currently collected. The new data on the spatiotemporal organization of cells offers new possibilities to build a mathematical model of the human lymph node - a virtual lymph node. The virtual lymph node can be applied to simulate drug responses and may be used in clinical diagnosis. Here, we review mathematical models of the human lymph node from the viewpoint of cellular processes. Starting with classical methods, such as systems of differential equations, we discuss the values of different levels of abstraction and methods in the range from artificial intelligence techniques formalism.
The lipid content of skin plays a determinant role in its barrier function with a particularly important role attributed to linoleic acid and its derivatives. Here we explored the consequences of interfering with the soluble epoxide hydrolase (sEH) on skin homeostasis. sEH; which converts fatty acid epoxides generated by cytochrome P450 enzymes to their corresponding diols, was largely restricted to the epidermis which was enriched in sEH-generated diols. Global deletion of the sEH increased levels of epoxides, including the linoleic acid-derived epoxide; 12,13-epoxyoctadecenoic acid (12,13-EpOME), and increased basal keratinocyte proliferation. sEH deletion (sEH-/- mice) resulted in thicker differentiated spinous and corneocyte layers compared to wild-type mice, a hyperkeratosis phenotype that was reproduced in wild-type mice treated with a sEH inhibitor. sEH deletion made the skin sensitive to inflammation and sEH-/- mice developed thicker imiquimod-induced psoriasis plaques than the control group and were more prone to inflammation triggered by mechanical stress with pronounced infiltration and activation of neutrophils as well as vascular leak and increased 12,13-EpOME and leukotriene (LT) B4 levels. Topical treatment of LTB4 antagonist after stripping successfully inhibited inflammation and neutrophil infiltration both in wild type and sEH-/- skin. While 12,13-EpoME had no effect on the trans-endothelial migration of neutrophils, like LTB4, it effectively induced neutrophil adhesion and activation. These observations indicate that while the increased accumulation of neutrophils in sEH-deficient skin could be attributed to the increase in LTB4 levels, both 12,13-EpOME and LTB4 contribute to neutrophil activation. Our observations identify a protective role of the sEH in the skin and should be taken into account when designing future clinical trials with sEH inhibitors.
Highlights
• Deletion of SPPL3 promotes resistance of malignant B cells to NK cell cytotoxicity
• Loss of SPPL3 blocks ligand binding to NK receptors via increased N-glycosylation
• B3GNT2 deletion reduces LacNAc addition and restores SPPL3-KO cell sensitivity to NK cells
• SPPL3-deficient cells are enriched in tetra-antennary N-glycans with LacNAc elongations
Summary
Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity. SPPL3-deleted cells accumulate glycosyltransferases and complex N-glycans, disrupting not only binding of ligands to NK receptors but also binding of rituximab, a CD20 antibody approved for treating B cell cancers. Notably, inhibiting N-glycan maturation restores receptor binding and sensitivity to NK cells. A secondary CRISPR screen in SPPL3-deficient cells identifies B3GNT2, a transferase-mediating poly-LacNAc extension, as crucial for resistance. Mass spectrometry confirms enrichment of N-glycans bearing poly-LacNAc upon SPPL3 loss. Collectively, our study shows the essential role of SPPL3 and poly-LacNAc in cancer immune evasion, suggesting a promising target for cancer treatment.
Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.
Tight control over transcription factor activity is necessary for a sensible balance between cellular proliferation and differentiation in the embryo and during tissue homeostasis by adult stem cells, but mechanistic details have remained incomplete. The homeodomain transcription factor MEIS2 is an important regulator of neurogenesis in the ventricular–subventricular zone (V-SVZ) adult stem cell niche in mice. We here identify MEIS2 as direct target of the intracellular protease calpain-2 (composed of the catalytic subunit CAPN2 and the regulatory subunit CAPNS1). Phosphorylation at conserved serine and/or threonine residues, or dimerization with PBX1, reduced the sensitivity of MEIS2 towards cleavage by calpain-2. In the adult V-SVZ, calpain-2 activity is high in stem and progenitor cells, but rapidly declines during neuronal differentiation, which is accompanied by increased stability of MEIS2 full-length protein. In accordance with this, blocking calpain-2 activity in stem and progenitor cells, or overexpression of a cleavage-insensitive form of MEIS2, increased the production of neurons, whereas overexpression of a catalytically active CAPN2 reduced it. Collectively, our results support a key role for calpain-2 in controlling the output of adult V-SVZ neural stem and progenitor cells through cleavage of the neuronal fate determinant MEIS2.
Background: A good physician should be empathic and altruistic, among other qualities. Therefore, the levels of socially undesirable personality traits (Dark Triad) as well as implicit motives of achievement, affiliation and power (Multi-Motive Grid) among medical students as future physicians were analyzed at two different points in their medical training.
Methods: This study includes 380 medical students in their first year and 217 in their third year in Germany. All participants completed the Dirty Dozen (DD) and Multi-Motive Grid (MMG) questionnaires at the end of two different classes as paper-and-pencil tests. Relevant differences of the Dark Triad traits between the medical students and reference sample and the two different cohorts, as well as their implicit motives, the associations of Dark Triad traits and MMG components and gender differences of the Dark Triad traits were calculated.
Results: There were no significant group differences between year one and year three medical students in narcissism, psychopathy and Machiavellianism (Dark Triad). There were no significant differences between the medical students and reference sample except in psychopathy. Male students scored significantly higher in the Dark Triad traits than female students. In the MMG, first-year students scored significantly higher levels in Fear of Rejection, and lower levels in Hope of Success and Hope of Power than the third-year students. Some associations were found between narcissism and Machiavelliansim with Hope of Success, Hope of Power and Fear of power.
Conclusions: Dark Triad traits already appear to exist before the commencement of medical studies. These traits do not differ significantly between the medical students and reference sample; only a few MMG components seem to differ at different stages of their studies. This lack of differences between the medical students and validation cohort indicates that tests based on (undesirable) personality traits are not suitable criteria for the admission selection of medical students.
Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily1. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome2,3,4,5,6,7. Earlier studies concluded that FLVCR1 may function as a haem exporter8,9,10,11,12, whereas FLVCR2 was suggested to act as a haem importer13, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters14,15,16. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation–π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.
Highlights:
• Assessment of body composition parameters in a large cohort of patients with HCC undergoing TACE.
• Fully automated artificial intelligence-based quantitative 3D volumetry of abdominal cavity tissue composition.
• Skeletal muscle volume and related parameters were independent prognostic factors in patients with HCC undergoing TACE.
Background & Aims: Body composition assessment (BCA) parameters have recently been identified as relevant prognostic factors for patients with hepatocellular carcinoma (HCC). Herein, we aimed to investigate the role of BCA parameters for prognosis prediction in patients with HCC undergoing transarterial chemoembolization (TACE).
Methods: This retrospective multicenter study included a total of 754 treatment-naïve patients with HCC who underwent TACE at six tertiary care centers between 2010–2020. Fully automated artificial intelligence-based quantitative 3D volumetry of abdominal cavity tissue composition was performed to assess skeletal muscle volume (SM), total adipose tissue (TAT), intra- and intermuscular adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue (SAT) on pre-intervention computed tomography scans. BCA parameters were normalized to the slice number of the abdominal cavity. We assessed the influence of BCA parameters on median overall survival and performed multivariate analysis including established estimates of survival.
Results: Univariate survival analysis revealed that impaired median overall survival was predicted by low SM (p <0.001), high TAT volume (p = 0.013), and high SAT volume (p = 0.006). In multivariate survival analysis, SM remained an independent prognostic factor (p = 0.039), while TAT and SAT volumes no longer showed predictive ability. This predictive role of SM was confirmed in a subgroup analysis of patients with BCLC stage B.
Conclusions: SM is an independent prognostic factor for survival prediction. Thus, the integration of SM into novel scoring systems could potentially improve survival prediction and clinical decision-making. Fully automated approaches are needed to foster the implementation of this imaging biomarker into daily routine.
Impact and implications: Body composition assessment parameters, especially skeletal muscle volume, have been identified as relevant prognostic factors for many diseases and treatments. In this study, skeletal muscle volume has been identified as an independent prognostic factor for patients with hepatocellular carcinoma undergoing transarterial chemoembolization. Therefore, skeletal muscle volume as a metaparameter could play a role as an opportunistic biomarker in holistic patient assessment and be integrated into decision support systems. Workflow integration with artificial intelligence is essential for automated, quantitative body composition assessment, enabling broad availability in multidisciplinary case discussions.
Highlights
• It is important to distinguish acute provoked seizures due to autoimmune encephalitis from chronic unprovoked seizures due to autoimmune-associated epilepsy.
• Currently it is hardly possible in an individual AIE/ALE/RE patient to separate acute provoked seizures from chronic unprovoked seizures due to limitations in determining seizure outcomes, unclear time courses, potential causal interactions between both seizure origins, compartmentalized immune-inflammation, and a lack of licensed drugs to reliably resolve immune-inflammation in the brain parenchyma.
• This makes it hard to decide when to terminate ASMs and to counsel the individual patient regarding driving abilities and other behavioral restrictions and recommendations.
• Studies are urgently needed to define clinical and paraclinical biomarkers in a hypothesis-free, data-driven approach reliably predicting (or not) the development of AAE and the cognitive and behavioral outcome in the due course of an individual patient´s disease.
• These studies should be experimentally validated in suitable animal models.
Abstract
The current International League Against Epilepsy (ILAE) definition and classification guidelines for the first time introduced the category of immune-mediated focal epilepsy in addition to structural, genetic, infectious, and metabolic aetiologies. Moreover, the ILAE Autoimmunity and Inflammation Taskforce recently provided a conceptual framework for the distinction between acute “provoked” seizures in the acute phase of autoimmune encephalitis from chronic “unprovoked” seizures due to autoimmune-associated epilepsy. The first category predominately applies to those autoimmune encephalitis patients with autoantibodies against cell surface neural antigens, in whom autoantibodies are assumed to exert a direct ictogenic effect without overt structural damage. These patients do not exhibit enduring predisposition to seizures after the “acute phase” encephalitis, and thus do not fulfil the definition of epilepsy. The second category applies to those autoimmune encephalitis patients with autoantibodies against intracellular neural antigens and Rasmussen's encephalitis, in whom T cells are assumed to cause epileptogenic effects through immune-inflammation and overt structural damage. These patients do exhibit enduring predisposition to seizures after the “acute phase” of encephalitis and thus fulfil the definition of epilepsy. AAE may result from both, ongoing brain autoimmunity and associated structural brain damage according to the current ILAE definition and classification guideline. We here discuss the shortcomings and defaults of this concept and suggest an unbiased translationally validated and data-driven approach to predict in an individual encephalitis patient the propensity to develop (or not) AAE and the cognitive and behavioural outcome.