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Evolutionary processes and drivers of agricultural functions in Chinese villages
Therapy for MYD88 L265P DLBCL
Impact of high frequency electromagnetic radiation on bacterial survival and antibiotic activity in exposed bacteria
Abstract High-frequency electromagnetic waves (HFEMWs) have been shown to influence cellular functions, including bacterial behavior, potentially affecting growth and antibiotic sensitivity. This study evaluated the response of Escherichia coli and Staphylococcus aureus to HFEMWs across a frequency range of 900 MHz to 73 GHz. The Bacterial sensitivity to antibiotics, including ceftazidime, ceftaroline, gentamycin, doxycycline, and ciprofloxacin, was assessed. The growth rate was evaluated by measuring the optical density (OD) and the number of colony-forming units (CFUs). Our results revealed significant electromagnetic interference (EMI) effects at frequencies of 51.8 GHz and 53 GHz, with 53 GHz showing the most pronounced impact. These frequencies enhanced bacterial susceptibility, with previously resistant E. coli and S. aureus strains becoming sensitive to tested antibiotics. Conversely, 70.6 GHz and 73 GHz frequencies showed limited effects, while exposure to 900 MHz and 1800 MHz caused no notable changes. These findings highlight the frequency-dependent effects of HFEMWs on bacterial viability and antibiotic sensitivity. This research underscores the potential of HFEMWs as a complementary antimicrobial strategy, offering opportunities for improved infection control and innovative sterilization technologies to mitigate hospital-acquired infections.
Molecular glue unexpectedly mimics the effect of cancer mutations
Air pollution is associated with increased risk of venous thromboembolism: the Multi-Ethnic Study of Atherosclerosis
Abstract Air pollution exposure may induce procoagulant effects, and chronic exposure may be linked to greater risk of venous thromboembolism (VTE). We tested the hypothesis that air pollution is associated with increased VTE risk in the prospective Multi-Ethnic Study of Atherosclerosis, which has well-characterized air pollution measures and information on potential confounding factors. We included 6651 participants recruited in 2000 to 2002 (baseline age range, 45-84 years; 53% female). Air pollution was assessed with a validated spatiotemporal model that incorporates cohort-specific monitoring. Four indexes of air pollution updated each fortnight over follow-up were averaged to estimate participant-level chronic exposure: fine particulate matter ≤2.5 micrometers in aerodynamic diameter (PM2.5), oxides of nitrogen (NOx), nitrogen dioxide (NO2), and ozone (O3). Mean±SD PM2.5 was 13.5±3.0 μg/m3, NO2 17.9±8.2 parts per billion (ppb), NOx 36.1±19.6 ppb, and O3 22.2±3.7 ppb. Incident VTE was identified using hospitalization discharge codes through 2018. A total of 248 VTE events accrued over a median follow-up of 16.7 years. After adjustment for baseline demographics, health behaviors, and body mass index, the hazard ratio (95% confidence interval) for incident VTE associated per 3.6 μg/m3 higher PM2.5 was 1.39 (1.04-1.86); per 13.3 ppb higher NO2 concentration was 2.74 (1.57-4.77); and per 30 ppb higher NOx was 2.21 (1.42-3.44). O3 was not related. In this prospective community-based cohort with individual-level estimation of chronic air pollution exposure, higher average ambient concentrations of PM2.5, NO2, and NOX were associated with greater risk of developing VTE. Findings add to accumulating evidence of adverse health effects attributed to air pollution exposure.
Comparison of plasma p-tau217 and p-tau181 in predicting amyloid positivity and prognosis among Korean memory clinic patients
Artificial intelligence could boost eye care in low-income countries
Lasalocid A selectively induces the degradation of MYD88 in lymphomas harboring the MYD88 L265P mutation
Abstract Myeloid differentiation primary response protein 88 (MYD88) is a key adaptor molecule in the signaling pathways of toll-like receptor and interleukin-1 receptor. A somatic mutation resulting in a leucine-to-proline change at position 265 of the MYD88 protein (MYD88 L265P) is one of the most prevalent oncogenic mutations found in patients with hematological malignancies. In this study, we used high-throughput screening to identify lasalocid A as a potent small molecule that selectively inhibited the viability of lymphoma cells expressing MYD88 L265P and the associated activation of NF-κB. Further investigations using CRISPR-CRISPR–associated protein 9 genetic screening, proteomics, and biochemical assays revealed that lasalocid A directly binds to the MYD88 L265P protein, enhancing its interaction with the ubiquitin ligase RNF5. This interaction promotes MYD88 degradation through the ubiquitin-dependent proteasomal pathway, specifically in lymphomas with the MYD88 L265P mutation. Lasalocid A exhibited strong antitumor efficacy in xenograft mouse models, induced disease remission in ibrutinib-resistant lymphomas, and showed synergistic activity with the B-cell lymphoma 2 inhibitor venetoclax. This study highlights the potential of inducing MYD88 L265P degradation using small molecules, offering promising strategies for treating lymphomas that harbor the MYD88 L265P mutation.
Empirical potential calculations of UO2 for a better understanding of its stringlike motion at high temperature
Hippocampal neuronal activity is aligned with action plans
Mutations in <i>AMBRA1</i> aggravate β-thalassemia by impairing autophagy-mediated clearance of free α-globin
Abstract Accumulation of free α-globin is a critical factor in the pathogenesis of β-thalassemia. Autophagy plays a crucial role in clearing toxic free α-globin, thereby reducing disease severity. However, the impact of natural mutations in autophagy-related genes (ATGs) on the phenotypic variability of β-thalassemia remains unclear. In this study, we systematically investigated the relationship between variants in ATGs and disease phenotypes in a cohort of 1022 patients with β-thalassemia, identifying 4 missense mutations in the autophagy and beclin 1 regulator 1 (AMBRA1) gene. Disruption of the Ambra1 gene in β-thalassemic mice was found to reduce autophagic clearance of α-globin in red blood cell precursors, exacerbating disease phenotypes. Functional characterization of the AMBRA1 gene and these mutations in patient-derived CD34+ cells, edited human umbilical cord blood–derived erythroid progenitor 2 (HUDEP-2) cells, and engineered HUDEP-2 β-thalassemic cells confirmed that AMBRA1 facilitates the autophagic clearance of free α-globin in human erythroid cells. Functional studies demonstrated that AMBRA1 missense mutants destabilize Unc-51-like kinase 1 protein, inhibit light chain 3 protein lipidation, and subsequently hinder autophagic flux, leading to increased α-globin deposition. Additionally, these mutations were associated with erythrotoxic effects in vitro, including increased intracellular reactive oxygen species levels, higher apoptosis rates, and impaired erythroid differentiation and maturation. This study sheds light on the molecular association between mutations in ATGs and the exacerbation of β-thalassemia, highlighting the potential role of the AMBRA1 gene as a promising diagnostic and therapeutic target for β-hemoglobinopathies.
Drivers of spring migration phenology in Rocky Mountain elk
Childhood Langerhans cell histiocytosis hematological involvement: severity associated with <i>BRAF</i> <i>V600E</i> loads
Abstract Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin &lt;10 g/dL, platelets &lt;100 × 109/L, leukopenia (white blood cell count &lt;4 × 109/L), and/or neutrophils &lt;1.5 × 109/L. Among the 2313 patients aged &lt;18 years enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis, 1 year); median follow-up lasted 8.1 years. Bone marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis, or myelofibrosis but never confirm the diagnosis. Fifty-eight patients (17%) developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; &gt;7 g/dL and &gt;20 × 109/L, respectively) and severe HI (SHI; ≤7 g/dL and/or ≤20 × 109/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities, and outcomes (MHI and SHI 10-year survival rates, 98% and 73%, respectively). Since 1998, mortality first declined with combination cladribine-cytarabine therapy and then with MAPK inhibitors since 2014. Forty-one patients (12%) developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, because it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted therapy approaches would be better adapted for these patients, whereas MHI can be managed with classic therapies.
Distinct assembly processes of intestinal and non-intestinal microbes of bark beetles from clues of metagenomic insights
Over 4 decades, French children teach about LCH
Global lightning-ignited wildfires prediction and climate change projections based on explainable machine learning models
The contribution of the monocyte-macrophage lineage to immunotherapy outcomes
Abstract Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic hematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)–dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with chimeric antigen receptor T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualize this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.