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The ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma

Abstract Immunomodulatory drugs (IMiDs) are a major class of drugs for treating multiple myeloma (MM); however, acquired resistance to IMiDs remains a significant clinical challenge. Although alterations in cereblon and its pathway are known to contribute to IMiD resistance, they account for only 20% to 30% of cases, and the underlying mechanisms in the majority of the resistance cases remain unclear. Here, we identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of lenalidomide resistance in MM. We showed that lenalidomide activates the MDA5-mediated double-stranded RNA (dsRNA)–sensing pathway in MM cells, leading to interferon (IFN)-mediated apoptosis, with ADAR1 as the key regulator. Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation, which in turn triggered dsRNA-sensing pathways and enhanced IFN responses. Conversely, ADAR1 overexpression reduced lenalidomide sensitivity, attributed to increased RNA editing frequency, reduced dsRNA accumulation, and suppression of the dsRNA-sensing pathways. In summary, we report the involvement of ADAR1-regulated dsRNA sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.

ADAR1 in lenalidomide resistance: still immunomodulation?

Acute myeloid leukemia with <i>RUNX1</i>::<i>CBFA2T3</i> fusion

Superconductivity and quantized anomalous Hall effect in rhombohedral graphene

A super-gel stays supple from −115 ºC to 143 ºC

Engineered heart muscle allografts for heart repair in primates and humans

Abstract Cardiomyocytes can be implanted to remuscularize the failing heart1–7. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques. After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation8, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed. The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.

Impact of thermal treatment on the quality, total antioxidant and antibacterial properties of fermented camel milk

Abstract This study investigated the impact of thermal treatments on the quality, antioxidant, and antibacterial properties of fermented camel milk during refrigerated storage. Two thermal treatment categories were applied: moderate (63 °C for 30 min and 72 °C for 15 s) and high (85 and 90 °C for 15 s and 30 min). Findings indicated that raw camel milk was found to be microbiologically unacceptable. Heating milk to 90 °C for 30 min notably reduced fermentation time, increased fermented milk viscosity, and altered whey protein electrophoretic patterns. While thermal treatments below 90 °C boosted lactic acid bacteria count in fermented milk compared to raw milk-derived samples (control), all treatments exceeded the recommended standards throughout storage. Thermal treatment decreased the proteolysis degree and DPPH radical scavenging activity but enhanced the ferric-reducing power of fermented milk compared to the control. Among, thermal treatments, samples from milk heated at 90 °C exhibited the highest scavenging activity and reducing power. Antibacterial efficacy against Salmonella Typhimurium surpassed that against Escherichia coli and Staphylococcus aureus; the most pronounced effect was observed in samples from milk heated at 90 °C. In conclusion, thermal treatment of camel milk is crucial to ensure sufficient hygiene for safe milk consumption. Heating camel milk at 90 °C before fermentation positively impacted most of the studied properties.

Extant life detection using label-free video microscopy in analog aquatic environments

The ability of microbial active motion, morphology, and optical properties to serve as biosignatures was investigated by in situ video microscopy in a wide range of extreme field sites where such imaging had not been performed previously. These sites allowed for sampling seawater, sea ice brines, cryopeg brines, hypersaline pools and seeps, hyperalkaline springs, and glaciovolcanic cave ice. In all samples except the cryopeg brine, active motion was observed without any sample treatment. Active motion was observed in the cryopeg brines when samples were subjected to a temperature gradient above in situ. In general, levels of motility were low in the field samples collected at temperatures &lt;  4ºC. Non-motile cells could be distinguished from microminerals by differences in passive motion (e.g., density measured by sinking/floating), refractive index and/or absorbance, or morphology in the case of larger eukaryotes. Dramatic increases in the fraction of motile cells were seen with simple stimuli such as warming or the addition of L-serine. Chemotaxis and thermotaxis were also observed in select samples. An open-source, autonomous software package with computational requirements that can be scaled to spaceflight computers was used to classify the data. These results demonstrate the utility of volumetric light microscopy for life detection, but also suggest the importance of developing methods to stimulate cells in situ and process data using the restrictions imposed by mission bandwidth, as well as instruments to capture cell-like objects for detailed chemical analysis.

A new method of accurate pedicle screw navigation

Performance of pelican optimizer for energy losses minimization via optimal photovoltaic systems in distribution feeders

In distribution grids, excessive energy losses not only increase operational costs but also contribute to a larger environmental footprint due to inefficient resource utilization. Ensuring optimal placement of photovoltaic (PV) energy systems is crucial for achieving maximum efficiency and reliability in power distribution networks. This research introduces the Pelican Optimizer (PO) algorithm to optimally integrate solar PV systems to radial electrical distribution grids. The PO is a novel bio-inspired optimization algorithm that draws inspiration from pelicans’ intelligence and behavior which incorporates unique methods for exploration and exploitation, improving its effectiveness in various optimization challenges. It introduces a hyper-heuristic for phase change, allowing the algorithm to dynamically adjust its strategy based on the problem’s characteristics. The suggested PO aims to reduce the energy losses to the possible minimum value. The developed PO version is tested on the Ajinde 62-bus network, a practical Nigerian distribution system, and a typical IEEE grid with 69 nodes. The simulation findings demonstrate the enhanced PO version’s efficacy, showing a significant decrease in losses of energy. With the Ajinde 62-node grid, the suggested PO version obtains a substantial 30.81% decrease in the total energy loss expenses in contrast to the initial scenario. Similarly, the IEEE 69-node grid achieves a significant decrease of 34.96%. Additionally, the model’s findings indicate that the proposed PO version performs comparably to the Differential Evolution (DE), Particle Swarm Optimization (PSO), and Satin bowerbird optimizer (SBO) algorithms.

Malabaricone C isolated from edible plants as a potential inhibitor of SARS-CoV-2 infection

Microfluidic isolation and release of live disseminated breast tumor cells in bone marrow

Breast cancer represents a significant therapeutic challenge due to its aggressive nature and resistance to treatment. A major cause of treatment failure in breast cancer is the presence of rare, low-proliferative disseminated tumor cells (DTCs) in distant organs including the bone marrow. This study introduced a microfluidic-based approach to improve the immunodetection and isolation of these rare DTCs for downstream analysis, with an emphasis on optimizing immunocapture, release, and enrichment methods of live DTCs as compared to the standard approach for blood-borne circulating tumor cells (CTCs). EGFR (epidermal growth factor receptor) and EpCAM (epithelial cell adhesion molecule), two key cell surface markers in breast cancer, were validated as efficient cell capture targets for DTCs within microfluidic chambers. Furthermore, we demonstrated that a combination of 0.25% trypsin and impulse was the most effective for releasing captured cells, maintaining high viability, and preserving essential cellular characteristics. Using a metastatic mouse breast cancer model, we achieved a 47.9-fold enrichment of live DTCs. Analysis of blood and bone marrow samples obtained from a breast cancer patient with minimal residual disease at two timepoints revealed a reduction in CTCs and an increase in DTCs following adjuvant chemotherapy. This observation suggested a potential dynamic interplay between CTCs and DTCs in response to therapy. Our results underscore the potential of the microfluidic approach in enhancing DTC detection and shed light on the importance of monitoring both CTCs and DTCs in breast cancer prognosis and treatment response assessment.

Starvation-induced HBP metabolic reprogramming and STAM2 O-GlcNAcylation facilitate bladder cancer metastasis

A methodological framework for deriving the German food-based dietary guidelines 2024: Food groups, nutrient goals, and objective functions

Background For a growing number of food-based dietary guidelines (FBDGs), diet optimization is the tool of choice to account for the complex demands of healthy and sustainable diets. However, decisions about such optimization models’ parameters are rarely reported nor systematically studied. Objectives The objectives were to develop a framework for (i) the formulation of decision variables based on a hierarchical food classification system; (ii) the mathematical form of the objective function; and (iii) approaches to incorporate nutrient goals. Methods To answer objective (i), food groups from FoodEx2 levels 3-7 were applied as decision variables in a model using acceptability constraints (5 th and 95 th percentile for food intakes of German adults ( n  = 10,419)) and minimizing the deviation from the average observed dietary intakes. Building upon, to answer objectives (ii) and (iii), twelve models were run using decision variables from FoodEx2 level 3 ( n  = 255), applying either a linear or squared and a relative or absolute way to deviate from observed dietary intakes, and three different lists of nutrient goals (allNUT-DRV, incorporating all nutrient goals; modNUT-DRV excluding nutrients with limited data quality; modNUT-AR using average requirements where applicable instead of recommended intakes). Results FoodEx2 food groups proved suitable as diet optimization decision variables. Regarding deviation, the largest differences were between the four different objective function types, e.g., in the linear-relative modNUT-DRV model, 46 food groups of the observed diet were changed to reach the model’s goal, in linear-absolute 78 food groups, squared-relative 167, and squared-absolute 248. The nutrient goals were fulfilled in all models, but the number of binding nutrient constraints was highest in the linear-relative models (e.g. allNUT-DRV: 11 vs. 7 in linear-absolute). Conclusion Considering the various possibilities to operationalize dietary aspects in an optimization model, this study offers valuable contributions to a framework for developing FBDGs via diet optimization.

The application of neutron imaging to examine ethene hydrogenation over a carbon-supported palladium catalyst

Abstract The combination of a heterogeneous catalyst operating within a defined reactor comes within the domain of reaction engineering, which takes cognisance of combined roles for both the catalyst and the reactor to define the overall operational system. One technique which is demonstrating much promise in investigating reaction engineering issues is neutron imaging. The technique is skewed towards monitoring hydrogen and hydrogenous species so, with hydrogen being ubiquitous in industrial organic chemistry and the penetrating power of the neutrons, neutron imaging can monitor hydrogen concentrations distributed throughout steel reactors whilst the reaction is taking place. In this way, neutron imaging can be used to assess the homogeneity of active catalyst beds and, additionally, determine how hydrogen is being partitioned throughout the catalyst bed as a function of time-on-stream. These are important parameters in the reaction engineering of catalytic systems involving transformations of hydrogen containing species. The article commences by reviewing the handful of existing neutron imaging studies in this field, then progresses to describe the application of the neutron imaging technique to investigate ethene hydrogenation over a 5 wt% Pd/C powder catalyst at 333 K and ambient pressure in a rectangular stainless-steel reactor. Modulations of the incident gas stream are seen to lead to spatially resolvable fronts moving across the bed and illustrate the diffusion of reagents from the reactor inlet across to the reactor exit. Thus, the investigation reveals spatially and temporally resolved elementary reactions that contribute to the hydrogenation process.

Oral fluid supplementation for the prevention of post-dural puncture headache: A noninferiority randomized controlled trial

Aim(s) To investigate the impact of the absence of specific advice for oral fluid intake, compared to supplementation water intake on the occurrence of post-dural puncture headache. Design A prospective, open-label, non-inferiority, multicenter trial including hospitalized patients requiring a diagnostic lumbar puncture in seven hospitals in France. Methods Patients were randomly allocated (1:1) either to receive no specific advice on oral fluid intake (FREE-FLUID), or to be encouraged to drink 2 liters of water (CONTROL) within the 2 hours after lumbar puncture. The primary outcome was the post-dural puncture headache rate within the 5 days after lumbar puncture, with a non-inferiority margin of 10%. The secondary outcome was the time-to-post-dural puncture headache onset between Day 0 and Day 5. Results From November 2016 and July 2019, we have included 554 participants. The primary outcomes occurs in 33.1% patients in the FREE-FLUID group, versus 38.0% in the CONTROL group with adjusted difference of 3.7%. Conclusion Among patients who had lumbar puncture, our study shows the noninferiority of the absence of specific advice on water intake after a lumbar puncture, compared with advice to increase oral fluid to prevent a post-dural puncture headache. Impact The value of questioning the appropriateness of non-evidence-based nursing care may allow time to be devoted to more relational and comforting care. Reporting method The study adheres to the CONSORT reporting guidelines. Patient or public contribution No patient or public contribution. Trial Registration Clinical Trials.gov (NCT02859233, August 9, 2016).

Relative importance of soil fertility and microtopography as CO2 and CH4 exchange drivers in a northern boreal fen ecosystem

Relationship between sleep variables and interoceptive awareness in daytime workers

Interoception refers to the sensation of internal and physiological bodily states, such as heart rate, and contributes to the maintenance of bodily internal homeostasis. Some studies showed that interoceptive awareness is related to experiencing nightmares and subjective sleep quality. Similarly to the perception of heart rate variability, sleepiness is thought to be mainly evoked by homeostatic processes and is based on the awareness and recognition of internal body signals. However, the relationship between subjective excessive daytime sleepiness and interoceptive awareness has not been addressed. Therefore, this study examined the relationship between interoceptive awareness and multiple sleep variables including subjective excessive sleepiness in daytime workers. A web questionnaire survey was conducted targeting daytime workers in Japan, and data from 461 participants were used for analyses. Multiple regression analyses showed weak but significant relationships between subjective excessive daytime sleepiness, insomnia symptoms, nightmare distress, and dream frequency and the components of interoception awareness measured by the Multidimensional Assessment of Interoceptive Awareness. However, no components of interoceptive awareness were related to workday sleep loss or social jetlag of day workers. The results of this study suggest that subjective sleepiness, in addition to nightmare distress and sleep quality, is associated with interoceptive awareness. To the best of our knowledge, this study is the first to analyze the relationship between subjective daytime excessive sleepiness and interoceptive awareness. Further investigation of this relationship is expected to lead to a better understanding of sleep disorders and to elucidate individual differences in the accuracy of subjective assessments of sleepiness.

Study on the multi-wavelength variation of 3C 454.3

Abstract The variation mechanism of the blazar is still an open question. In this study, we collect the long-term multi-wavelength data of 3C 454.3 to conduct a comprehensive study. The local cross-correlation functions were computed between the $$\gamma$$ -ray and R band fluxes, as well as between B and K band fluxes. No significant time lags were found among these bands, which suggests that the optical and $$\gamma$$ -ray emissions are co-spatial. The color indices variation behavior showed a redder-when-brighter trend in the lower state, and a saturation state in the higher state. The slope of the linear correlations between the logarithms of synchrotron and inverse-Compton fluxes changed from 0.61 to 3.34 for different band pairs, which could be explained by a model of Doppler-boosted log-parabolic synchrotron emission combined with stable background contamination. The model could also reproduce the spectral energy distributions at different brightness. This study can help us to better understand the variation mechanism of blazars.