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Refining ammonia inventories through top-down inverse modelling in high-density swine farming regions
Coordinated charge-discharge scheduling of large-scale EVs in V2G scenarios
Retraction Note: Prediction of uniaxial compressive strength of limestone from ball mill grinding characteristics using supervised machine learning techniques
Characterization of hepatocellular carcinoma patient-derived organoids from patients receiving transarterial chemoembolization as a model for preclinical drug response assessment
Abstract Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and is often diagnosed at an intermediate stage in patients with chronic liver disease. Transarterial chemoembolization (TACE) is the first-line treatment in this setting. However, drug response remains variable and optimal chemotherapeutic selection unresolved. Idarubicin (IDA) has previously demonstrated antitumor activity comparable to doxorubicin (DOX), with improved emulsion stability and membrane permeability. 3D patient-derived organoids (PDOs) have also recently emerged as physiologically relevant systems that recapitulate tumor characteristics and inter-patient heterogeneity more accurately than conventional 2D cell cultures. In this study, we characterized HCC PDOs and investigated their utility as an ex vivo model to assess therapeutic responses. We generated organoids from tumor and non-tumor liver biopsies collected from HCC patients prior to TACE-treatment. PDOs partially preserved tumor architecture and phenotypic features. IDA exposure resulted in a concentration-dependent reduction in organoid growth, with marked inter-patient variability in drug response. Comparative analyses showed that IDA was more potent than DOX, with lower IC₅₀ values across all patient-derived samples. IDA also induced transcriptional changes associated with cellular stress, inflammation, and proliferation pathways. However, ex vivo drug‑sensitivity testing in PDOs did not correlate with clinical response to TACE. These findings confirm the feasibility of generating HCC PDOs and using them to evaluate differential sensitivity to TACE‑associated chemotherapeutic agents ex vivo, although their ability to predict clinical efficacy remains unproven. While IDA exhibited greater cytotoxic activity than DOX in organoid cultures, this observation was based on in vitro sensitivity assays and does not establish clinical superiority. Furthermore, the absence of correlation between PDO drug sensitivity and clinical TACE response indicates that PDO-based prediction of treatment outcome remains challenging in this setting.
Hybrid reinforcement learning and attention mechanism framework for intelligent fault diagnosis of rolling element bearings
The significance of turbulent coherent structures on the initiation and evolution of sub-orbital ripples
Abstract Motivated by the observation of vortices generated by ripples, numerous studies have focused on how vortex dynamics drive sediment transport and shape ripple geometry. However, during ripple initiation from a flat bed and for low-steepness ripples, such vortices are absent. Turbulent coherent structures (TCS), in contrast, exist within the boundary layer regardless of ripple steepness. This study investigates the role of TCS in ripple initiation and evolution under oscillatory flows using fully coupled three-dimensional Eulerian two-phase large-eddy simulations performed with SedFoam . The results show that TCS initiate ripple marks through localized pockets of turbulent sweep events, supporting the hypothesis that TCS drive ripple initiation from a flat bed. Quadrant analysis further reveals a strong preferential coupling between ejection (sweep) events and particle upward (downward) motion, demonstrating how TCS organize local sediment mobilization and redistribution during ripple initiation. The resulting ripple marks initially exhibit a cross-hatched pattern and subsequently evolve into quasi-two-dimensional rolling-grain ripples. Quantitative analyses further support the hypothesis that sub-orbital ripple evolution involves a transition from TCS-dominated initiation to increasingly wave-orbital-controlled growth and equilibrium development as ripple dimensions exceed the turbulence integral length scale. These findings provide new insights into the mechanisms governing sub-orbital ripple evolution and may help improve the prediction of low-steepness ripple geometry in coastal environments.
Development of an investigational medicinal stem cell gene therapy product to attempt curing human immunodeficiency virus infection
Abstract For most people living with Human immunodeficiency virus (HIV), virus control and sufficient immune function can be achieved with polypharmacotherapy. A minority is intolerant to thereto, and drug-resistant mutants are emerging. Additionally, people living with HIV (PLWH) have significantly higher risk of cardiovascular morbidity and malignant diseases. HIV is in principle immunogenic. If T-cell depletion could be avoided immunological HIV eradication should be achievable. The “Berlin patient” in whom allogeneic stem cell transplantation from a CCR5Δ32/Δ32 donor induced long-term remission without antiviral therapy raised the hope that stem cell gene therapy with CCR5-deleted autologous stem cells could provide a cure, but the strategy did not live up to expectations. We propose to test an alternative strategy, namely expression of a designer recombinase which specifically excises HIV provirus from the genome under a Tat-inducible promoter so that expression is restricted to infected cells. A cGMP-compliant manufacturing protocol and quality control strategy for this investigational medicinal product was developed, validated, and a manufacturing authorization obtained. A First-in-Human-clinical trial, testing engraftment, repopulation of peripheral specific immunity, and ability to control HIV infection without antiviral medication is in preparation. Protocols can be adapted to other stem cell gene therapies by transferring alternative lentviral cargo.
Unsupervised dietary-behavioral profiling identifies PFAS (per- and polyfluoroalkyl substances) and metal exposure patterns in Korean adults
Abstract Beyond “what and how much you eat,” modern nutritional epidemiology is paying attention to how dietary and behavioral patterns, which combine food selection and the context of cooking, packaging, and ingestion, organize health and environmental exposure. This cross-sectional secondary analysis used adult data from the 4th Korea National Environmental Health Survey (KoNEHS Cycle 4, 2018–2020; n = 4239). Multi-question variables related to diet, cooking, packaging, and ingestion behaviors were mapped into a latent space through unsupervised learning, clusters were derived, and the exposure levels of PFAS, bisphenols, urinary cadmium, and blood lead biomarkers were compared by cluster. As a result, serum PFAS concentrations were higher in the “basic diet/seafood propensity” cluster, with weighted geometric means ranging from 10.998 to 21.767 µg/L for PFOS and from 5.082 to 8.323 µg/L for PFOA across clusters. In the “packaging/contact propensity” cluster, higher PFOA was observed in the adjusted analysis, while blood lead showed an elevated direction but was not robust after FDR correction. On the other hand, the differences between clusters for bisphenols and urinary cadmium were not robust when considering covariates and multiple comparisons, suggesting the possibility that the variability of single urine measurements, uncertainty in exposure assessment, and complexity of indicator characteristics may have affected the results. This study provides an empirical basis for identifying population-level dietary-behavioral exposure profiles and informing targeted risk communication by showing how lifestyle-based dietary and behavioral structures are associated with environmental exposure patterns before directly linking dietary patterns with diseases.
Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease.
Recipient endothelial cells (ECs) actively respond to inflammation during allogeneic hematopoietic cell transplant (allo-HCT), yet mechanisms by which ECs influence acute graft-versus-host-disease (GVHD) pathology remain incompletely defined. Single cell RNA-sequencing of ECs isolated from a GVHD target organ, the liver, showed rapid, subset-specific transcriptional reprogramming after allo-HCT, with induction of canonical interferon-γ (IFNγ)-inducible genes including interferon regulatory factor 1 (IRF1), MHC II, and PD-L1 in lymphatic ECs (LECs). In allo-HCT recipients, circulating IFNγ peaked on day 4 (early), decreased but remained elevated at day 14 (late), and declined by day 21, with a concordant induction of IRF1+ LECs in the liver and GI tract. IFNγ neutralization with anti-IFNγ monoclonal antibody at either early or late time points attenuated IRF1⁺MHCII⁺PD-L1⁺ LEC activation. Notably, early donor T cell expansion was IFNγ-independent, whereas late IFNγ blockade selectively impaired donor Treg, but not Th1, expansion, leading to accelerated GVHD. Using in vitro LEC-CD4 T cell co-cultures and allo-HCT in Irf1-/- bone marrow chimera recipients, we show that recipient ECs that cannot mediate IFNγ-IRF1 signaling exhibit reduced activation and apoptosis, but also have impaired Treg expansion, increased donor Th1/Treg ratios, and worsened GVHD severity. Finally, pharmacological JAK inhibition in allo-HCT recipient mice spares IRF1+ LECs and Tregs while reducing pathogenic Th1 cells, correlating with reduced GVHD severity and improved survival. Our findings identify a role for the lymphatic endothelial IFNγ-IRF1 axis in regulating early vascular remodeling, donor T cell mediated tolerance, underscoring a potential "goldilocks" level of pathway activation required to improve post-transplant outcomes.
Retraction Note: A novel malignant mesothelioma organoids-T cell co-culture platform for personalized immunochemotherapy testing
Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC
Acute myeloid leukemia (AML) is an aggressive blood cancer with a 5-year overall survival rate of ~30%. Although immunotherapies engaging T cells demonstrate remarkable success in treating many solid tumors and blood cancers, they show little to no efficacy in treating AML. Therefore, immunotherapies are traditionally underappreciated and underdeveloped in AML. Through a drug re-purpose screen, we identified and validated that combined MEK and HDAC inhibitions via trametinib and quisinostat (TQ) potently inhibited the growth of mouse and human NRAS;ASXL1-AML (NA-AML), MLLr, and NPM1 mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged their survival. The survival benefits of TQ largely relied on T cell functions. We show that TQ synergized to downregulate immune checkpoint ligands and upregulate STAT1- and CIITA-mediated expression of MHC-I and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was thus expanded in central memory and effector memory T cells in TQ-treated NA-AML mice. More importantly, TQ directly acted on AML-associated mouse and human T cells, reverting them from a dysfunctional state to an active state. In leukemia:T cell co-cultures, TQ-treated T cells demonstrated greatly improved MHC-dependent leukemia killing. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and anti-leukemia killing of endogenous T cells, leading to effective AML clearance.
Spatial patterns and factors associated with suicide death among individuals with suicide attempts in northern Iran
Functional restoration of immune defects in STAT1 gain-of-function disease following stem cell gene editing
Germline gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) gene cause a dominantly inherited inborn error of immunity (IEI) characterized by chronic mucocutaneous candidiasis, autoimmunity, severe opportunistic infections and an increased risk of malignancy. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is curative but is associated with increased risk of morbidity and mortality in STAT1 GOF patients compared to other IEI. To develop a curative, autologous alternative to HSCT, we evaluated gene editing strategies in STAT1 GOF model cell lines, primary T cells, and patient-derived HSCs. Universal and mutation-specific strategies using CRISPR/Cas-mediated homology-directed repair (HDR) were limited by low efficacy (<25%), poor viability, and a lack of allele-specificity. In contrast, adenine base editing corrected the recurrent and highly pathogenic p.T385M mutation with upwards of 90% efficiency in patient T cells and HSCs without significant unintended on- or off-target genomic aberrations. Gene editing functionally restored total STAT1 expression (p<0.0217), STAT1 phosphorylation (p<0.0056), interferon-stimulated gene expression (OAS1; p=0.0005) and improved IL-17 production (p<0.0001). Edited HSCs retained multilineage differentiation capacity and sustained engraftment with persistence of the corrected allele at 16 weeks in humanized immunodeficient mice. These data demonstrate efficient and precise correction of STAT1 GOF mutations by base editing, with maintenance of the correction through long-term engraftment in vivo. This represents the first application of gene editing to correct a dominant gain-of-function mutation causing immunodeficiency, with potential applicability to other genetic disorders associated with heterozygous and gain-of-function mutations.
Retinal disease classification from spectral domain optical coherence tomography using lesion attentive fusion
Transcranial ultrasound stimulation of the subthalamic nucleus modulates cognitive function in humans
A multi-dataset crop yield prediction framework using adaptive cooperative metaheuristic optimization
Abstract Crop yield prediction is an essential element for agricultural planning and policy development, although the results may be less accurate because of the high variability that could exist in soil types, weather patterns, and crop growing dynamics for each region. The existing approaches for crop yield prediction have been hampered by the fact that they have been using limited data sources and rigid hyperparameter optimization techniques, thus inhibiting the ability to cope with the diversified agricultural data. The problem encountered by the existing approaches is addressed by the proposed work. The proposed framework focuses on the comprehensive integration of crop yield statistics, climatic variables, soil property data, and satellite-based vegetation indices acquired from various open-access datasets. This multi-source data integration thus allows capturing complementary information in the models regarding crop growth, which is not possible in any of the single datasets alone. To determine the optimized parameter settings for the models, a novel adaptive cooperative PSO–DE–Jaya (AC-PDJ) metaheuristic is proposed by hybridizing the global searching capability of PSO, the variation mechanism of DE, and the exploitation strength of the Jaya algorithm. The cooperation among the participating strategies will be adaptively regulated to enhance the convergence with better preservation of solution diversity. The proposed methodology will be evaluated using various machine learning and deep learning models and compared against various state-of-the-art optimization techniques. Experimental results on different crops in various geographical locations have demonstrated that AC-PDJ-optimized models result in lower prediction errors and improved goodness-of-fit with faster and more stable convergence performance. The framework uses only opensource datasets and computation analysis, hence making it suitable for practical expert decision-support applications with no requirement of actual field experiments or specialized equipment.