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The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment

An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA

Abstract X-linked sideroblastic anemia (XLSA) is a congenital anemia caused by mutations in ALAS2, a gene responsible for heme synthesis. Treatments are limited to pyridoxine supplements and blood transfusions, offering no definitive cure except for allogeneic hematopoietic stem cell transplantation, only accessible to a subset of patients. The absence of a suitable animal model has hindered the development of gene therapy research for this disease. We engineered a conditional Alas2-knockout (KO) mouse model using tamoxifen administration or treatment with lipid nanoparticles carrying Cre-mRNA and conjugated to an anti-CD117 antibody. Alas2-KOBM animals displayed a severe anemic phenotype characterized by ineffective erythropoiesis (IE), leading to low numbers of red blood cells, hemoglobin, and hematocrit. In particular, erythropoiesis in these animals showed expansion of polychromatic erythroid cells, characterized by reduced oxidative phosphorylation, mitochondria’s function, and activity of key tricarboxylic acid cycle enzymes. In contrast, glycolysis was increased in the unsuccessful attempt to extend cell survival despite mitochondrial dysfunction. The IE was associated with marked splenomegaly and low hepcidin levels, leading to iron accumulation in the liver, spleen, and bone marrow and the formation of ring sideroblasts. To investigate the potential of a gene therapy approach for XLSA, we developed a lentiviral vector (X-ALAS2-LV) to direct ALAS2 expression in erythroid cells. Infusion of bone marrow (BM) cells with 0.6 to 1.4 copies of the X-ALAS2-LV in Alas2-KOBM mice improved complete blood cell levels, tissue iron accumulation, and survival rates. These findings suggest our vector could be curative in patients with XLSA.

Evaluating the relationship between news source sharing and political beliefs

Evaluating body roundness index and systemic immune inflammation index for mortality prediction in MAFLD patients

Cows that are less active in the chute have more optimal grazing distribution

AbstractIndividual grazing patterns among cattle can contribute to sustainability of land use, however, little is known about the consistency of these grazing patterns. To address this knowledge gap, fifty Angus x Hereford cows were observed in repeated assays: A management assay (handling procedure, narrow chute, hydraulic squeeze), a social-feed trade-off assay (SFTA; choice between social mates and feed item), and novel approach assay (choice between social mates and feed item with novel pattern). The same cattle were tracked with GPS collars over two grazing seasons (June-August 2021 and 2022) and average grazing-related metrics (e.g., elevation used, distance traveled) were calculated within each season. Cows with a more passive response in the chute were found at higher elevation (p = 0.017), further from water (p = 0.043), and closer to supplement sites (p = 0.029). Cows that had higher latency to supplement in the SFTA traveled shorter distances on rangeland (p = 0.035). Thus, there was some evidence that cows with a more passive response to isolation and management had more optimal grazing patterns (grazed underutilized areas of the range at higher elevations and further from water sources). Selecting cattle with more optimal foraging patterns based on observable behaviors during handling and isolation could improve the sustainability of rangeland grazing.

Floatable artificial leaf to couple oxygen-tolerant CO2 conversion with water purification

Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma

Abstract Ciltacabtagene autoleucel (cilta-cel) was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. Overall, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel, of which 54% would not have met CARTITUDE-1 eligibility criteria. In treated patients (N = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Overall and complete response rates were as follows: all patients who received cilta-cel (N = 236), 89% and 70%; patients receiving conforming cilta-cel (n = 191), 94% and 74%; and conforming cilta-cel with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from cilta-cel, the median progression-free survival (PFS) was not reached, with 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

CDC40 suppression induces CDCA5 splicing defects and anti-proliferative effects in lung cancer cells

The mediating effect of emotional schemas in the relationship between online gaming addiction and life satisfaction

Study of the spatial strength distribution patterns and microstructure characteristics of ultra-fine tailings cemented paste backfill

AbstractIn this study, the spatial distribution of the mechanical strength of ultra-fine tailings cemented paste backfill (UCPB) in underground stopes was examined, and the micro-mechanism responsible for differences in spatial strength performance via changes in particle deposition was elucidated. To better understand this phenomenon, we constructed a similar backfilling stope model using the ultra-fine tailings of a gold mine. We manufactured specimens at different spatial locations and conducted a novel series of tests, including uniaxial compressive strength, shear strength, and conventional triaxial tests, to obtain the strength parameters in different spatial distributions. The strength parameters for the different UCPB locations in this model were revealed and examined along with the original pore and particle size distributions. Computer tomography (CT) and scanning electron microscopy (SEM) observations before and after the UCPB failed revealed that the particle deposition effect at different positions was the primary cause of the size effect. The strength distribution pattern demonstrated that the UCPB material has an apparent spatial effect. Consequently, considering the position relationship between the stope and filling mouth is crucial when designing the strength of adjacent mining rooms. This research may guide both backfill study and design.

Discretized representations in V1 predict suboptimal orientation discrimination

XLSA breakthrough: gene therapy potential

Crowd counting in domain generalization based on multi-scale attention and hierarchy level enhancement

AbstractIn order to solve the problem of weak single domain generalization ability in existing crowd counting methods, this study proposes a new crowd counting framework called Multi-scale Attention and Hierarchy level Enhancement (MAHE). Firstly, the model can focus on both the detailed features and the macro information of structural position changes through the fusion of channel attention and spatial attention. Secondly, the addition of multi-head attention feature module facilitates the model’s capacity to effectively capture complex dependency relationships between sequence elements. In addition, the three-stage encoding and decoding processing mode enables the model to effectively represent crowd density information. Finally, the fusion of multi-scale features derived from different receptive fields is further enhanced through multi-scale hierarchy level feature fusion, thereby enabling the model to learn high-level semantic information and low-level multi-scale visual field feature information. This method enhances the model’s capacity to capture key feature information, even in highly differentiated datasets, thereby improving the model’s generalization ability on a single domain. The model has demonstrated strong generalization capabilities through extensive experiments on different datasets. This study not only improves the accuracy of crowd counting, but also introduces a new research approach for single domain generalization of crowd counting.

pACP-HybDeep: predicting anticancer peptides using binary tree growth based transformer and structural feature encoding with deep-hybrid learning

A nomogram predicting the risk of venous thromboembolism in patients following urologic surgeries

L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer

Vitamin C deprivation puts stem cells to sleep

CHST3, PGBD5, and SLIT2 can be identified as potential genes for the diagnosis and treatment of osteoporosis and sarcopenia

Research and application of multi-frequency electromagnetic technology in real-time online characterization of steel microstructures and mechanical properties

Restoring small water bodies to improve lake and river water quality in China

AbstractClimate change, population growth, and agricultural intensification are increasing nitrogen (N) inputs, while driving the loss of inland water bodies that filter excess N. However, the interplay between N inputs and water body dynamics, and its implications for water quality remain poorly understood. Analyzing data from 1995 to 2015 across China, here, we find a 71% reduction in the area of small (<104.5 m2) water bodies (SWB), primarily in high-N-input agricultural regions. Preferential loss of SWBs, the most efficient nutrient filters, places 42% of China at high water quality risk due to increasing N inputs and declining SWB density. Currently, N removal by water bodies is 986 kilotonnes year−1, but restoring 2.3 million hectares of SWB could increase removal by 21%, compared to just 5% for equivalent restoration of large water bodies. Targeted SWB restoration is crucial for improving water quality and mitigating N pollution in China.