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Oncogenic and microenvironmental signals drive cell type specific apoptosis resistance in juvenile myelomonocytic leukemia
No full textJuvenile myelomonocytic leukemia (JMML) is caused by constitutively activated RAS signaling and characterized by increased proliferation and predominant myelomonocytic differentiation of hematopoietic cells. Using MxCre;Ptpn11D61Y/+ mice, which model human JMML, we show that RAS pathway activation affects apoptosis signaling through cell type-dependent regulation of BCL-2 family members. Apoptosis resistance observed in monocytes and granulocytes was mediated by overexpression of the anti-apoptotic and down-regulation of the pro-apoptotic members of the BCL-2 family. Two anti-apoptotic proteins, BCL-XL and MCL-1, were directly regulated by the oncogenic RAS signaling but, in addition, were influenced by microenvironmental signals. While BCL-XL and BCL-2 were required for the survival of monocytes, MCL-1 was essential for neutrophils. Interestingly, stem and progenitor cells expressing the oncogenic PTPN11 mutant showed no increased apoptosis resistance. BCL-XL inhibition was the most effective in killing myeloid cells in vitro but was insufficient to completely resolve myeloproliferation in vivo
Daxx and HIRA go viral - how chromatin remodeling complexes affect DNA virus infection
No full textDaxx and HIRA are key proteins in the host response to DNA virus infections. Daxx is involved in apoptosis, transcription regulation, and stress responses. During DNA virus infections, Daxx helps modulate the immune response and viral progression. Viruses like adenoviruses and herpesviruses can exploit Daxx to evade immune detection, either by targeting it for degradation or inhibiting its function. Daxx also interacts with chromatin to regulate transcription, which viruses can manipulate to enhance their own gene expression and replication. HIRA is a histone chaperone and reported to be essential for chromatin assembly and gene regulation. It plays a critical role in maintaining chromatin structure and modulating gene accessibility. During DNA virus infection, HIRA influences chromatin remodeling, affecting both viral and host DNA accessibility, which impacts viral replication and gene expression. Additionally, the histone variant H3.3 is crucial for maintaining active chromatin states. It is incorporated into chromatin independently of DNA replication and is associated with active gene regions. During viral infections, H3.3 dynamics can be altered, affecting viral genome accessibility and replication efficiency. Overall, Daxx and HIRA are integral to orchestrating viral infection programs, maintaining latency and/or persistence, and influencing virus-induced transformation by modulating chromatin dynamics and host immune responses, making them significant targets for therapeutic strategies once fully understood. Here, we summarize various DNA viruses and their crosstalk with Daxx and HIRA
A simple CT score predicts early neurological disability and survival in supratentorial intracerebral hemorrhage - the intracerebral mass and brain edema score (IMBES)
No full textIntroductionTreatment of spontaneous intracerebral hemorrhage (ICH) remains challenging, and intracerebral mass and brain edema (IMBE) are accused of being the main factors influencing patient course.Research questionCT scan assessment of the space-occupying effect after initial ICH was evaluated using an IMBE-score to detect the sulcal effacement of the subarachnoid space.Material and methodsSupratentorial ICH-patients within a 10 years observation period were identified. Two independent reviewers screened each CT scan in three defined axial planes. Where the combined mass effect of hemorrhage and edema showed sulcal effacement of more than half of the hemisphere, one point was assigned, resulting in an IMBES between 0 and 6. The primary endpoint was neurological outcome measured by the modified Rankin Scale (mRS) and mortality.ResultsWe identified 762 patients, median age was 75.4 years (IQR: 64.3–81.1) and mean ICH volume was 46.1 cc. Multiple regression for mRS at discharge (mean: 12.5 days, IQR: 7.1–22.3) identified age, presence of intraventricular hemorrhage, ICH volume, renal insufficiency, intake of anticoagulants and IMBES as statistically significant variables. This was confirmed during follow-up examination, although ICH volume was not significantly associated with neurological outcome.Discussion and conclusionWe observed a decreased neurological recovery and an increased mortality for patients with high IMBES during acute care and at early follow-up, indicating that IMBES had the strongest association in all regression analysis. We conclude that the fast and simple IMBES may be a useful tool to estimate patient risk for impaired neurological outcome and death
BENTA disease or CARD11 gain-of-function? A novel variant with atypical features and a literature review
No full textFrom smartphones to satellites: uniting crowdsourced biodiversity monitoring and earth observation to fill the gaps in global plant trait mapping
No full textCommentary on the "Effects of static and low-frequency magnetic fields on gene expression"
No full textAutomated inflammatory bowel disease detection using wearable bowel sound event spotting
No full textIntroduction: Inflammatory bowel disorders may result in abnormal Bowel Sound (BS) characteristics during auscultation. We employ pattern spotting to detect rare bowel BS events in continuous abdominal recordings using a smart T-shirt with embedded miniaturised microphones. Subsequently, we investigate the clinical relevance of BS spotting in a classification task to distinguish patients diagnosed with inflammatory bowel disease (IBD) and healthy controls.Methods: Abdominal recordings were obtained from 24 patients with IBD with varying disease activity and 21 healthy controls across different digestive phases. In total, approximately 281 h of audio data were inspected by expert raters and thereof 136 h were manually annotated for BS events. A deep-learning-based audio pattern spotting algorithm was trained to retrieve BS events. Subsequently, features were extracted around detected BS events and a Gradient Boosting Classifier was trained to classify patients with IBD vs. healthy controls. We further explored classification window size, feature relevance, and the link between BS-based IBD classification performance and IBD activity.Results: Stratified group K-fold cross-validation experiments yielded a mean area under the receiver operating characteristic curve ≥0.83 regardless of whether BS were manually annotated or detected by the BS spotting algorithm.Discussion: Automated BS retrieval and our BS event classification approach have the potential to support diagnosis and treatment of patients with IBD
Simulator training for enhanced interventional radiology education
No full textTo address the challenges of staff shortages and the need to gain practical experience in interventional radiology by increasing attention in the medical curriculum, especially in combination with the opportunity to successfully gain hands-on experience, can help influence medical students’ career decisions in favor of IR. Regular training on VR simulators can reduce the amount of X-ray radiation needed to adequately care for patients. Ten medical students underwent five angiographic training sessions using an endovascular simulator. Virtual fluoroscopy time was recorded during each session to measure skill development. Pre- and post-training questionnaires were conducted to assess changes in subjective proficiency and career interests. The median virtual fluoroscopy time decreased from 19.3 min initially to 9.3 min (p = 0.007), indicating enhanced procedural proficiency. Post-training questionnaires revealed a notable increase in interest in interventional radiology among participants. Additionally, participants reported improvements in practical skills, understanding of interventional radiology, and readiness for real-world interventions. Simulator-based training significantly enhances procedural proficiency and could impact career interests in interventional radiology. Despite the small sample size, the findings support the efficacy of VR training in medical education, highlighting the need for further research to optimize the implementation of simulation technology in medical training
Neuron-restricted cytomegalovirus latency in the central nervous system regulated by CD4+ T-cells and IFN-γ
No full textAll human herpesviruses establish latency following the resolution of the primary infection. Among these, α-herpesviruses HSV-1, HSV-2 and VZV establish latency in neurons, whereas neurons are not traditionally considered a site of latency for other herpesviruses. Using a combination of in vivo murine models and ex vivo human fetal tissues, we discovered that cytomegalovirus (CMV), a ubiquitous β-herpesvirus, can persist in neurons and that CD4+ T-cell-derived interferon-gamma is critical in restricting active viral replication in this cell type. Furthermore, we show that mouse CMV can establish latency in neurons and that CD4+ T-cells are essential in preventing viral reactivation. Our findings may have translational significance because human cytomegalovirus (HCMV) is the leading cause of congenital viral infections resulting in neurodevelopmental and neuroinflammatory lesions with long-term functional sequelae