Esophageal Cancer: Molecular Biology/Pathology
Oesophageal adenocarcinoma is a rapidly rising cancer with poor prognosis. Despite advances in surgery, chemotherapy, and targeted therapy, five-year survival remains below 20%. Treatment failure is largely driven by acquired chemoresistance, enabling tumour cells to survive under therapeutic pressure. Understanding resistance mechanisms is critical to identify vulnerabilities and improve outcomes.
Matched parental and acquired chemoresistant oesophageal adenocarcinoma cell models were profiled by quantitative proteomics. Cell lysates were processed by filter-aided sample preparation with tryptic digestion and analysed by data-independent acquisition LC-MS/MS. Peptides were identified and quantified using established DIA analysis pipelines with standard quality control, alignment and normalisation; thousands of proteins were consistently quantified across datasets. Protein abundance profiles were compared between resistant and parental counterparts and across resistant models generated against distinct chemotherapeutic agents to delineate shared versus agent-specific adaptations. Differential abundance testing used pre-specified thresholds for statistical significance (p < 0.05) and effect size (fold-change cut-offs), implemented in Perseus and complemented by custom R scripts for data integration, overlap analysis, and visualisation. Prioritisation focused on robustly upregulated proteins supported by reproducibility across models. Functional annotation, pathway enrichment, and protein interaction analyses were applied to identify convergent resistance programmes and nominate candidates for follow-up.
Thousands of proteins were consistently quantified across datasets, enabling robust comparison of chemoresistant versus parental counterparts and cross-model integration. Differential abundance analysis used p < 0.05 with an initial fold-change cut-off greater than 2 to define resistance-associated changes. Resistant and parental phenotypes segregated clearly, showing remodelling of metabolic, stress-response, and structural pathways. Cross-comparison of six resistant models identified substantial heterogeneity, with many alterations unique to individual models, but also recurrently enriched proteins shared across multiple datasets, including subsets shared between models exposed to the same agent or drug class. In dose-stratified oxaliplatin-resistant models (5 μM and 10 μM), low and high exposure states displayed highly concordant proteomic responses, with conserved alterations that became more pronounced at higher exposure. More stringent filtering (fold change >4) of the shared oxaliplatin response yielded nine consistently upregulated candidates. Three of these candidates also recurred in a carboplatin-resistant model, supporting a potential platinum-class resistance signature.
Quantitative proteomic profiling of acquired chemoresistant oesophageal adenocarcinoma cell models identifies broad adaptive changes with both heterogeneous and recurrent components. Cross-model integration highlights shared adaptations, including patterns consistent with drug class–specific responses, and suggests a platinum-class component supported by overlap between oxaliplatin- and carboplatin-resistant models. The prioritised candidates provide a focused starting point for orthogonal validation in independent models and translational settings, and for mechanistic studies to define actionable vulnerabilities relevant to therapy resistance.
This study constructed a pH-responsive P-TN/SF@Fe-Cur composite coating that demonstrated significant anti-infective, anti-inflammatory, antioxidant, pro-angiogenic, and pro-osteogenic effects in rat subcutaneous infection and femoral defect models.
ProteinReasoner is developed, a multimodal generative protein foundation model that sequentially connects amino acid sequence, evolutionary constraints and three-dimensional structure within a shared autoregressive architecture and suggests a general route towards reasoning across interdependent representations in other scientific domains.
Chaozhong Liu, Linlin Chao, Shaomin Ji et al.· bioRxiv· 1 citation
Due to its importance and wide adoption, wheat cultivation is promptly required to shift towards sustainable practices, reducing the dependency on chemical components. Among bio-based solutions aimed at securing the sustainability of wheat cultivation, biostimulants offer a versatile platform of eco-friendly tools assuring sustainability and profitability. Microalgae present a concrete example of a biostimulant source due to their richness in metabolites and high value products. Therefore, this study evaluated the biostimulant potential of eleven eco-extracts prepared from soil-isolated microalgae strains. Eco-extracts applied via soil drench at low dose (0.1 g/L) were investigated for their biostimulant effects on wheat growth, physiology, yield, and quality under controlled conditions. Results demonstrated significant ameliorations in treated plants as compared to the control, with no phytoinhibitory effects. Remarkable enhancements were notable in growth parameters such as shoot and root lengths (+40-70%), physiological traits such as total chlorophyll and stomatal conductance (+7-52%), yield components in the example of grain number per spike and thousand grain weight (+17-103%), and grain quality namely protein and polyphenol content (+2-fold to 4-fold). Similarly, phosphorus accumulation and uptake were significantly improved, while soil physicochemical status was ameliorated, indicating enhanced fertility. Multivariate analysis and composite index ranking marked Chlorella sp. GA18, Chlorella sp. GA65, Scenedesmus sp. GA69, and Chlorococcum sp. GA63 as eco-extracts with consistent performances across all plant traits. These findings highlighted the promising potential of integrating microalgae-based eco-friendly extracts in sustainable wheat cultivation.
Amer Chabili, Z. Hakkoum, F. Minaoui et al.· Plant Science· 1 citation
Effective control of fluid flows is critical across transportation, energy and medicine, where it can increase lift, reduce drag, enhance mixing and attenuate noise1-3. Yet fluids are notoriously difficult to control because they involve high-dimensional, nonlinear and multiscale dynamics that resist conventional approaches4-6. Reinforcement learning has driven remarkable progress in fields such as protein folding and complex games, which have shared benchmarks and standardized environments7-10. Fluid dynamics has lacked such infrastructure, so each controller is typically tuned to a single geometry and operating condition, making progress difficult to accumulate, transfer and compare11-13. Here we introduce HydroGym, a solver-independent reinforcement learning platform providing more than 60 validated, openly available flow control environments spanning from canonical laminar flows to complex turbulent flows, with systematic progression in the Reynolds number up to Re = 4 × 105, and Mach number variations in two and three dimensions. Across these environments, agents repeatedly discover robust control principles, including boundary layer manipulation, disruption of acoustic feedback and reorganization of turbulent wakes. Critically, we demonstrate a proof of concept for zero-shot transfer, in which agents that are trained exclusively in inexpensive surrogate environments are deployed to challenging real-world scenarios such as a three-dimensional wing section. We achieve a 38% reduction in local skin friction while reducing exploration costs by four orders of magnitude compared with direct on-wing optimization. As this transfer exploits shared near-wall physics, the breadth of generalization remains open, suggesting a new pathway for research toward policy generalization across computationally prohibitive simulation environments. By offering a common, extensible foundation for reproducible research, HydroGym moves flow control from isolated case studies toward a cohesive community effort.
Christian Lagemann, Sajeda Mokbel, Miro Gondrum et al.· Nature· 1 citation
ABSTRACT Microplastics (MPs) accumulation in ecosystem and human organs poses urgent environmental and health risks, yet few enzymes efficiently degrade polyethylene terephthalate (PET) under physiological conditions. We leveraged deep learning to mine unexplored sequence space across 246 million proteins, discovering AhPETase, an evolutionarily distinct hydrolase with low homology (<50% sequence identity) to known PET‐degrading enzymes. This noncanonical biocatalyst efficiently depolymerizes PET at 37°C, outperforming all typical PETases and achieving a 7.76‐fold enhancement over IsPETase, one of the most representative mesophilic PETases. Additionally, engineered variant AhPETaseM1 retains functional activity for over 20 days under physiological conditions and can degrade post‐consumer PET MPs 34‐fold faster than recombinant human‐derived enzyme MG8 (rMG8) under equal enzyme loading. Critically, it reversed PET‐induced toxicity in human lung and colon cells, establishing the first proof‐of‐concept for enzymatic MPs detoxification.
Yuxuan Wang, Shijie He, Yuheng Chang et al.· Advancement of science· 0 citations
BACKGROUND
Electrical muscle stimulation (EMS) is used in critically ill patients to prevent intensive care unit-acquired weakness. It promotes anabolic responses partly through interleukin-6 (IL-6) signaling under non-inflammatory conditions; however, its effects during systemic inflammation remain unclear. We hypothesized that EMS applied during lipopolysaccharide (LPS)-induced systemic inflammation exacerbates skeletal muscle atrophy through activation of IL-6-mediated catabolic signaling.
METHODS
Male C57BL/6J mice were randomly assigned to control, EMS, LPS, or EMS/LPS groups. Intraperitoneal LPS (2 mg/kg) or phosphate-buffered saline was administered, followed by EMS applied to the left hindlimb 8 h later (80 Hz, 5 mA, 30 min). Gastrocnemius muscle fiber cross-sectional area (CSA) was measured as an index of muscle atrophy, with three mice analyzed per group. Gastrocnemius muscles and blood samples were collected after treatment, and muscle morphology and CSA were analyzed histologically. Protein expression of Atrogin-1, MuRF1, C/EBPδ, phosphorylated mTOR, p70S6K, and STAT3 was assessed by Western blot, and IL-6 expression by qRT-PCR and ELISA. Data are presented as mean ± standard deviation (SD).
RESULTS
Compared with control, EMS alone increased CSA (mean ± SD,1610 ± 468 vs 1350 ± 437 μm2; P < .0001), and the phosphorylation of mTOR (1.72 ± 0.234-fold; P < .0001) and p70S6K (2.34 ± 0.559-fold; P < .0001). In contrast, compared with LPS alone, EMS applied under LPS did not enhance the phosphorylation of mTOR or p70S6K, but reduced muscle fiber CSA (680 ± 327 vs 991 ± 453 μm2; P < .0001), and upregulated Atrogin-1 (13.1 ± 3.72 vs 7.85 ± 2.26-fold; p = 0.0014) and MuRF1 (3.77 ± 1.45 vs 2.50 ± 0.998 -fold; p = 0.0094) expression. These catabolic changes were accompanied by increased STAT3 phosphorylation and C/EBPδ expression (8.28 ± 4.16 vs 4.56 ± 1.88 -fold; p = 0.0098, 39.2 ± 16.4 vs 22.8 ± 12.3-fold; p = 0.0107). Additionally, IL-6 expression was elevated in both stimulated muscle (335 ± 242 vs 140 ± 23.1-fold; p = 0.0095) and serum (28.5 ± 4.60 vs 9.35 ± 3.19 ng/mL; P < .0001) in the EMS/LPS group. Similar atrophic changes were observed in the contralateral, non-stimulated limb.
CONCLUSIONS
EMS applied during LPS-induced systemic inflammation exacerbated skeletal muscle atrophy and was associated with activation of IL-6/STAT3-C/EBPδ signaling and proteolytic pathways. These findings provide mechanistic insight into the effects of EMS under inflammatory conditions and warrant further investigation.
Shino Matsukawa, Shinichi Kai, Hideya Seo et al.· Anesthesia and Analgesia· 0 citations