The Radio of RDW/ALB: A Cost-Effective Biomarker for Early-Stage Risk Stratification in Acute Ischemic Stroke.

Background and Aims: The red blood cell distribution width (RDW) to albumin (ALB) ratio (RAR) has been identified as a prognostic indicator for mortality in critically ill patients across various diseases. Nevertheless, the impact of RAR on clinical functional prognosis in Acute ischemic stroke (AIS) remains uncertain. This study aimed to evaluate the prognostic significance of RAR in AIS patients. Methods: A secondary analysis was performed on a cohort study, involving 1906 AIS patients recruited from a South Korean academic hospital. Both univariate and multivariate logistic regression was employed to assess the connections between RAR and negative functional results in AIS. To explore potential non-linear relationships in this association, a generalized additive model (GAM) and smooth curve fitting were utilized. Further, a mediation analysis was performed to identify possible mediators. Results: Out of the 1906 eligible patients, 546 (28.65%) were found to have an unfavorable prognosis. Patients with elevated RAR had a higher likelihood of facing a negative prognosis in AIS (all P<0.001). RAR demonstrated a dose-response relationship with the probability of poor functional prognosis. When analysis of RAR as a continuous variable, an increase in RAR was correlated with a higher risk of adverse prognosis.When RAR was analyzed as quartile variables, the highest RAR remained an independent contributing factor for both 3-month unfavorable outcomes (adjusted OR, 1.4; 95% CI: 1.0-2.1, P=0.046) and 3-month mortality (adjusted OR, 5.2; 95% CI, 2.0-13.9; p<0.001). More interestingly, the presence of a pro-inflammatory state may serve as a mediator in the connections between RAR and adverse functional outcomes. Conclusion: Given its cost-effectiveness and ease of measurement, baseline RAR holds promise as a valuable biomarker for early risk assessment in AIS patients.

Progression of disease within 24 months (POD24) in multiple myeloma implicates poor prognosis and limitations of current prediction models for POD24.

Multiple myeloma (MM) is a common hematological malignancy, and its prognostic factors have been extensively studied. Progression of disease within 24 months (POD24) suggests a poor prognosis in many malignancies, but is rarely mentioned in MM. This study aimed to investigate the prognostic value of POD24 in MM and risk factors of POD24, and to evaluate the predictive value of existing MM prognostic models for POD24. The research retrospectively analyzed the clinical data of MM patients and found that the occurrence of POD24 is an independent prognostic factor affecting overall survival in MM, while non-transplantion and genetic abnormality are independent risk factors for the occurrence of POD24. The existing prognostic models are not effective in predicting POD24. Therefore, it's still necessary to explore a prognostic model that can predict POD24 more accurately.

USP18 Is Associated with PD-L1 Antitumor Immunity and Improved Prognosis in Colorectal Cancer.

BACKGROUND: Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to targeted immunotherapy. The deubiquitinating enzyme USP18 is known to play an important role in various aspects of the immune response, but its role in tumor immunity in CRC remains unclear. METHODS: In this study, multiple online datasets were used to systematically analyze the expression, prognosis, and immunomodulatory role of USP18 in CRC. The effect of USP18 on CRC was assessed via shRNA-mediated knockdown of USP18 expression in combination with CCK-8 and colony formation assays. Finally, molecular docking analysis of USP18/ISG15 and programmed death-ligand 1 (PD-L1) was performed via HDOCK, and an ELISA was used to verify the potential of USP18 to regulate PD-L1. RESULTS: Our study revealed that USP18 expression was significantly elevated in CRC patients and closely related to clinicopathological characteristics. The experimental data indicated that silencing USP18 significantly promoted the proliferation and population-dependent growth of CRC cells. In addition, high USP18 expression was positively correlated with the CRC survival rate and closely associated with tumor-infiltrating CD8+ T cells and natural killer (NK) cells. Interestingly, USP18 was correlated with the expression of various chemokines and immune checkpoint genes. The results of molecular docking simulations suggest that USP18 may act as a novel regulator of PD-L1 and that its deficiency may potentiate the antitumor immune response to PD-L1 blockade immunotherapy in CRC. CONCLUSIONS: In summary, USP18 shows great promise for research and clinical application as a potential target for CRC immunotherapy.

Unsupervised denoising of photoacoustic images based on the Noise2Noise network.

In this study, we implemented an unsupervised deep learning method, the Noise2Noise network, for the improvement of linear-array-based photoacoustic (PA) imaging. Unlike supervised learning, which requires a noise-free ground truth, the Noise2Noise network can learn noise patterns from a pair of noisy images. This is particularly important for in vivo PA imaging, where the ground truth is not available. In this study, we developed a method to generate noise pairs from a single set of PA images and verified our approach through simulation and experimental studies. Our results reveal that the method can effectively remove noise, improve signal-to-noise ratio, and enhance vascular structures at deeper depths. The denoised images show clear and detailed vascular structure at different depths, providing valuable insights for preclinical research and potential clinical applications.

Deep-learning-based segmentation of perivascular spaces on T2-Weighted 3T magnetic resonance images.

Purpose: Studying perivascular spaces (PVSs) is important for understanding the pathogenesis and pathological changes of neurological disorders. Although some methods for automated segmentation of PVSs have been proposed, most of them were based on 7T MR images that were majorly acquired in healthy young people. Notably, 7T MR imaging is rarely used in clinical practice. Herein, we propose a deep-learning-based method that enables automatic segmentation of PVSs on T2-weighted 3T MR images. Method: Twenty patients with Parkinson's disease (age range, 42-79 years) participated in this study. Specifically, we introduced a multi-scale supervised dense nested attention network designed to segment the PVSs. This model fosters progressive interactions between high-level and low-level features. Simultaneously, it utilizes multi-scale foreground content for deep supervision, aiding in refining segmentation results at various levels. Result: Our method achieved the best segmentation results compared with the four other deep-learning-based methods, achieving a dice similarity coefficient (DSC) of 0.702. The results of the visual count of the PVSs in our model correlated extremely well with the expert scoring results on the T2-weighted images (basal ganglia: rs = 0.845, P < 0.001; rs = 0.868, P < 0.001; centrum semiovale: rs = 0.845, P < 0.001; rs = 0.823, P < 0.001 for raters 1 and 2, respectively). Experimental results show that the proposed method performs well in the segmentation of PVSs. Conclusion: The proposed method can accurately segment PVSs; it will facilitate practical clinical applications and is expected to replace the method of visual counting directly on T1-weighted images or T2-weighted images.

Refractory massive chylothorax following robot-assisted laparoscopic splenectomy with pericardial devascularization treated with trans-jugular intrahepatic portosystemic shunt: a case report.

The development of a chylothorax after robot-assisted laparoscopic splenectomy combined with pericardial devascularization (LSPD) is rare. The robot-assisted procedure is similar to the standard LSPD, but surgeons must remain vigilant about potential chylothorax caused by recurrence of portal hypertension in patients with cirrhosis, an event that leads to variceal bleeding in the gastric fundus or a massive chylothorax caused by a thoracic duct fistula. We report a rare case of massive chylothorax after robot-assisted LSPD and review the literature to help elucidate the mechanisms of portal hypertension after LSPD, reduce surgical complications, and improve long-term patient outcomes. After LSPD, portal pressure monitoring, coagulation function testing, and portal vein CT imaging help in excluding portal vein thromboses and ensuring appropriate anticoagulation to reduce the development of thoracic duct fistulas. If portal hypertension recurs after surgery and a high-output chylothorax develops, conservative treatment becomes ineffective. Treatment with an active trans-jugular intrahepatic portosystemic shunt (TIPS) is recommended to lower the portal pressure.

Rifaximin ameliorates influenza A virus infection-induced lung barrier damage by regulating gut microbiota.

Prior research has indicated that the gut-lung-axis can be influenced by the intestinal microbiota, thereby impacting lung immunity. Rifaximin is a broad-spectrum antibacterial drug that can maintain the homeostasis of intestinal microflora. In this study, we established an influenza A virus (IAV)-infected mice model with or without rifaximin supplementation to investigate whether rifaximin could ameliorate lung injury induced by IAV and explore the molecular mechanism involved. Our results showed that IAV caused significant weight loss and disrupted the structure of the lung and intestine. The analysis results of 16S rRNA and metabolomics indicated a notable reduction in the levels of probiotics Lachnoclostridium, Ruminococcaceae_UCG-013, and tryptophan metabolites in the fecal samples of mice infected with IAV. In contrast, supplementation with 50 mg/kg rifaximin reversed these changes, including promoting the repair of the lung barrier and increasing the abundance of Muribaculum, Papillibacter and tryptophan-related metabolites content in the feces. Additionally, rifaximin treatment increased ILC3 cell numbers, IL-22 level, and the expression of RORγ and STAT-3 protein in the lung. Furthermore, our findings demonstrated that the administration of rifaximin can mitigate damage to the intestinal barrier while enhancing the expression of AHR, IDO-1, and tight junction proteins in the small intestine. Overall, our results provided that rifaximin alleviated the imbalance in gut microbiota homeostasis induced by IAV infection and promoted the production of tryptophan-related metabolites. Tryptophan functions as a signal to facilitate the activation and movement of ILC3 cells from the intestine to the lung through the AHR/STAT3/IL-22 pathway, thereby aiding in the restoration of the barrier. KEY POINTS: • Rifaximin ameliorated IAV infection-caused lung barrier injury and induced ILC3 cell activation. • Rifaximin alleviated IAV-induced gut dysbiosis and recovered tryptophan metabolism. • Tryptophan mediates rifaximin-induced ILC3 cell activation via the AHR/STAT3/IL-22 pathway.

Context-aware single-cell multiomics approach identifies cell-type-specific lung cancer susceptibility genes.

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, underlying mechanisms and target genes are largely unknown, as most risk-associated variants might regulate gene expression in a context-specific manner. Here, we generate a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Identified candidate cis-regulatory elements (cCREs) are largely cell type-specific, with 37% detected in one cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs combined with transcription factor footprinting prioritize the variants for 68% of the GWAS loci. CCV-colocalization and trait relevance score indicate that epithelial and immune cell categories, including rare cell types, contribute to lung cancer susceptibility the most. A multi-level cCRE-gene linking system identifies candidate susceptibility genes from 57% of the loci, where most loci display cell-category-specific target genes, suggesting context-specific susceptibility gene function.

Stearic acid alleviates aortic medial degeneration through maintaining mitochondrial dynamics homeostasis via inhibiting JNK/MAPK signaling.

Aortic dissection is characterized pathologically by aortic medial degeneration (AMD) where disturbance of mitochondrial dynamics may be involved. Stearic acid (SA) can promote mitochondrial fusion and improve mitochondrial function. Here, we established an AMD mouse model through oral administration of ß-aminopropionitrile (BAPN) and a cellular model by treating primary vascular smooth muscle cells (VSMCs) with Angiotensin-II to explore the potential role of SA in AMD. Our results showed SA reduced AMD and prolonged survival of BAPN-treated mice. Excessive mitochondrial fission was observed during AMD both in vivo and in vitro, and SA reduced mitochondrial fission and increased fusion. Additionally, SA promoted expression of contractile phenotype markers of VSMCs. At the molecular level, SA reduced AMD by inhibiting JNK/MAPK signaling. Our study suggests SA can promote mitochondrial fusion and increase the contractile phenotype of VSMCs by inhibiting JNK/MAPK signaling, thereby reducing AMD formation and possibly the consequent risk of aortic dissection.

Genomic profiling and immune phenotyping of neuroendocrine bladder cancer.

PURPOSE: Neuroendocrine bladder cancer (NEBC) poses a formidable clinical challenge and attracts keen interests to explore immunotherapy as a viable treatment option. However, a comprehensive immunogenomic landscape has yet to be thoroughly investigated. EXPERIMENTAL DESIGN: Leveraging a long-term cohort of natural NEBC cases, we employed a multimodal approach integrating genomic (n = 19), transcriptomic (n = 3), single-cell RNA sequencing (n = 1), and immunohistochemical analyses (n = 34) to meticulously characterize the immunogenicity and immunotypes of primary NEBC tumors. Clinical, pathological, medical imaging, and treatment information was retrospectively retrieved and analyzed. RESULTS: Our study unveiled that despite a considerable mutational burden, NEBC was typically immunologically inactive, as manifested by 'immune-excluded' or 'immune-desert' microenvironment. Interestingly, a subset of mixed NEBC with concurrent urothelial bladder cancer (UBC) histology displayed an 'immune-infiltrated' phenotype with prognostic relevance. When compared to UBC, NEBC lesions were distinguished by a denser cellular composition and augmented peritumoral extracellular matrix, which might collectively impede lymphatic infiltration. As a result, single-agent immune checkpoint inhibitors demonstrated limited efficacy against NEBC, while pharmacologic immunostimulation with combination chemotherapy conferred a more favorable response. CONCLUSIONS: These new insights derived from genomic profiling and immune phenotyping pave the way for rational immunotherapeutic interventions in NEBC patients, with the potential to ultimately reduce mortality from this otherwise fatal disease.

Exploring thermophysical properties of CoCrFeNiCu high entropy alloy via molecular dynamics simulations.

High entropy alloys (HEAs) are alloys composed of five or more primary elements in equal or nearly equal proportions of atoms. In the present study, the thermophysical properties of the CoCrFeNiCu high entropy alloy (HEA) were investigated by a molecular dynamics (MD) method at nanoscale. The effects of the content of individual elements on lattice thermal conductivity k p were revealed, and the results suggested that adjusting the atomic content can be a way to control the lattice thermal conductivity of HEAs. The effects of temperature on k p were investigated quantitively, and a power-law relationship of k p with T -0.419 was suggested, which agrees with previous findings. The effects of temperature and the content of individual elements on volumetric specific heat capacity C v were also studied: as the temperature increases, the C v of all HEAs slightly decreases and then increases. The effects of atomic content on C v varied with the comprising elements. To further understand heat transfer mechanisms in the HEAs, the phonon density of states (PDOS) at different temperatures and varying atomic composition was calculated: Co and Ni elements facilitate the high-frequency vibration of phonons and the Cu environment weakens the heat transfer via low-frequency vibration of photons. As the temperature increases, the phonon mean free path (MFP) in the equiatomic CoCrFeNiCu HEA decreases, which may be attributed to the accelerated momentum of atoms and intensified collisions of phonons. The present research provides theoretical foundations for alloy design and have implications for high-performance alloy smelting.

Molecular characteristic, evolution, and pathogenicity analysis of avian infectious bronchitis virus isolates associated with QX type in China.

Infectious bronchitis virus (IBV) is one of the major avian pathogens plaguing the global poultry industry. Although vaccination is the primary preventive measure for IBV infection, the emergence of virus variants with mutations and recombination has resulted in IBV circulating globally, presenting a challenge for IB control. Here, we isolated 3 IBV strains (CZ200515, CZ210840, and CZ211063) from suspected sick chickens vaccinated with IBV live attenuated vaccines (H120, 4/91, or QXL87). Phylogenetic analysis of the S1 gene sequence of the spike (S) revealed that the 3 isolates belonged to the QX-type (GI-19 lineage). Whole genome sequencing and recombination analysis indicated that CZ200515 and CZ210840 contained genetic material from 4/91 and Scyz3 (QX-type), possibly due to recombination between the circulating strain and the 4/91 vaccine strain, while no evidence of recombination was found in CZ211063. Pathogenicity analysis in 1-day-old specific pathogen-free (SPF) chickens demonstrated that all 3 isolates caused severe tissue damage and varying degrees of mortality. Virus cross-neutralization assay revealed decreased antigen relatedness between the isolates and the QX-type vaccine strain (QXL87). Amino acid sequence homology analysis of S1 revealed 5%-6.5% variances between the isolates and QXL87. Analysis of the S1 subunit structure revealed that mutations of amino acid residues in the hypervariable region (HVR) and the neutralizing epitope region resulted in antigenic variation in isolates by changing the antigen conformation. Our data indicate antigenicity variances between QX isolates and QXL87 vaccine strains, potentially resulting in immune evasion occurrences. Overall, these results offer crucial insights into the epidemiology and pathogenicity of QX-type IBV, facilitating improved selection and formulation of vaccines for disease management.

Boron nitride quantum dots supported hollow NH2-MIL-125 drive photo-Fenton-PMS system for photocatalytic tetracycline degradation: Contribution of tannic acid etching.

NH2-MIL-125(Ti) materials had great potential for photocatalytic applications but had low activity due to exciton effect and narrow absorption range of visible light. The surface oxygen-containing negative functional groups of boron nitride quantum dots (BNQDs) could overcome these defects, but due to the low load capacity, a higher specific surface area of the substrate was usually required. In this paper, a hollow Ti-MOF material was developed by etching technology. The hollow structure formed by tannic acid etching broadened the absorption range of visable light and provided more alternative surfaces for loading BNQDs. The 85.2% of high tetracycline (TC) removal efficiency for the best sample (BNQDs-5@20-Ti-MOF + PMS) was obtained, which was about 56.8 and 1.9 times of the 20-Ti-MOF and BNQDs-5@20-Ti-MOF, respectively. BNQDs-5@20-Ti-MOF + PMS system showed a great TC degradation efficiency in a wide pH range (pH = 5-9). In addition, reaction temperature and the inorganic ions did not show significant inhibition effect for TC removal. Both free radical and non-free radical pathways were involved in the TC degration by BNQDs-5@20-Ti-MOF + PMS system, among which O2•- and 1O2 played the key roles. Interestingly, multiple 1O2 production paths contributed to the high efficiency and stability of BNQDs-5@20-Ti-MOF + PMS system. This study revealed a reasonable combination of Ti-MOF and BNQDs, which provided a new efficient photocatalyst for environmental remediation.

A predictive fuzzy logic and rule-based control approach for practical real-time operation of urban stormwater storage system.

Predictive real-time control (RTC) strategies are usually more effective than reactive strategies for the intelligent management of urban stormwater storage systems. However, it remains a challenge to ensure the practicality of RTC strategies that use accessible, non-idealized predictive information while improving their efficiency for successive rainfall events instead of specific phases. This study developed a predictive fuzzy logic and rule-based control (PFL-RBC) approach to address the continuous control of individual storage systems. This approach incorporates total rainfall depth forecast information with an intra-storm fuzzy logic system to optimize peak flow control and several rule-based strategies for pre-storm water detention, reuse, and release control. Computational experiments were conducted using a storage tank case study to test the proposed approach under various rainfall conditions and storage sizes. The results showed that PFL-RBC outperformed static rule-based control in infrequent design storms and realistic continuous rainfall events, reducing flood peaks and volumes by 55 %∼87 % and 7 %∼20 %, respectively, and significantly increasing water detention time and reuse volume. Meanwhile, PFL-RBC required less predictive information to achieve a 6 %∼15 % advantage in peak flow control compared to optimized model predictive control. More importantly, PFL-RBC was reliable in the face of input uncertainty, with <25 % performance loss for water quantity control when the realistic forecast error ranged from -50 % to +50 %. These findings suggest that the proposed approach has great potential to enhance the efficiency and practicality of stormwater storage operations.

[Tempo-spatial Variations in Nitrogen and Phosphorus Loads in Jianli-Hankou Reach of the Middle Yangtze River During the Past 20 Years].

Ammonia nitrogen （NH4+-N） and total phosphorus （TP） were the major control pollutants in the Yangtze River Basin. Based on measured data from 2003 to 2020, the temporal and spatial variations in concentrations and fluxes of NH4+-N and TP in the Jianli to Hankou （JL-HK） reach of the Middle Yangtze River were studied, and the impacts of flow-sediment factors, tributary inflows, and others on variations in NH4+-N and TP fluxes were discussed. The results showed that： ① In recent years, NH4+-N and TP concentrations in the mainstream have declined significantly, with annual NH4+-N and TP concentrations at each monitoring station in 2020 averagely decreasing by 41% and 34% compared to those in 2003, respectively. Spatially, NH4+-N and TP concentrations decreased and then increased along the mainstream. NH4+-N and TP concentrations of tributary inflows, which include the Dongting Lake and Han River, were generally lower than that of the mainstream. The multi-year average values of NH4+-N and TP concentrations were both averaged at 0.12 mg·L-1 in the mainstream and were averaged at 0.11 mg·L-1 and 0.09 mg·L-1 in the tributary inflows. ② The flux differences between the upper and lower sections net of tributary confluences showed that NH4+-N and TP fluxes were lost in the Jianli to Luoshan （JL-LS） sub-reach and increased in the Luoshan to Hankou （LS-HK） sub-reach in most years. NH4+-N and TP fluxes decreased in the JL-LS sub-reach, which was related to the lower NH4+-N and TP concentrations in lateral inflows, such as Dongting Lake, and thus lowered the NH4+-N and TP concentrations in the mainstream. The LS-HK sub-reach showed the opposite trends, and the water and sediment loads increased in this sub-reach. Across the whole JL-HK reach, TP flux as well as water and sediment loads were recharged along the reach, whereas NH4+-N flux was reduced greatly, which could be attributed to the pollution abatement conducted in the Yangtze River Basin, which mainly focused on NH4+-N. ③ The correlation analysis results showed that NH4+-N fluxes had the strongest correlation with NH4+-N concentrations but not significantly correlated with discharges and sediment transport rates, indicating that NH4+-N was mainly controlled by point source pollution in the study reach. TP fluxes had higher correlations with discharges and sediment transport rates in high flow level periods, and the correlations between TP fluxes and TP concentrations were better in low flow level periods, reflecting that point source pollution contributed more to TP in dry seasons compared to flood seasons.

Dual-modal Photoacoustic and Ultrasound Imaging: from preclinical to clinical applications.

Photoacoustic imaging is a novel biomedical imaging modality that has emerged over the recent decades. Due to the conversion of optical energy into the acoustic wave, photoacoustic imaging offers high-resolution imaging in depth beyond the optical diffusion limit. Photoacoustic imaging is frequently used in conjunction with ultrasound as a hybrid modality. The combination enables the acquisition of both optical and acoustic contrasts of tissue, providing functional, structural, molecular, and vascular information within the same field of view. In this review, we first described the principles of various photoacoustic and ultrasound imaging techniques and then classified the dual-modal imaging systems based on their preclinical and clinical imaging applications. The advantages of dual-modal imaging were thoroughly analyzed. Finally, the review ends with a critical discussion of existing developments and a look toward the future.

Effects of H9N2 avian influenza virus infection on metabolite content and gene expression in chick DF1 cells.

After viral infection, the virus relies on the host cell's complex metabolic and biosynthetic machinery for replication. However, the impact of avian influenza virus (AIV) on metabolites and gene expression in poultry cells remains unclear. To investigate this, we infected chicken embryo fibroblasts DF1 cells with H9N2 AIV at an MOI of 3. Our aim was to explore how H9N2 AIV alters DF1 cells metabolic pathways to facilitate its replication. We employed metabolomics and transcriptomics techniques to analyze changes in metabolite content and gene expression. Metabolomics analysis revealed a significant increase in glutathione-related metabolites, including reduced glutathione (GSH), oxidized glutathione (GSSG) and total glutathione (T-GSH) upon H9N2 AIV infection in DF1 cells. Elisa results confirmed elevated levels of GSH, GSSG, and T-GSH consistent with metabolomics findings, noting a pronounced increase in GSSG compared to GSH. Transcriptomics showed significant alterations in genes involved in glutathione synthesis and metabolism post-H9N2 infection. However, adding the glutathione synthesis inhibitor BSO exogenously significantly promoted H9N2 replication in DF1 cells. This was accompanied by increased mRNA levels of pro-inflammatory cytokines (IL-1ß, IFN-γ) and decreased mRNA levels of anti-inflammatory cytokines (TGF-ß, IL-13). BSO also reduced catalase (CAT) gene expression and inhibited its activity, leading to higher reactive oxygen species (ROS) and malondialdehyde (MDA) level in DF1 cells. qPCR results indicated decreased mRNA levels of Nrf2, NQO1, and HO-1 with BSO, ultimately increasing oxidative stress in DF1 cells. Therefore, the above results indicated that H9N2 AIV infection in DF1 cells activated the glutathione metabolic pathway to enhance the cell's self-defense mechanism against H9N2 replication. However, when GSH synthesis is inhibited within the cells, it leads to an elevated oxidative stress level, thereby promoting H9N2 replication within the cells through Nrf2/HO-1 pathway. This study provides a theoretical basis for future rational utilization of the glutathione metabolic pathway to prevent viral replication.

Transcriptomic changes and gene fusions during the progression from Barrett's esophagus to esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma (EAC) has surged by 600% in recent decades, with a dismal 5-year survival rate of just 15%. Barrett's esophagus (BE), affecting about 2% of the population, raises the risk of EAC by 40-fold. Despite this, the transcriptomic changes during the BE to EAC progression remain unclear. Our study addresses this gap through comprehensive transcriptomic profiling to identify key mRNA signatures and genomic alterations, such as gene fusions. We performed RNA-sequencing on BE and EAC tissues from 8 individuals, followed by differential gene expression, pathway and network analysis, and gene fusion prediction. We identified mRNA changes during the BE-to-EAC transition and validated our results with single-cell RNA-seq datasets. We observed upregulation of keratin family members in EAC and confirmed increased levels of keratin 14 (KRT14) using immunofluorescence. More differentiated BE marker genes are downregulated during progression to EAC, suggesting undifferentiated BE subpopulations contribute to EAC. We also identified several gene fusions absent in paired BE and normal esophagus but present in EAC. Our findings are critical for the BE-to-EAC transition and have the potential to promote early diagnosis, prevention, and improved treatment strategies for EAC.

Unlocking synergies of drawdown operation: Multi-objective optimization of reservoir emergency storage capacity.

Optimizing reservoir drawdown operations holds significant implications for hydropower generation, water supply, and drought mitigation strategies. However, achieving multi-objective optimization in reservoir drawdown operations poses fundamental challenges, particularly considering emergency storage capacity and seasonal drought patterns. This study introduces a novel multi-objective optimization framework tailored for a mega reservoir, focusing on drawdown operations to enhance hydropower generation and water supply reliability. A drawdown operation model leveraging a multi-objective ant lion optimizer is developed to simultaneously maximize reservoir hydropower output and minimize water shortage rates. China's Three Gorges Reservoir (TGR), situated over the upper reaches of the Yangtze River, constitutes the case study, with the standard operation policy (SOP) serving as a benchmark. Results showcase the efficacy of the proposed method, with substantial improvements observed: a 10.6% increase in hydropower output, a 6.0% reduction in water shortage days, and a 9.5% decrease in minimal reservoir water release compared to SOP. This study provides robust technical and scientific bolster to optimize reservoir ESC and enhance the synergy between hydropower generation, water supply, and drought resilience. Additionally, it offers decision-makers actionable strategies that account for emergency water supply capacities. These strategies aim to support mega reservoir's resilience against extreme drought events facilitating the collaboration between modelers and policy-makers, by means of intelligent optimization and decision-making technologies.